Hepatic hemangiomas (HH) are the most frequent benign tumors of the liver. They are usually asymptomatic and small in size. However, others can present as large tumors and can be symptomatic. In this case surgical resection is recomemend. We present a case report for treatment in our hospital. A 48 years old male, who was brought to the emergency room complaining of vomiting and pain in the right upper quadrant that had been going on for 8 years. The examination showed a firm mass in the right hypochondrium that extended below the umbilicus. The ultrasound (US) reported severe hepatomegaly secondary to giant hypoechoic lesions. The study was completed with a computed tomography scan (CT-scan) or Magnetic resonance imaging (MRI). This case was evaluated by a multi - disciplinary team, who decided to do a liver transplant. After three months signed up on the waiting list,the patient finally received a new liver from a matched brain - dead organ donor. In this case the surgery was completed with caval - preserving Piggy - back implant technique, without the need of a classic technique nor a veno - venous bypass. He received a transfusion of 8 units of packed red blood cells during the operation. The postoperative time passed with good evaluation. Patient went back home after 14 days in the hospital. The pathology report showed a giant multifocal hemangioma, with a size of 28 x 19 x 15 cms. Some HH needs surgery, there are different options: simple enucleation to complete hepatectomy associating liver transplant as our case. The correct treatment is too important, and these case have to be tried with multi - disciplinary team. This group is composed of hepatobiliary surgeons, hepatologists and anesthetists. The bleeding massive risk is large, so it is necessary to know the clasic surgery technique.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

Resection of malignant lesions in the oral and maxillofacial area causes functional and morphological defects. To recover from these defects, reconstruction surgery is needed such as a primary closure or a flap. There are advantages and disadvantages to the method of using the primary closure and the flap, and the choice of procedure is entirely up to a surgeon. The purpose of this study is to evaluate availability of primary closure in patients. For 10 years from January 2010 to May 2020, patients who recovered using flaps after removing malignant lesions from the oral cavity and those who closed the lesion using primary closure were investigated. The investigation was conducted by searching the database of the hospital. There were 85 patients who removed malignant lesions in the oral and maxillofacial area, and among them 16 patients closed the soft tissue defects using primary closure. Operation time, histologic types, stages, wound status, and period of hospitalization according to the patients' medical records were investigated retrospectively. Between the staging and the primary closure, statistically significant differences were observed between stage I and stage II patients in 13 patients using the primary closure. (P=0.046). Statistically significant differences were identified between operation time and primary closure, with an average of 4.02 hours (P=0.015). The average period of hospitality for patients who underwent primary closure was 13.4 days, compared to 26.7 days for those who underwent flap surgery. This difference was statistically significant (P=0.0003). This study evaluated the use of primary closure in patients who underwent resection of malignant lesions in the oral and maxillofacial area. Although the majority of patients underwent reconstruction with flaps, our results showed that primary closure can be a viable option for certain patients with early-stage lesions. Therefore, oral and maxillofacial surgeons should carefully consider various evaluation criteria and select appropriate reconstruction methods to optimize functional and aesthetic outcomes for each patient.

The peptide hormone kisspeptin attenuates liver steatosis, metabolic dysfunction-associated stea-tohepatitis (MASH) and fibrosis in mouse models, by signaling via the kisspeptin 1 receptor (KISS1R). However, whether kisspeptin impacts fibrogenesis in the human liver is not known. We investigated the impact of a potent kisspeptin analog (KPA) on fibrogenesis using human precision cut liver slices (hPCLS) from fibrotic livers from male patients, in human hepatic stellate cells (HSCs), LX-2 and in primary mouse HSCs. In hPCLS, 48 h and 72 h of KPA (3 nM, 100 nM) treatment decreased collagen secretion, and lowered expression of fibrogenic and inflammatory markers. Immunohistochemical studies revealed that KISS1R is expressed and localized to HSCs in MASH/fibrotic livers. In HSCs, KPA treatment reduced transforming growth factor beta (TGFb)-induced expression of fibrogenic and inflammatory markers, in addition to decreasing TGFb induced collagen secretion, cell migration, proliferation and colony formation. Mechanistically, KISS1R signaling downregulated TGFb signaling by decreasing SMAD2/3 phosphorylation, via activation of protein-phosphatases PP2A, that dehosphorylates SMAD 2/3. This study revealed for the first time that kisspeptin reverses human hepatic fibrogenesis thus identifying it as a new therapeutic target to treat hepatic fibrosis.

Background/Objectives: Conventional surgery gland using the naked eye remains the standard for submandibular gland resection. Owing to its excellent automatic focus and high magnification, the ORBEYE 3D system introduces precise submandibular resection with less stress. Therefore, we examined the usefulness of the exoscope in submandibular gland resection for the first time. Methods: This retrospective study enrolled 12 patients who underwent submandibular gland resection using an ORBEYE exoscope at the Department of Head and Neck Surgery and Otorhinolaryngology at Kansai Medical University from April 2021 to March 2024. Surgical outcomes were retrospectively reviewed. Results: The mean age of the 12 patients (six females and six males) was 58.5 years (23–83 years). The final histopathology showed pleomorphic adenoma in eight cases, non-sebaceous-type lymphadenoma and carcinoma ex pleomorphic adenoma in one case each, and sialolithiasis with chronic inflammation in two cases. We performed facial artery and vein sparing in all cases except one in which level I neck dissection, including the submandibular gland, was performed. In all cases, we identified the marginal mandibular branches of the facial, hypoglossal, and lingual nerves, as well as the submandibular duct. No postoperative complications occurred in any patient. The mean operative time was 104 min (80–129 min). The mean blood volume lost was 20 mL (5–43 mL). Conclusions: Using ORBEYE in submandibular gland resection will contribute to preserving the mandibular marginal branch of the facial and lingual nerves and the facial artery and vein, and visualizing the submandibular duct, which are important structures surrounding the submandibular gland.

Quick and appropriate diagnostics and the use of intraoperative monitoring (IM) of hearing during vestibular schwannoma (VS) resection increase the likelihood of hearing preservation. During surgery, various methods of IM can be used, i.e. auditory brainstem responses (ABR), transtympanic electrocochleography (TT-ECochG) and direct cochlear nerve action potentials. The aim of the study was to evaluate the prognostic values of IM of hearing using ABR and TT-ECochG in predicting postoperative hearing preservation, as well as to evaluate relationships between them during various stages of surgery. This retrospective study presents the pre- and postoperative audiological test results and IM of hearing records (TT-ECochG and ABR) in 75 (43 women, 32 men, aged 18-69) patients with diagnosed VS. The preoperative pure tone average hearing threshold was 25.02 dB HL, while after VS resection it worsened on average by 30.03 dB HL. According to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Hearing Classification, before and after (pre/post) the surgery, there were 47/24 patients in hearing class A, 9/8-B, 2/1-C, and 17/42-D. In speech audiometry, the average preoperative speech discrimination score at an intensity of 60 dB SPL was 70.93%, and after VS resection it worsened to 38.93%. The analysis of electrophysiological tests showed that before the tumor removal the I-V ABR interlatencies was 5.06 ms, and after VS resection it was 6.43 ms. The study revealed correlations between worse postoperative hearing and changes in intraoperatively measured ABR and TT-ECochG. IM of hearing is very useful in predicting postoperative hearing in VS patients and increases the chance of postoperative hearing preservation in these patients.

Abstract: Perihilar cholangiocarcinoma (phCC) is the most common type of cholangiocarcinoma, accounting for approximately 60 % of cases, followed by the distal and then the intrahepatic forms. There is not a staging system that allows comparation of all series and extract some conclusions to increase the long-survival rate in this dismal disease. The extension of the resection, which theoretically dependes on the type of phCC, is not closed subject. As surgery is the only known way to achieve a cure, many aggressive approachs have been adopted. Despite extended liver resections and even vascular resections, margins are positive in around one third of patients. In the past two decades, with advances in diagnostic and surgical techniques, the surgical outcomes and survival rates have gradually improved, although variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. Extended hepatectomies and portal vein resection even right hepatic artery reconstruction for the left side tumors are frequently needed. Salvage procedures when arterial reconstruction is not feasible, as well as hepatopancreatoduodenectomy, are still under evaluation too. In this article, we discuss the aggressive surgical approach to phCC focused on vascular resection. Disparate results on the surgical treatment of phCC made it impossible to reach clear-cut conclusions.

Background: Glioma surgery was remarkably renewed in the past 2 decades, with improved safety and limited but yet improved life expectations. Fluorescence-guided resection of high-grade gliomas (HGG) plays a central role in this sense, by allowing higher degrees of extent of resection (EOR). The introduction of the exoscopic guided surgery may be considered an implementation for fluorescence techniques over the traditional microscopes. We present the application and the advantages of the exoscopic guided surgery compared to the microscopic surgery in tumor resection guided by 5-ALA fluorescence in patients with HGG. Methods: ten consecutive patients underwent a surgery for HGG resection. The surgery was performed via an exoscopic-guided procedure (Olympus Orbeye) and after oral administration of Gliolan 5 hours before the procedure. During surgery, the procedure was shifted to microscope (Kinevo 900, Zeiss) view. The intensity of the fluorescence under the two different was subjectively measured in different picture samples during the surgery in a 1 to 5 (from minimum to maximum) scale. The brightness of the surgical field and the detailing of the anatomy were also analyzed comparatively. Results: among the ten patients the histopathological diagnosis was an high grade glioma in all cases. In 9 cases was possible to achieve the gross total resection. There was no perioperative mortality. The median fluorescence intensity, on a scale of 1–5, was 4.5 in the exoscope group and 3.5 in the microscope group (p<0.01). Conclusions: The exoscopic guided surgery adds advantages to the traditional fluorescence- guided surgery with 5-aminolevulinic acid. Beyond the important advantage of low cost and the possibility to perform collaborative surgeries, it adds a plain and continuous visualization of the tumor and the surgical field in the fluorescence guided glioma surgery compared to the microscopic guided one.

Ameloblastoma is an aggressive slow growing benign epithelial odontogenic tumor usually associated with an unerupted third molar. In this report, we present the case of a 71-year-old male with a large swelling on the left mandibular region causing a remarkable facial asymmetry. After clinical, radiological, and histopathological examinations the diagnosis of conventional ameloblastoma was made. To avoid probable recurrence our treatment choice was a segmental mandibular resection with the placement of a reconstructive titanium plate to maintain the space for subsequent bone graft.

Iron (Fe) is co-factor for enzymes of the developing brain necessitating sufficient supply. We investigated the effects of administering ferric derisomaltose/Fe isomaltoside (FDI) subcutaneously to Fe deficient (ID) pregnant rats on cerebral and hepatic concentrations of essential metals and gene expression of ferroportin and hepcidin. Pregnant rats subjected to ID were injected with FDI on the day of mating (E0), 14 days into pregnancy (E14), or the day of birth (Postnatal (P0)). The efficacy was evaluated by determination of cerebral and hepatic Fe in pups on P0 and as adults on P70, and the concentration of copper (Cu) and zinc (Zn). Females fed an ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral and hepatic Fe compared to female controls fed a standard diet (158 mg/kg Fe). Cerebral Cu increased irrespective of supplying a standard diet or administering FDI combined with the standard diet. Hepatic hepcidin was significantly lower following ID, whereas cerebral hepcidin was virtually undetectable in all experimental groups. In conclusion, administering FDI subcutaneously to ID pregnant rats on EO normalizes cerebral Fe in the fetus, but when applied at later gestational ages, additional Fe to the offspring is needed to normalize cerebral and hepatic Fe.

Hepatic encephalopathy (HE) is a form of brain dysfunction that is specifically caused by liver insufficiency and/or portal-systemic shunt. The exact nature of HE is debated, so that conflicting uses of the term HE may cause inconsistencies in its detection and, in turn, issues with its management. This review highlights the meaning of the term HE on the basis of both its historical origins and current consensus. It also provides criteria for the diagnosis of the condition, on the basis of its phenotypes and the risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical recording of HE episodes is discussed.

Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibrogenesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Real-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The releasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interactions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the ability of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting a promising role of β-CIT in anti-hepatic fibrosis therapies.

Background: Colorectal cancer is a major global health burden, with surgical resection being the standard treatment aimed at curative tumor removal. Oxidative stress plays a crucial role in colorectal cancer progression and prognosis. This study hypothesized that physical removal of colorectal cancer, a primary source of oxidative stress, would reduce blood levels of reactive oxygen metabolite derivatives (d-ROMs), a marker of oxidative stress, and biologic antioxidant potential (BAP) levels, a marker of antioxidant potential. Methods: The study included 123 patients who underwent radical resection for colorectal cancer. d-ROM and BAP levels were measured before and one month after surgery. Results: The clinicopathological analysis showed a correlation between preoperative d-ROM levels and tumor size (p&lt;0.001). The study confirmed a significant reduction in d-ROM levels following tumor resection, indicating reduced systemic oxidative stress. The reduction was significant in stages II and III but not in stage I. The d-ROM ratio before and after tumor resection was significantly higher in cases with positive lymph node metastasis and larger tumor size. BAP levels showed no significant changes post-surgery. Conclusion: These results suggest that d-ROMs could serve as a valuable biomarker for monitoring tumor burden and surgical efficacy in patients with colorectal cancer.

Background: Seizures in the early postoperative period may impair patient recovery and increase risk of complication. The aim of this study is to determine whether there is any advantage in postoperative seizure prophylaxis following meningioma resection. Methods: This systematic review was conducted in accordance with PRISMA guidelines. PUBMED, Web of Science, Embase, Science Direct, and Cochrane were searched for papers until April 2023. Results: Among 9 studies, a total of 3,249 were evaluated patients, of which 984 patients received antiepileptic drugs (AEDs). A comparison between patients who received AEDs and those who did not showed a non-significant differences between both groups (RR 1.22, 95% CI 0.66 to 2.40; I² = 57%). Postoperative seizures occurred in 5% (95% CI: 1% to 9%) within the early time period (<7 days), and 9% (95% CI: 1% to 17%) in the late time period (>7 days), with significant heterogeneity (I² = 91% and 97% respectively). In seizure-naive patients, the rate of postoperative seizures was 2% (95% CI: 0% to 6%) in the early period and increased to 6% (95% CI: 0% to 15%) in the late period. High heterogeneity led to the use of random-effects models in all analyses. Conclusion: The current evidence does not provide sufficient support for the effectiveness of prophylactic AED medications in preventing postoperative seizures in patients undergoing meningioma resection. This underscores the importance of considering diagnostic criteria and conducting individual patient analysis to guide clinical decision-making in this context.

The optimal surgical approach for thymoma resection is still an object of debate. The increasing experience in robotic-assisted thoracic surgery (RATS) has led to the progressive affirmation of this technique as a valid alternative to Video-Assisted Thoracic Surgery (VATS), sternotomy and thoracotomy in this setting. The present study aims to compare the post-operative and short-term results of RATS Thymectomy for thymoma with those of other main surgical approaches (sternotomy, thoracotomy, and VATS) from a high-volume single center.Between May 2021 - September 2023, 40 consecutive patients underwent RATS Thymectomy for I to limited-stage III thymoma in our center. Three homogenous groups of consecutive patients who received thymic surgery by main alternative approaches (sternotomy, thoracotomy, VATS) over the last 5 years, were identified in order to perform a comparative analysis. Data of operative technique, time of surgery, associated resections, conversion rate, overall morbidity, tumor size, radicality, postoperative pain, length of hospital stay, and cosmetic results were recorded and compared between each control group and the RATS group. Tumor size was higher in the sternotomy group, but not significantly. The mean operative time of RATS interventions was significantly lower than that of sternotomy and VATS. It was significantly shorter compared to thoracotomy if excluding docking-undocking time. Higher rate of associated adjacent structures resection was reported in the sternotomy group (p=0.005). Conversion rate was significantly higher in VATS group (p= 0.026) compared to RATS. Postoperative pain at 24 and 48 hours was significantly lower in RATS group compared to the others. Improved cosmetics results were reported after RATS compared to sternotomy (p= 0.0001) and thoracotomy (p= 0.001) groups, with a trend towards better results compared to VATS (p=0.05). Length of hospital stay was shorter in the RATS group with a significant difference vs. the sternotomy group (p<0.001). These results from a single center confirm the safety and effectiveness of RATS for the treatment of limited stage thymoma. Advantage in terms of operative outcomes, post-operative pain, cosmetic results, and hospital stay was observed if compared to the alternative approaches. Short-term oncologic outcome was excellent based on the high complete excision rate of the tumor.

The study aimed to manage and to analyse the results of the laboratory tests, routinallypractice for hepatitis C diagnosis, using blood tests. Statistical analysis of this study results, was performed using the laboratory informatic system. The results of the study are substantial and intricate reffering to comparision between two methods concretlly ELISA method (Enzyme-Linked Immunosorbent Assay) and chemiluminescence methods and their results. Good to know our opinion that RT-PCR technique, it is considered proper for the diagnosis of HCV ( Hepatitis C virus).

Background: The purpuse was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally-induced with acetaminophen (AAPh) and potentiated by ciprofloxacin addition in rats. Material and methods: The experiment was performed on 5 animals groups: group 1 – control, treated for 6 weeks with normal saline, 1mL/kg; group 2 – AAPh, treated for 6 weeks with AAPh, 100 mg/ kg/day; group 3 – AAPh+C, treated AAPh 100 mg/kg/ day for 6 weeks and ciprofloxacin, 50mg /kg/day, only in the last 14 days of the experiment; group 4 – AAPh+C+Mg, with the same treatment as group 3, but, and in the last 14 days, MgCl2 10 mg/ kg/day was added; group 5 – AAPh+C+Zn, with the same treatment as group 3, but, and in the last 14 days, zinc gluconate (ZnG),10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase and, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (P < 0.001 group 2 vs. group 1 for all mentioned parameters). Also, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, 0.001 < P < 0.01, respectively 0.01 < P < 0.05). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea and creatinine (0.01 < P < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against liver enzymes increase and a more pronounced protection against the increase in serum urea and creatinine (0.001 < P < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < P < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in case of ZnG, to a higher extent especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < P < 0.05 group 5 vs. group 4). Conclusions: This study represents a furthermore proof for beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney’s function; the antioxidant profile improvement has a key role, especially in case of zinc gluconate.

Background: Despite their generally favorable prognosis, hepatic fibrosis remains a possible complication for hepatitis B virus (HBV) inactive carriers. This study aimed to estimate the prevalence of significant fibrosis and associated risk factors among Omani HBV inactive carriers. Methods: A retrospective study was conducted of 200 Omani HBV inactive carriers visiting a tertiary hospital in Muscat, Oman, between January 2017 and December 2018. Significant fibrosis (stage F2 or higher) was identified using two-dimensional shear-wave elastography. Baseline clinical, laboratory, and radiological data were analyzed to determine associations. Results: Of the total sample, 106 patients (53%) were male, and the mean age was 44.6 ± 9.3 years. The prevalence of significant fibrosis was 20% (n = 40). Male gender (p = 0.007), age ≥60 years (p = 0.024), and fatty changes in liver ultrasound (p = 0.044) were found to be independent factors for significant fibrosis. Conclusion: the prevalence of significant fibrosis was relatively high among a sample of Omani HBV inactive carriers, with several sociodemographic and clinical risk factors identified. Periodic assessment of liver function is needed for patients with these risk factors; moreover, routine biochemical parameters could be useful predictors of disease prognosis. Further research is recommended to substantiate these findings.

Background: Spinal schwannomas and meningiomas are the most common spinal cord benign tumors in adults and total excision is the goal of the treatment. The traditional surgical approach is performed by total laminectomy, but recently unilateral hemilaminectomy has been recognized as a valuable surgical alternative. We report the clinical results of patients affected by spinal schwannoma and meningioma in whom total laminectomy or unilateral hemilaminectomy were performed. Material and Methods: A retrospective study of patients who underwent resection of spinal meningioma or schwannoma by laminectomy or unilateral hemilaminectomy approaches in our Institute from January 2013 to January 2023 was made. The baseline data of these patients, operative approach and postoperative outcome were compared. Results: The study was performed on 41 patients with mean age of 62.5 ±14.6 years. Our series included 24 (59%) cases of schwannomas and 17 (41%) cases of meningiomas, with a prevalent location in the thoracic spine. The average schwannomas volume was 3,6 ±2,7 cm3, whereas the average meningiomas volume was 1.1 ±0.5 cm3. Total excision was achieved in all cases. Operative time of schwannomas was longer (p=0.001) respect to meningiomas with higher intra-operative blood loss (p=0.000). Total laminectomy approach was performed in 24 out of 41 patients (59%) and unilateral hemilaminectomy approach in 17 out of 41 (41%) patients. Unilateral hemilaminectomy was associated with shorter postoperative bed rest (p=0.003), shorter hospitalization (p=0.028) and lower postoperative pain (p=0.02) respect to total laminectomy. Conclusions: Both spinal schwannomas and spinal meningiomas in various size can be safely and effectively treated with unilateral hemilaminectomy approach. This approach grants more advantages compared with standard total laminectomy, including shorter postoperative bed rest, shorter hospitalization and reduced postoperative pain.

Background: Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here we report studies that address this question. Methods: 14 weeks on high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Results: Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and prevent cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Conclusions: Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

Insulin signaling plays a crucial role in cellular uptake of glucose and different metabolic pathways. Impairment in cellular insulin sensitivity due to various molecular pathways leads to Insulin resistance (IR) as well as fatty liver. In this review, mechanisms by which zinc involved in decreasing IR are described, focusing on oxidative stress, inflammation, immune system, gut flora and hepatic lipophagy. This study reviews the cause of IR and highlights the role of zinc in mechanisms diminishing IR and fatty liver.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here we show that despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox [LPL KD]) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to WT controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence Lifetime Imaging Microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of the free vs. bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in, or over-expressing, LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

Background Main treatment modality for spinal meningiomas (SM) is gross total resection (GTR). However, optimal timing of surgery, especially in cases with absent or mild neurological symptoms remains unclear. The aim of this study is to assess the impact of early-stage resection on neurological outcome, quality of life (QoL) and quality of care. The primary objective was a favorable neurological outcome (McCormick scale 1); Methods: We retrospectively analyzed data from patients operated on SM between 2011 and 2021. Patients with mild neurological symptoms preoperatively (McCormick scale 1 and 2) were compared to those with more severe neurological symptoms (McCormick scale 3-5). Disabilities and QoL were assessed according to validated questionnaires (SF36, ODI, NDI). Results: Age, spinal cord edema, thoracic localization, and spinal canal occupancy ratio were associated with more severe neurological symptoms (all p<.05). Patients presented with mild symptoms were associated with favorable neurological outcome (OR: 14.778 (95%CI 3.918-55.746, p<.001), which is associated with shorter hospitalization, better QoL and less disabilities (p<.05). Quality of care was comparable in both cohorts; Conclusions: Early surgical intervention of SM, before the development of severe neurological deficits, should be considered as it is associated with a favorable neurological outcome and quality of life.

Introduction: Novel robotic surgery systems (da Vinci Xi) are superior to classical open and laparoscopic techniques with its clear and three-dimensional view. We aimed to present the first case low anterior resection of rectal cancer and vaginal specimen extraction with Da Vinci Xi.Case: A 75-year-old female patient with rectum adenocarcinoma was undergone robotic-assisted low anterior resection (LAR) of the rectum, vaginal removal of the specimen, colorectal anastomosis and loop ileostomy. The operation time was 190 minutes. There were no postoperative complications. Pathological tumor stage was stage pT1N0 with negative proximal, distal and radial resection margins. The patient was discharged on the third postoperative day.Conclusion: Robot-assisted LAR, total mesorectal excision, vaginal removal of the specimen, colorectal anastomosis, and loop ileostomy can be performed easily and safely with Da Vinci Xi at early stage rectal cancer. And the vaginal extraction of the specimen avoids us from a traditional abdominal incision.

Background: This is a propensity matched, single centre study of limited versus extended resections for Type A acute aortic dissections (AAAD). Methods: Retrospective data for 440 patients with acute Type A aortic dissection repairs (Limited Resection, LR-215, Extended Resection, ER-225). 109 pairs were propensity matched to LR versus ER. Multivariate analysis was performed for inpatient death, long term survival and composite of inpatient death/TIA/stroke. Kaplan Meier survival curves were compared at 1, 3, 5, 10 and 15 years using the log-rank test. Results: Mean age was 66.9±13 years and mean follow up was 5.3±4.7 years. 48.9% had LR. In-hospital mortality was 10% (LR;6% vs ER;13.8%, p<0.01). ER, NYHA class, salvage surgery and additional procedures were predictors of increased mortality in unmatched data. Propensity matched data showed no difference in TIA/stroke rates, LOS, in-patient mortality or composite outcomes. LR had better survival (LR; 77.1% vs ER; 51.4%, p<0.001). ER (OR; 1.97, 95%CI; 1.27, 3.08, p=0.003) was a significant predictor of worse long term survival. At 15 years, aortic re-operation was 17% and freedom from re-operation and death was 42%. Conclusions: Type A aortic dissection repair has high mortality and morbidity although results have improved over two decades. ER was predictor of worse perioperative results and long term survival.

Background: Locally advanced rectal cancers (10-20%) can present with infiltration into adjacent viscera. R0 resections remain the key factor for better survival. Traditionally these cases have been managed with open surgery. There are some limitations of laparoscopic surgery in these case, which can potentially be overcome by robotic surgery. Objectives: To determine the feasibility and outcome results of robotic multi-visceral resection of stage T4 rectal carcinoma. Methods: Consecutive patients having locally advanced carcinoma of rectum, who undergone robotic multi-visceral resection as the primary treatment between 2015 -2018 were included, through our database which was maintained prospectively. All perioperative and intraoperative parameters were analyzed. Patient demographics, co-morbidities, preoperative imaging, endoscopic findings, operative data, histopathology results, postoperative hospital course and procedure related postoperative adverse events were noted and analyzed. Results: Twenty-one patients with the diagnosis of nonmetastatic locally advanced rectal cancers were operated with Robotic Si/X platform. The median body mass index was 28.5 kg/m2 (range 21-42). The mean blood loss during operation was 20 ml (range 5-200), and the mean duration of surgery was 280 min (range 240-430). The median hospital stay after operation was 6 days (range 4-25 days). On postoperative histopathology, R0 resection rate was 90.5% (19/21). Conclusions: The robotic multi-visceral en-bloc resection of stage T4 rectal carcinoma is technically feasible and oncologically safe. Advanced technical skills, accurate radiological staging and careful patient selection can allow the extension of minimal access surgery to this challenging group of patients.

Abstract Background: Massive resection of the small intestine leading to short bowel syndrome (SBS) deprives organism of many immunocompetent cells concentrated in gut associated lymphoid tissue- the largest immune organ in humans. We have aimed to access the influence of bowel resection on adaptive immunity in children, basing on peripheral lymphocyte subsets and serum immunoglobulins. Methods: 15 children, who underwent bowel resection in the first month of life and required further home parenteral nutrition were enrolled into the study.. Based on flow cytometry the following subsets of lymphocytes were evaluated: T, B, NK, CD4+, C8+and activated T cells. Results: Significantly statistical differences were found for the rates of lymphocytes B, T, CD8 + and NK cells. Absolute count of NK cells was lower in SBS group than in the control group. Absolute counts of lymphocytes, lymphocytes B, T, CD4+ and percentages of lymphocytes CD4+, and activated T cells inversely correlated with the time after resection. Conclusions: Children with SBS do not present with clinical signs of immunodeficiency as well as deficits in peripheral lymphocyte subsets and serum immunoglobulins. The tendency of the lymphocyte subpopulations to decrease over time after resection points out the necessity for longer follow- up.

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration and fibrosis, NASH at a molecular level involves lipid induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage by lipotoxicity results in the release of extracellular RNAs (eRNAs) which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravating inflammation, and cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increased cellular viability and reduced NF-kB mediated cytokine production. Similarly, RNase 1 administration significantly improved hepatic steatosis, inflammatory and injury markers in a murine NASH model. This study, therefore, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.

Obesity results in hepatic fat accumulation, i.e., steatosis. Besides the fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in mitochondria and peroxisomes. Usually very long chain and branched-chain fatty acids are first oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout (Pex16Alb-Cre) mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high fat diet (HFD) feeding, body weights were increased in PEX16 floxed (Pex16fl/fl) mice and adipose-specific PEX16 knockout (Pex16AdipoQ-Cre) mice but not in the Pex16Alb-Cre mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. However, it was previously reported that HFD-induced obesity in the Pex16AdipoQ-Cre mice was more severe than in the wild type mice, which was not observed until 27 weeks of HFD feeding. Thus, liver initiates the development of obesity, which is enhanced by abnormal adipocytes. HFD increased liver mass in the Pex16fl/fl mice but somehow reduced the already enlarged liver mass in the Pex16Alb-Cre mice. Basal levels of serum triglyceride, free fatty acids and cholesterol were decreased whereas serum bile acids were increased in the Pex16Alb-Cre mice, and HFD-induced steatosis was not observed in the Pex16Alb-Cre mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.

Alcoholic Liver Disease (ALD) and Non-Alcoholic Fatty Liver Disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepa-titis). Hepatic steatosis and subsequent fibrosis, whose continuous progression is accompanied by angiogenesis, lead to hypoxia, inducing the activation of vascular factors, which in turn triggers pathological angiogenesis and subsequent fibrosis, resulting in a vicious cycle. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that antiangiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural antiangiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural antian-giogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation.

The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transactivity of each other. Mttp mRNA and protein levels of Shp^/– mice were similar to those of wild-type; however, those of Chrebp^–/–Shp^–/– and Chrebp^–/– mice were much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp^–/–- mice were similar to wild-type, but were much lower in Chrebp^–/– and Chrebp^–/–Shp^–/–- mice. These findings suggested that ChREBP rather than SHP regulates VLDL secretion and that ChREBP and SHP do not affect the transactivities of each other.

Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteopancreatic neuroendocrine tumors (GEP-NETs), and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data. This lack of generalizability requires even larger, more diverse training datasets. The objective of this study is to investigate the feasibility of improving DL algorithm performance by better matching the background noise in training datasets to higher noise, out-of-domain testing datasets. 68Ga-DOTATATE PET/CT datasets were obtained from two scanners: Scanner1, a state-of-the-art digital PET/CT (GE DMI PET/CT; n=83 subjects), and Scanner2, an older-generation analog PET/CT (GE STE; n=123 subjects). Set1, the data set from Scanner1 was reconstructed with standard clinical parameters (5 minutes; Q.Clear) and list-mode reconstructions (VPFXS 2, 3, 4, and 5-minutes). Set2, data from Scanner2, representing out-of-domain clinical scans, used standard iterative reconstruction (5 minutes; OSEM). Reconstructed datasets were divided into training, validation, and testing datasets in a 60%, 20%, 20% proportion, and a deep neural network was trained with each: Network1 for Scanner1 and Network2 for Scanner2. DL performance (Network1) was tested with out-of-domain test data (Set2). To evaluate the effect of training sample size, we tested DL model performance using a fraction (25%, 50%, and 75%) of Set1 for training. Scanner1, list-mode 2-minute reconstructed data demonstrated the most similar noise level compared that of Set2, resulting in the best performance (F1=0.713). This was not significantly different compared to the highest performance, upper-bound limit using in-domain training for Network2 (F1=0.755; p-value=0.103). Regarding sample size, the F1 score significantly increased from 25% training data (F1=0.478) to 100% training data (F1=0.713; p&lt;0.001). List-mode data from modern PET scanners can be reconstructed to better match the noise properties of older scanners. Using existing data and their associated annotations dramatically reduces the cost and effort in generating these datasets, and significantly improves the performance of existing DL algorithms. List-mode reconstructions can provide an efficient, low-cost method to improve DL algorithm generalizability.

Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. FTO is ubiquitously expressed, but appears to have tissue-specific roles. Earlier studies have focused on the role of hypothlamic FTO in the regulation of metabolism. However, it appears that FTO plays a role in the regulation of metabolism in a tissue-specific manner. Recent studies suggest that expression of hepatic FTO is regulated by metabolic signals such as nutrients and hormones and altered FTO levels in liver affects glucose and lipid metabolism. This review outlines recent findings on hepatic FTO in the regulation of metabolism, with particular focus on hepatic glucose and lipid metabolism. It is proposed that abnormal activity of hepatic signaling pathways involving FTO links metabolic impairments such as obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Therefore, a better understanding of these pathways may lead to therapeutic approaches to treat these metabolic diseases by targeting hepatic FTO. The overall goal of this review is to place FTO within the context of hepatic regulation of metabolism.

Sublobar resection is a standard surgical procedure for small-sized non-small cell lung cancer (NSCLC). However, clinical role of adjuvant chemotherapy for small-sized NSCLC with pathological lymph node (LN) metastasis after sublobar resection is unknown. National Cancer Database was queried for NSCLC patients between 2004 and 2018. Eligibility included sublobar resection with pathological LN metastasis, R0 resection, Charlson comorbidity score = 0, clinical stage T1a-b, and tumor size ≤ 20 mm. Kaplan-Meier method with log-rank test and multivariable Cox proportional hazards analyses were used for assessing survival. Samples were evaluated before and after propensity score matching (PSM) with respect to age, sex, histologic type, and pathological LN status. Of 810 patients who met the eligibility criteria, 567 (70.0%) underwent adjuvant chemotherapy. After PSM, patients with adjuvant chemotherapy had a significantly longer survival than those without (median survival: 64.3 vs. 34.0 months, hazard ratio for death: 0.61, p < 0.0001). Multivariate analyses after PSM showed that younger age (p = 0.0206), female (p = 0.0005), and adjuvant chemotherapy (p < 0.0001) were independent prognostic factors for longer survival. Adjuvant chemotherapy has a prognostic impact in patients with small-sized NSCLC and pathological lymph node metastasis who undergo sublobar resection.

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, has potency to prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel blocking action of cilnidipine, prevent the palmitic ac-id-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high fat diet-fed mouse livers. These results propose that targeting Drp1-filimin interaction becomes a new strategy for the prevention or treatment of fatty liver disease.

The role of upfront primary tumor resection (PTR) in patients with unresectable metastatic col-orectal cancer (CRC) without severe symptoms remains controversial. We retrospectively ana-lyzed the role of PTR in overall survival (OS) in different subgroups. Among 331 patients diag-nosed with synchronous metastatic CRC between 2010 and 2020, 223 were analyzed. The PTR group (n = 42) showed better performance (p = 0.038); higher frequencies of right-sided origin (p = 0.014), T4 stage (p = 0.005), M1a stage (p = 0.015), and <2 organ metastases (p = 0.002); and re-ceived fewer targeted agents (p < 0.001) than the chemotherapy group (n = 181). The PTR group showed longer OS (20.5 versus 14.0 months, p = 0.016), but PTR was marginally related to OS in multivariate analysis (p = 0.060). Male sex (p = 0.022), good performance status (p = 0.07), left-sided tumor (p = 0.069), low serum carcinoembryonic antigen level (p = 0.092), T3 stage (p = 0.029), M1a stage (p = 0.025), <2 organ metastases (p = 0.017), and administration of targeted agents, especially bevacizumab (p = 0.024), were related to survival benefit after PTR. Upfront PTR should be considered when selecting patients with favorable prognoses for bevacizumab administration.

Hip dysplasia is a prevalent hereditary condition affecting dogs and cats, characterized by inadequate development of the hip joint. This condition leads to pain due to capsular distension, microfractures, and joint incongruity in young animals, ultimately progressing to osteoarthritis in adult and elderly animals. The pursuit of pain relief and improved quality of life for individuals with osteoarthritis has been a focal point in several studies. In this context, veterinary physiotherapy has gained prominence in small animal practice, serving as both palliative care and a supportive modality in the clinical or post-surgical management of degenerative joint diseases. Laser therapy and hydrotherapy, recognized for their analgesic effects and capacity to promote muscle mass gain, have garnered attention for their potential efficacy in treating joint diseases. This study aims to evaluate the therapeutic effects of super pulsed laser therapy and controlled low-impact exercises (water treadmill) on a patient recovering from surgery involving bilateral femoral head and forehead resection. We observed positive outcomes, including pain resolution, improved muscle mass, and enhanced range of motion, contributing to the patient's overall recovery.

Hip dysplasia is a prevalent hereditary condition affecting dogs and cats, characterized by inadequate development of the hip joint. This condition leads to pain due to capsular distension, microfractures, and joint incongruity in young animals, ultimately progressing to osteoarthritis in adult and elderly animals. The pursuit of pain relief and improved quality of life for individuals with osteoarthritis has been a focal point in several studies. In this context, veterinary physiotherapy has gained prominence in small animal practice, serving as both palliative care and a supportive modality in the clinical or post-surgical management of degenerative joint diseases. Laser therapy and hydrotherapy, recognized for their analgesic effects and capacity to promote muscle mass gain, have garnered attention for their potential efficacy in treating joint diseases. This study aims to evaluate the therapeutic effects of super pulsed laser therapy and controlled low-impact exercises (water treadmill) on a patient recovering from surgery involving bilateral femoral head and forehead resection. We observed positive outcomes, including pain resolution, improved muscle mass, and enhanced range of motion, contributing to the patient's overall recovery.

Hsp70.1 has dual functions as chaperone protein and lysosomal stabilizer. Previously, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes ischemic neuronal death by inducing lysosomal rupture. Recently, we found that the consecutive injections of vegetable oil-peroxidation product ‘hydroxynonenal’ induces hepatocyte death via the similar cascade. As Hsp70.1 is related also to fatty acid β-oxidation in the liver, its deficiency is known to cause accumulation of fat. Genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing decrease of phosphatidylcholine with the resultant hepatic steatosis. Here, focusing on disorders of Hsp70.1 and BHMT, we studied the mechanism of hepatocyte degeneration and steatosis, using monkeys after the consecutive injections of synthetic hydroxynonenal. As these monkeys showed a significant impairment of liver functions, the liver tissues without and with hydroxynonenal injections were compared by proteomics, immunoblotting, immunohisto-chemical and electron microscopic analyses. Western blotting showed upregulation of neither Hsp70.1 nor BHMT, but an increased cleavage of both proteins. Proteomics showed downregulation of Hsp70.1, while 2-fold increments of carbonylated BHMT. Hsp70.1 carbonylation was negligible, showing a marked contrast to ischemic neurons which were associated with ~10-fold increments. The control liver histologically showed lipid droplets in Ito cells, but lipid depositions within hepatocytes were very little. In contrast, after hydroxynonenal injections, widespread fatty degeneration and focal coagulation necrosis were observed with accumulation of numerous tiny lipid droplets within and around the degenerating/dying hepatocytes. Electron microscopy showed lysosomal membrane permeabilization/rupture, remarkable dissolution of mitochondria and rough ER membrane, and proliferation of abnormal peroxisomes. It is probable that disruptions of rough ER caused impaired synthesis of Hsp70.1 and BHMT proteins, while impairments of mitochondria and peroxisomes presumably contributed to the sustained generation of reactive oxygen species. Since both Hsp70.1 and BHMT are vulnerable to the long-standing oxidative stressor, hydroxynonenal-induced disorders facilitated degeneration and steatosis of hepatocytes, respectively.

Circulating microparticles (MPs) are novel potential biomarkers in cancer patients. Their role in hepatocellular carcinoma (HCC) is under intensive investigation. In this study we tested the hypothesis that MPs expressing the antigen HepPar1 are increased in the blood of subjects with HCC and may serve as markers of early recurrence after liver resection (LR). We studied fifteen patients affected by HCC undergoing LR and used flow cytometry to assess the number of circulating HepPar1+ MPs. Ten subjects without HCC (five with liver cirrhosis and 5 with healthy liver) were used as controls. After LR, HCC patients were followed-up for early recurrence, which occurred in seven cases. The number of circulating HepPar1+ MPs was significantly higher in subjects affected by HCC, compared to individuals without cancer (p<0.01). We also found that, among HCC patients, the number of circulating HepPar1+ MPs, measured before LR, was significantly higher in those who displayed early recurrence compared to those without recurrence (p=0.02). Of note, other types of circulating MPs, such as those derived from endothelial cells (CD144+) or those produced by the activated endothelium (CD144+/CD62+) were not associated with HCC, neither could predict HCC recurrence. HepPar1+ MPs deserve further investigation as novel biomarkers of disease and prognosis in HCC patients.

The objective of this study is to assess the hepatic/renal and splenic/renal echointensity ratios in ultrasonography in patients with and without diabetic nephropathy. This retrospective study included patients with diabetes mellitus who underwent ultrasound examinations at our hospital between January 2023 and May 2023. Ultrasound examinations done with renal cortical echogenicity and cortico-medullary differentiation by using B-mode ultrasonography. The hepatic/renal and splenic/renal echo intensity ratios were compared among study groups (diabetic patients with diabetic nephropathy and without nephropathy). The diabetic nephropathy group exhibited significantly higher right renal echointensity and left renal echointensity compared to the non-nephropathic group. Additionally, the splenic/renal echointensity ratio and hepatic/renal echointensity ratio were significantly lower in the diabetic nephropathy group. Urinary microalbumin levels was significantly correlated with Right renal echointensity (r=0.65, p&lt;0.001) and Left renal echointensity (r=0.69, p&lt;0.001). There was also a significant inverse correlation between urinary albumin and splenic/renal echointensity ratio (r=-0.58, p&lt;0.001). Ultrasonography, specifically the assessment of hepatic/renal and splenic/renal echointensity ratios, shows promise as a non-invasive and cost-effective method for evaluating morphological changes in the kidneys in patients with diabetic nephropathy. These findings suggest that ultrasonography can be a valuable tool for monitoring the progression of diabetic nephropathy and contributing to its early detection and management.

Background: Exposure to inorganic arsenic (iAs) remains a global public health problem. The liver is the main target organ of arsenic, leading to arsenic-induced liver fibrosis. Autophagy is involved. Phosphatase and tensin homology deleted on chromosome ten (PTEN) may participate in arsenic-induced liver fibrosis by regulating autophagy, but the exact mechanisms remain unclear. We established a mouse model of arsenic poisoning through the drinking water, and a fibrosis model using the huma stellate cell (HSC) line LX-2, which was exposed to NaAsO₂ for 24h. HE and Masson staining was adopted to observe the degree of liver fibrosis. The cells were transfected using PTEN overexpression plasmid. Western blot and qRT-PCR were used to determine the levels of protein/mRNA expression. The in vivo results were confirmed in HSCs exposed to NaAsO₂, with changes suggesting fibrosis as seen in mice. NaAsO₂ upregulated the expression of the autophagic markers microtubule-associated protein light chain A/B (LC3), recombinant human autophagy effector protein (Beclin-1), hairy and enhancer of split homolog-1 (HES1), but downregulated PTEN. α-smooth muscle actin (α-SMA) expression was significantly upregulated in all NaAsO₂ groups. PTEN overexpression altered NaAsO₂-induced autophagy which LC3, Beclin-1 were downregulated. Notch1, HES1, α-SMA, and collagenⅠexpression were all downregulated in the NaAsO₂ groups. In conclusion, PTEN overexpression might decrease autophagy and inhibit fibrosis progression caused by this toxin. The NOTCH1/HES1 pathway is likely to be involved in this process. Most previous studies did not investigate PTEN and arsenic-induced liver fibrosis specifically. The present study highlights the importance of targeting PTEN for the management of arsenic exposure.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of 90Y or 166Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cells killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit of the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacting liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate reducing by 4 the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

Organoid engineering promises to revolutionize medicine with wide ranging applications of scientific, engineering, and clinical interest, including precision and personalized medicine, gene editing, drug development, disease modeling, cellular therapy, and a basic understanding of human development. Organoids are a three-dimensional (3D), miniature, caricature of a target organ, are initiated with stem/progenitor cells, and are extremely promising tools to model organ function. The biological basis for organoids is that they foster stem cell-self renewal, differentiation, and self-organization, recapitulating tissue structure or function better than 2D systems. In this review, we first discuss the importance of epithelial organs and the general properties of epithelial cells to provide context for the liver, pancreas, and gall bladder and rationale for organoid cultures. Next, we develop a general framework to understand self-organization, tissue hierarchy, and organoid cultivation. For each of these areas, we provide historical context, and review both a wide range of biological and/or biophysical/mathematic perspectives that enhances understanding of organoids. Next, we review existing techniques and progress in hepatobiliary and pancreatic organoid engineering. To do this, we review organoids from both primary tissues, cell lines, and stem cells, and introduce engineering studies when applicable. Noninvasive assessment of 1 organoids can reveal underlying biology and enable improved assays for growth, metabolism, and function. Applications of organoid for cell therapy are also discussed. Taken together, we establish a broad strong scientific foundation for organoids and provide an in-depth review of hepatic, biliary and pancreatic organoids.

Hepatic Encephalopaty (HE) is a common complications of advanced liver disease and acute liver failure. It is a condition that features both neurological and psychiatric symptoms, that affects mortality, morbidity and quality of patients and caregivers’ life. HE diagnosis is generally an exclusion diagnosis. Once the patient is admitted to hospital, clinical examination, blood tests and eventually neuroimaging should be performed in order to rule out other causes of acute brain dysfunction. Moreover, HE recognizes various precipitants that can potentially promote its onset, alone or in combination, that must be identified. Once the diagnostic process is complete, a correct treatment should be started. The anti-HE treatment is based on a combination of correction of precipitants and non-absorbable disaccharides and non-absorbable antibiotic, such as rifaximin. Once the patient is discharged from the hospital, specific anti-HE therapy should be maintained in order to prevent other HE episodes.

Background: Intradialytic hypotension (IDH) is a critical pathological condition associated with all−cause mortality in patients undergoing hemodialysis (HD). However, few studies have investigated IDH-related changes in hepatic and cerebral regional tissue oxygen saturation (rSO2). This study investigated IDH-induced changes in hepatic and cerebral rSO2. Methods: Hepatic and cerebral rSO2 during HD were measured using an INVOS 5100C oxygen saturation monitor, and their percentage (%) changes during IDH development were analyzed. Ninety-one patients undergoing HD were investigated, including 20 with IDH development. Results: In patients with IDH, % changes in hepatic and cerebral rSO2 decreased at IDH onset. Additionally, the % change in hepatic rSO2 was significantly larger than those in cerebral rSO2 (P < 0.001). In patients without IDH, no significant differences were found between the % changes in hepatic and cerebral rSO2 at time of the lowest systolic blood pressure during HD. Multivariable linear regression analysis showed that the difference between the % change in cerebral and hepatic rSO2 was significantly associated with IDH development (P < 0.001) and ultrafiltration rate (P = 0.010). Conclusion: Hepatic and cerebral rSO2 significantly decreased in IDH development and hepatic rSO2 was more largely decreased than cerebral rSO2 at IDH onset.

Background: Only few pediatric reports exist regarding the prevalence, cause and evolution of liver and renal injury in patients with anorexia nervosa (AN). The aim of this study is to describe the prevalence and the risk factors of hepatic and renal failure at admission and during hospitalization, especially during refeeding in a cohort of hospitalized adolescents with AN.Methods: In a retrospective cohort study of adolescents with AN in a single hospital of Marseille from 2013 to 2019, we compared four groups on admission: elevated aminotransferases (AT)/normal AT and renal injury/no renal injury to analyze the differences between them (demographic factors, anthropometric factors, disease duration, initial prescribed calories, speed of refeeding, aminotransferase level, glomerular filtration rate). We observed the evolution of AT and renal injury for these four groups during refeeding (by the increase of kilocalories). Results: A total of 29 subjects with AN met eligibility criteria (age: 14.2 years, female (86.2%), BMI at admission (Z-score= -2.8 standard deviation (SD)) with elevated AT (20.7 %) and renal injury (13.8 %) on admission. Lower Z-score BMI (-4.05 vs -2 SD, p = 0.013), lower expected weight for height (69% vs 76%, p = 0.034) and longer disease duration (2.1 vs 0.9 years, p =0,032) were significantly associated with elevated liver enzymes at admission. Lower Z-score BMI (-3.35 vs -2.5 SD, p = 0.002), lower expected weight for height at admission (69% vs 74,5%, p = 0.002) and loss of weight before admission (0.66 vs à 0.20 kg per day, p = 0.002) were associated with renal injury at admission. Time nadir BMI (13.5 vs 6.5 days, p = 0.034) and duration of hospitalization (55 vs 41 days, p = 0.036) were longer in elevated enzymes on admission group. During refeeding, liver enzymes (95% confidence interval (CI), odds ratio (OR) aspartate aminotransferase: -0.07 [-0.11; -0.03] and OR alanine aminotransferase: -0.16 [-0.27; -0.06]) and renal injury (95% CI, OR creatinine: -0.013 [-0.017; -0.008]) have normalized with the increase of calories, with significant association.Conclusions: The results of this study suggest that degree of malnutrition is associated with liver and renal injury on admission. Theses failures disappeared with refeeding. In the future, prospective multicentric studies could examine evolution of renal and hepatic failure undergoing refeeding in large pediatric cohort of AN.

During chronic liver injury, inflammation leads to liver fibrosis— particularly due to the activation of hepatic stellate cells (HSCs). However, the involvement of inflammatory cytokines in HSC activation and the relationship among different liver cells is unclear. To examine their interactions, many in vitro liver models are performed in organoid or spheroid culture with random 3D structure, complicating analysis. Herein, we demonstrated the hierarchical coculture of primary rat hepatocytes with non-parenchymal cells such as the human-derived HSC line (LX-2) and liver sinusoidal endothelial cell line (TMNK-1). The cocultured tissue had high usability with simple operation of separating solid and liquid phases with improved liver functions such as albumin production and hepatic cytochrome P450 3A4 activity. We also studied the effects of stimulation by both oxygen tension and the key pro-fibrogenic cytokine, transforming growth factor beta (TGF-β), on HSC activation. Gene expression analysis revealed that lower oxygen tension and TGF-β1 stimulation enhanced collagen type I and alpha-smooth muscle actin expression from LX-2 cells in the hierarchical coculture. Therefore, this hierarchical in vitro cocultured liver tissue could provide an improved platform as a disease model for elucidating the interactions of various liver cell types and biochemical signals in future liver fibrogenesis studies.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wildtype (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of PEPCK mRNA independent of genotype, while increasing CPT1 mRNA only in GPR109a -/- mice. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator activated receptor α (PPARα) mRNA expression. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the ketogenic state or the pharmacological benefits associated with niacin.

Toll-like receptor 5 ligand, flagellin, and Vascular Adhesion Protein-1 (VAP-1) are involved in non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected to C57BL/6J WT and C57BL/6-Aoc3^-/- (VAP-1 KO) mice on high-fat diet twice a week every two weeks for 10-weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration and lipolysis in visceral adipose tissue. Consequently, increased release of glycerol led to hepatic steatosis in WT but not KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

Objective: Surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain-tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence-guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we developed an intraoperative rapid fluorescence cytology system, and evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: Twenty-five selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence.Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was a useful to evaluate the presence of tumor cells in the resection cavity walls, and provides surgical implications for the more complete resection of malignant gliomas.

Objectives: To analyze the clinical characteristics and factors associated with adverse drug reactions (ADR) in liver cancer patients receiving oxaliplatin‐based hepatic arterial infusion chemotherapy (HAIC). Methods: A retrospective analysis was performed on the clinical data of 137 patients with liver cancer who received oxaliplatin‐based HAIC. Changes in baseline characteristics, inflammatory factors, and other laboratory indicators in the no‐ADR and ADR groups were analyzed. Results: The incidence of serious ADR (CTCAE ≥ 3) was 21.9% (30/137). There was no significant difference in the cumulative dose of oxaliplatin between the two groups [157.3 (80.3, 322.4) vs. 206.6 (139.1, 324.2), P=0.161]. The increase in NEUT and IL‐6 was greater in the group treated with ADR than in the group not treated with ADR. Changes in NEUT [4.1 (1.5, 6.2) vs. 2.5 (0.5, 4.9), P=0.045] and changes in NEUTIL‐6 [4.2 (‐0.2, 22.9) vs. 0.8 (‐3.9, 7.7), P=0.026]. TBIL, ALT, AST, ALP, WBC, NEUT, PCT, CRP, TNF, IL‐2R, IL‐6, and IL‐10 were significantly higher after treatment than before in the ADR group (P < 0.05). In contrast, ALB and AFP were decreased. Conclusions: The severe ADR (CTCAE ≥ 3) associated with oxaliplatin‐based HAIC may be closely related to increased inflammatory factors such as NEUT and IL‐6. We should be vigilant for allergic reactions to oxaliplatin and increase monitoring during treatment

The process of identifying and approving a new drug is a time-consuming and expensive procedure. One of the biggest issues to overcome is the risk of hepatotoxicity, which is one of the main reasons for drug withdrawal from the market. While animal models are the gold standard in preclinical drug testing, the translation of results into therapeutic intervention is often ambiguous due to interspecies differences in hepatic metabolism. The discovery of human induced Pluripotent Stem Cells (hiPSCs) and their derivatives has opened new possibilities for drug testing. We used mesenchymal stem cells and hepatocytes both derived from hiPSC, together with endothelial cells, to miniaturize the process of generating hepatic organoids. These organoids were then cultivated in vitro using both static and dynamic cultures. Additionally, we tested spheroids composed solely by induced hepatocytes. By miniaturizing the system, we demonstrated the possibility of maintaining the organoids, but not the spheroids, in culture for up to 15 days. This timeframe may be sufficient to carry out a hypothetical pharmacological test or screening. In conclusion, we propose that the hiPSC-derived liver organoids model could complement or, in the near future, replace the pharmacological and toxicological tests conducted on animals.

Background and Aims: Of all primary liver tumors, primary hepatic angiosarcoma (PHA) is a rare and aggressive malignant vascular tumor. The standard therapeutic care for hepatic angiosarcoma remains unclear. This study compared the survival outcomes of aggressive treatment (resection and liver transplant) and nonaggressive treatment (chemotherapy, transarterial chemoembolization [TACE], and conservative treatments) for patients with PHA and analyzed the prognostic factors influencing survival. Materials and Methods: Data of patients diagnosed as having PHA at our facility were retrospectively reviewed. The primary outcome was survival time. The secondary outcome was calculated baseline characteristics. Results: We included a total of 19 patients, who were divided into 2 treatment groups: aggressive (8 patients had undergone resection or transplants) and nonaggressive (11 patients had undergone TACE, chemotherapy, or conservative treatment). The mean survival time was 233.1 ± 189.7 days in the aggressive treatment group and 146.5 ± 115.8 days in the nonaggressive treatment group. A Kaplan-Meier plot revealed no significant difference in survival time between the 2 treatment groups (P = .3256). Conclusions: The survival time of patients receiving aggressive treatment was longer than that of those receiving nonaggressive treatment. The long term survival time in some selective cases of aggressive treatment will be achieved. Thought a difference was not significant between the groups. Because the number of patients was limited, more cases are required to confirm these findings.

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

Food-grade titanium dioxide (E171) contains variable percentages of TiO2 nanoparticles (NPs) posing awareness about its potential effects on human and animal health. Despite many studies, the actual relationship between the physicochemical properties of E171 NPs and their interaction with biological targets is still far from clear. We evaluated the acute toxicity of E171 in invertebrate and vertebrate animals. In the nematode C. elegans, E171 up to 1.0 mg/mL did not affect worm’s viability and lifespan but significantly impaired pharyngeal function, reproduction, and development. We also focused our attention on the fate of E171 after its penetration inside the circulatory tree, investigating whether its intravenous administration to mice could result in an acute over-absorption to filter organs. A significant increase of hepatic Ti concentration and the formation of microgranulomas were observed. Interstitial inflammation and parenchymal modification were found in lung coupled with Ti accumulation, probably due to the propensity of TiO2 NPs to agglomerate, as demonstrated by transmission electron microscopy experiments showing that the incubation of E171 with serum promoted the formation of compact clusters. Overall, these data emphasize, once again, the actual risk for human and animal exposure to E171.

Definitive surgical resection is the preferred treatment for early-stage non-small-cell lung cancer (NSCLC). Research into genetic alterations, including epidermal growth factor receptor (EGFR) mutation, in early stage NSCLC remains insufficient. Here, we investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutation and recurrence after complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resection at a single regional cancer center were recruited. We compared the clinical and pathological data between the recurrence and non-recurrence groups. Multivariate logistic regression was used to predict the risk factors for recurrence. Among the 659 enrolled cases, the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutation was 43% (194/451). Among them, L858R point mutation and exon 19 deletion was 52.3% and 42%, respectively. ALK rearrangement was found at 5.7% (26/453), and ROS1 fusion was found at 1.6% (7/441). The recurrence rate of the entire population was 19.7%. In multivariate analysis, the presence of EGFR mutation, stage II or III (vs. stage I), and pathologic subtype (presence of solid type) were associated with recurrence. Among the recurred group, 86.5% of the patients with EGFR mutation experienced distant recurrence compared to only 66.7% of wild-type (p = 0.016), with no significant difference in median disease-free survival (p = 0.983). In conclusion, the prevalence of EGFR mutation, ALK rearrangement, and ROS1 fusion was 43.0%, 5.7%, and 1.6%, respectively in patients with early-stage NSCLC who underwent curative resection. Along with stage II/III and solid pathologic subtype, EGFR mutation was an independent risk factor for recurrence. In the recurrence group, the rate of distant metastasis was higher in patients with EGFR mutation than in those with wild-type.

Considering the controversial benefits of video-assisted thoracoscopic surgery (VATS), we intended to evaluate the impact of surgical approach on cardiac function after lung resection using myocardial work analysis. Echocardiographic data of 45 patients (25 thoracotomy vs. 20 VATS) were retrospectively analyzed. All patients underwent transthoracic echocardiography (TTE) 2 weeks before and after surgery, including two-dimensional speckle tracking and tissue doppler imaging. No notable changes in left ventricular (LV) function, assessed mainly using the LV global longitudinal strain (GLS), global myocardial work index (GMWI), and global work efficiency (GWE), were observed. Right ventricular (RV) TTE values, including tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TASV), and RV free-wall GLS (RVFWGLS), indicated greater RV function impairment in the thoracotomy group than in the VATS group [TAPSE (mm): 17.90 ± 3.80 vs. 20.60 ± 3.50, p &lt; 0.018; TASV (cm/s): 12.40 ± 2.90 vs. 14.60 ± 2.50, p &lt; 0.010; RVFWGLS (%): −11.50 ± 8.50 vs. −17.50 ± 9.70, p &lt; 0.033), respectively]. Unlike RV function, LV function remained preserved after lung resection. The thoracotomy group exhibited greater RV function impairment than did the VATS group. Further studies should evaluate the long-term impact of surgical approach on cardiac function.

Arsenic is a prevalent environmental pollutant with recognized carcinogenic properties. Liver fibrosis is a frequent consequence of arsenic poisoning, with the activation of hepatic stellate cells (HSCs) being a central event. Solute Carrier Family 7 Member 11 (SLC7A11), a pivotal regulator of ferroptosis, may be involved in the process of arsenic-induced liver fibrosis. This study utilized lentiviral vector-mediated SLC7A11 silencing in LX-2 cells (a type of human hepatic stellate cells) to establish an SLC7A11 knockout cell model, which was then exposed to sodium arsenite (NaAsO2). Protein interactions were assessed through Protein Immunoprecipitation (IP), and protein levels were evaluated via Western blot analysis. It was found that NaAsO2 decreased cellular Fe2+ levels and nuclear receptor co-activator 4 (NCOA4) expression, with SLC7A11 silencing reversing these effects. Additionally, IP analysis revealed an interaction between Beclin1 and SLC7A11 proteins in LX-2 cells exposed to NaAsO2. Silencing SLC7A11 attenuated the reduction in Tumor Protein p53(P53), and p-mammalian target of rapamycin (p-mTOR) protein levels, along with the rise in Beclin1, Phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), α-smooth muscle actin (α-SMA) and Fibroblast activation protein-α (FAP) induced by NaAsO2. Consequently, SLC7A11 silencing promoted cellular ferroptosis, reduced autophagy levels through the P53/AMPK/mTOR pathway, and inhibited HSC activation by NaAsO2, potentially mitigating liver fibrosis.

: Plant-derived terpenes have aroused considerable interest as chemotherapeutic agents for a variety of diseases. This study aimed at the isolation and purification of the scarce terpenes psiadin, plectranthone and saudinolide from their respective plants, followed by the determination of antiproliferative activity, against hepatic cancer cell lines (HepG2, Hep3B), and the potential molecular mechanisms. Time- and dose-dependent cytotoxicity, evaluated using MTT and colony-forming assays, were exhibited by psiadin and plectranthone against the cancer cells. Flow cytometry showed that these two terpenes blocked cell cycle progression and induced mitochondrial-mediated apoptosis, particularly through increased cytochrome c and disruption of mitochondrial membrane potential. Additionally, they initiated the generation of reactive oxygen species as well as inhibiting NF-B. Psiadin lowered several essential cyclins and cyclin-dependent kinases and reduced RB activation. It was concluded that psiadin, in particular, has a significant therapeutic potential with the biggest advantage of differentiating between cancer and normal cells which is acutely lacking in current cytotoxic drugs. Its precise mode of action needs further investigation but appears predominantly to cause cell cycle arrest by interfering with cyclin production. It will be important to determine, in future studies, whether these terpenes will similarly inhibit other cancer cell lines and retain its activity against tumors in vivo.

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. In this study, the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in liver were investigated. Rats were fed the diets with (0.54 %) or without EGCG supplementation for four weeks and were then intraperitoneally injected with acetaminophen (1g/kg). Results showed EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by increasing the Bax/Bcl2 ratio in liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen-glutathione and acetaminophen-protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in liver after acetaminophen treatment. Our results indicate that EGCG may lower oxidative stress and reduce the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in liver and thus lower hepatotoxicity

Epilepsy is a non-communicable neurological disease characterized by abnormal brain activity with conceivable peripheral implications. Few studies examine the role of peripheral and brain inflammation in the relationship between seizure predisposition and nonalcoholic fatty liver disease. Severe early-life infections leading to sepsis results in increased inflammation that can aggravate epilepsy and hepatic damage progression both associated with increased odds for hospital admissions in epileptic patients. Here, we examined the effect of early LPS challenge (1 mg/kg, i.p. at post-natal day3, PND3) in inducing hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45), evaluating the intra- and inter-gender differences on systemic and liver inflammation, hepatic lipid dysmetabolism and oxidative damage associated to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Early LPS challenge induced a major inflammatory and immune response in male epileptic rats than females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-insulted females showed a marked alteration in hepatic metabolic and lipid profile and the reduction in mitochondrial fatty acid oxidation. The two different gender-related mechanisms of LPS-induced liver injury converge in mitochondrial oxidative damage with intensified ROS production in both sexes, that notably induced a compensatory increase in antioxidant defense only in females. Our study with a translational potential points out that early postnatal infections predispose epileptic rats to develop or worsen hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

(1) Background: This retrospective study aimed to compare the efficacy and safety of one-stage computed tomography (OSCT)- to that of two-stage computed tomography (TSCT)-guided localization for the surgical removal of small lung nodules. (2) Methods: We collected data from patients with ipsilateral pulmonary nodules who underwent localization before surgical removal at Veteran General Hospital Kaohsiung between October 2017 and January 2022. The patients were divided into the OSCT and TSCT groups. (3) Results: We found that OSCT significantly reduced the localization time and risky time compared to TSCT, and the success rate of localization and incidence of pneumothorax were similar in both groups. However, the time spent under general anesthesia was longer in the OSCT group than in the TSCT group. (4) Conclusions: The OSCT-guided approach to localize pulmonary nodules in hybrid operation room is a safe and effective technique for the surgical removal of small lung nodules.

Abstract Introduction Minimally invasive approaches to oncological liver resection is common in many hepatobiliary centres. This study aims to compare the key oncological and survival outcomes of patients with colorectal liver metastases (CRLM) undergoing laparoscopic or open resections using propensity score matching (PSM). Methods A single-centre retrospective study was performed using a prospective database of patients undergoing liver resection for CRLM between January 2016 and December 2019. Different co-variates were selected for matching using PSM. Pre-matching and post-matching analyses were compared. Surgical and survival outcomes were analysed. Results In total, 303 patients who met the inclusion criteria were identified: 214 underwent open liver resection (OLR) and 91 laparoscopic liver resection (LLR). LLR had a significantly reduced length of intensive treatment unit (ITU) and overall in-patient stay but longer pringle and operative times. In the unmatched cohort, the median overall and disease-free survival time was significantly longer in patients undergoing laparoscopic compared with open surgery. A PSM model demonstrated significantly reduced blood loss and length of hospital stay, with a significantly greater Pringle and operative time in the LLR group. Differences seen in overall and disease-free survival were lost with propensity score matching, possibly due to lack of bi-lobar disease within the minimally invasive group. Conclusion In selected patients with CRLM, LLR presents similar survival and oncological outcomes with the advantages of the short-term results associated with the laparoscopic approach.

Hepatic encephalopathy (HE) reduces survival in cirrhotic patients and correlates with systemic inflammation and gut-liver disequilibrium. We investigated the association between propranolol treatment and outcomes for cirrhotic patients with HE. Using data from the Taiwan National Health Insurance Research Database, we identified 4,754 cirrhotic patients newly diagnosed with HE. Among them, 519 patients received propranolol treatment and the other 519 patients without exposure to propranolol were enrolled into our study, both of which were matched by sex, age, and propensity score. The median overall survival (OS) was longer in the propranolol-treated cohort than in the untreated cohort (3.46 versus 1.88 years, p<0.001). A dose-dependent increase in survival was observed (median OS: 4.49, 3.29, and 2.46 years in patients treated with propranolol >30mg/day, 20–30mg/day, and <20mg/day, respectively [p<0.001, p=0.001, and p=0.079 versus the untreated group]). In addition to reduce the risk of mortality (adjusted hazard ratio, 0.58; p<0.001), propranolol also diminished the risk of sepsis-related death (adjusted hazard ratio, 0.31; p=0.006) according to the multivariate analysis. However, the risk of circulatory or hepatic failure was non-significantly altered by propranolol treatment. In conclusion, propranolol treatment was associated with a better OS in cirrhotic patients with HE and its effects were dose-dependent.

Equine metabolic syndrome (EMS) is a major health threat in veterinary endocrinology medicine worldwide, and there is growing interest in utilizing molecular agents for modulation of hepatocyte function for potential clinical applications with recent studies showing promising results in the inhibition of PTP1B on adipose-derived stromal cells. In this study, we investigated the effects of MSI-1436 on equine hepatic progenitor cells (HPCs) in terms of their proliferative activity, glucose uptake, and mitochondrial morphogenesis under lipotoxic condition. Our study found that MSI-1436 promotes the entry of HPCs in the cell cycle and rescues them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the morphological architecture of the cells. Additionally, our findings suggest that MSI-1436 enhances the 2-NBDG internalization by increasing the expression of SIRT1, which is associated with liver insulin sensitivity, and promotes mitochondrial dynamics by modulating their number and morphotype through PINK1, MFN1, and MFN2 increased expression. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in the treatment of EMS and insulin dysregulation.

Background: The liver is involved in disseminated tuberculosis in more than 80% of the cases while primary liver involvement is rare, representing < 1% of all cases. Hepatic tuberculosis (TB) can be treated by conventional anti-TB therapy, however, diagnosing this disease still remains a challenge. The diagnosis might be particularly difficult in patients with a single liver lesion that could be misdiagnosed as a tumor or other focal liver lesions. While computed tomography and magnetic resonance imaging findings have been described, there is a paucity of literature on contrast-enhanced ultrasound (CEUS) features of hepatic TB. Case Summary: herein, we describe a case of a patient with tuberculous lymphadenopathy and chronic HCV-related liver disease who developed a single macronodular hepatic TB lesion. Due to the finding of a hepatocellular carcinoma (HCC) highly suggestive CEUS pattern, specifically a LR5 category according to the Liver Imaging Reporting and Data System (LI-RADS), and a good response to antitubercular therapy, a non-invasive diagnosis of HCC was made, and the patient underwent liver resection. We also review the published literature on imaging features of hepatic TB and discuss the diagnostic challenge represented by hepatic TB when occurs as a single focal liver lesion. Conclusions: this report shows for the first time that CEUS pattern of hepatic TB might be misinterpreted as HCC and specific imaging features are lacking. Personal history and epidemiological data are mandatory in interpreting CEUS findings of a focal liver lesion even when the imaging pattern is highly suggestive of HCC.

Ingrown toenails are a commonly occurring foot complaint. The condition occurs when the nail plate pierces the sulcus, giving rise to pain, inflammation and infection. As the skin attempts to heal itself, hypergranulation tissue may form. This is a case report of phenolic nail surgery treatment for a bilateral presentation with sharp resection of hypergranulation tissue performed in only one (the lateral) of the two affected sulci. Sharp resection of the residual medial hypergranulation tissue was performed two months after the index procedure when this had not settled. The case highlights the potential role of sharp resection in the overall improvement of treatment outcomes.

Introduction. “Vein definition” for locally advanced pancreatic ductal adenocarcinoma (LA PDAC) assumes portal-to-superior mesenteric vein (PV/SMV) unreconstructability due to tumor involvement or occlusion. Radical pancreatectomies with SMV resection without PV/SMV reconstruction are scarcely discussed in the literature. Retrospective analysis of 19 radical pancreatectomies for “low” LA PDAC with SMV and all its tributaries resection without PV/SMV reconstruction has shown zero mortality, overall morbidity – 56%, Dindo-Clavien – 3-10,5%, R0- rate – 82%, mean operative procedure time – 355±154 min, mean blood loss – 330±170 ml, delayed gastric emptying– 25%, clinically relevant postoperative pancreatic fistula – 8%. In three cases surgery was associated with superior mesenteric (n2) and common hepatic artery (n1) resection. Surgery was completed without vein reconstruction (n13) and with inferior mesenteric-to-splenic anastomosis (n6). There were no cases of liver, gastric, or intestinal ischemia. A specific complication of the SMV resection without reconstruction was 2-3 days-long intestinal edema (48%). Median overall survival – 25 months, median progression-free survival – 18 months. All the relapses, except two, were distant. The possibility of successful SMV resection without PV/SMV reconstruction can be predicted before surgery by CT-based reconstructions. The mandatory anatomical conditions for the procedure were: 1) preserved SMV-SV confluence; 2) occluded SMV for any reason (tumor or thrombus); 3) well-developed inferior mesenteric vein collaterals with dilated intestinal veins; 4) no right-sided vein collaterals, and 5) no varices in the upper abdomen. Conclusion: “Low” LA PDACs involving SMV with all its tributaries can be radically and safely resected in highly and specifically selected cases without PV/SMV reconstruction with an acceptable survival rate.

Digitization of tissues allows examination of tissue morphologies in new ways enabling patient stratification for effective treatments. Current slide-scanning techniques capture the visible details of the tissue as whole-slide images and digitally record them in the form of spatial and color relationships. Specialized experimental techniques like Dielectric spectroscopy can also be used to investigate a tissue’s response to an applied electric field. This study used the dielectric spectroscopy method to collect the complex permittivity of healthy and abnormal biopsy tissues excised during gastroenterology procedures. A single pole Cole-Cole model is fitted to the measurements dataset to extract the parameters which are used as features in machine learning binary classification models. The models achieved high accuracy, demonstrating the feasibility of using microwave-based spectroscopy measurements to create a digital dielectric fingerprint for tissues under investigation.

Overconsumption of an unbalanced diet and overweight, leading to insulin resistance, dyslipidemia, hepatic steatosis, cardiovascular diseases and obesity, is nowadays a worldwide health issue, with different patterns of metabolic disturbances in the young and adult popula-tions, in both gender. Preclinical models that closely mimic the gradual weight gain that occurs in humans upon consumption of a “western-type” diet (WD) are of great interest. In particular, the diet-induced obesity (DIO) model in the C57BL/6J mouse sub-strain is often used in biomed-ical research, considering that it is prone to metabolic disorders and obesity, and is widely used to generate genetically modified mice. This study aimed to phenotypically characterize the C57BL/6J mouse strain fed a WD-like diet, using high-frequency ultrasound imaging (HFUS) as a complementary tool to longitudinally monitor morphofunctional changes in the liver, heart and kidney associated with DIO. Long term WD feeding increased mice body weight (BW), liver/BW ratio and body condition score (BCS), serum transaminases, glucose and insulin, as well as Homeostasis model assessment (HOMA) indexes, and caused dyslipidemia and insulin resistance. According to the 3Rs, ultrasound imaging has enabled a comprehensive study of metabolic syndrome in mice, in vivo and non-invasive, improving the identification of early stages of diseases.

Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism during fasting. The wild-type (WT) and LRH-1 liver-specific knockout (LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. During fasting, the LRH-1 LKO mice showed greater accumulation of triglycerides in the liver compared to that in WT mice. Interestingly, LRH-1 LKO liver decreased the perilipin 5 (PLIN5) expression and genes involved in β-oxidation. Additionally, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Moreover, fasted WT primary hepatocytes showed increased co-localization of PLIN5 in lipid droplets (LDs) compared to that in fasted LRH-1 LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be a novel target of LRH-1 to mobilize LDs and manage the cellular needs.

Hepatic fibrosis is the wound-healing process of chronic hepatic disease that leads to end-stage of hepatocellular carcinoma and demolition of hepatic structures. EMT has been identified to phenotypic conversion of the epithelium to mesenchymal phenotype that occurred during fibrosis. Smad decoy oligodeoxynucleotide (ODN) is a synthetic DNA fragment containing complementary sequence of Smad transcription factor. Thus, this study evaluated the anti-fibrotic effects of Smad decoy ODN on carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice. As shown in histological results, CCl₄ treatment triggered hepatic fibrosis and increased Smad expression. On the contrary, Smad decoy ODN administration suppressed fibrogenesis and EMT process. The expression of Smad signaling and EMT-associated protein was markedly decreased in Smad decoy ODN treatment mice compared with CCl₄-injuried mice. In conclusion, these data indicate the practicability of Smad decoy ODN administration for preventing hepatic fibrosis and EMT processes.

Environmental pollution is one of today's main ecological and social concerns. Among these pollutants are the heavy metals present in the burning of fossil fuels, mining, smelting of metallic minerals, fertilizers and pesticides. Billions of tons of heavy metals are emitted every year from industrial chimneys and sewers, contaminating the hydrosphere and polluting rivers, lakes and seas. In this context, freshwater fish are the most affected due to their proximity to the source of contamination and are therefore used as bioindicators in assessing environmental impact following exposure to metals. However, our understanding of the effects of heavy metals on detoxification organs - such as the liver and gills - in freshwater fish in situ is still limited. Therefore, we conducted a systematic review to determine the main changes and mechanisms involved in morphological modifications in the liver and gills of cichlid fish following exposure to heavy metals in situ. Based on a structured search, 36 original articles were selected from the PubMed and SCOPUS databases. The selection of studies and the identification of duplicates were identified by Rayyan, and the study selection process was presented in the PRISMA statement diagram. Bias analysis was carried out using the Software Review Mananger (RevMan) 5.3, from the Cochrane Collaboration. Thirty-six studies were selected which showed negative effects attributed to environmental contamination by heavy metals, ranging from bioaccumulation to morphophysiological alterations. Almost all the heavy metals analyzed were found in the liver and gill tissues, especially cadmium, copper, lead, zinc, iron and manganese. In view of the continuous morphophysiological changes identified in the liver and gill studies, it is possible to state that bioaccumulation analyses, combined with these configurations, are emerging as crucial tools for assessing and guiding environmental monitoring. This approach aims not only to preserve but also to strengthen the integrity of the aquatic ecosystem and the ichthyofauna.

Alcohol abuse can lead to alcoholic liver disease, becoming a major global burden. Hovenia dulcis fruit peduncle polysaccharides (HDPs) has the potential to alleviate alcoholic liver injury may play essential roles in treating for alcohol-exposed liver disease, however, the hepatoprotective effects and mechanisms remain unclear. In this study, the hepatoprotective effects of HDPs and its potential mechanisms were investigated in alcohol-exposed mice by liver metabolomics and gut microbiome. The results found that HDPs reduced medium-dose alcohol-caused dyslipidemia (significantly elevated T-CHO, TG, LDL-C), elevated liver glycogen levels and inhibited intestinal-hepatic inflammation (significantly decreased IL-4, IFN-γ and TNF-α), consequently reversing hepatic pathological changes. By applying gut microbiome analysis, HDPs showed significant decreases in Proteobacteria while significant increases in Firmicutes at the phylum level, and increased Lactobacillus abundance while decreased Enterobacteria abundance, maintaining the composition of gut microbiota. Further hepatic metabolomics analysis revealed that HDPs had a regulatory effect on hepatic fatty acid metabolism, by increasing the major metabolic pathways including arachidonic acid metabolism and glycerophospholipid metabolism and identified two important metabolites C00157 and C04230 involved in the above metabolism. Overall, HDPs reduced intestinal dysbiosis and hepatic fatty acid metabolism disorders in alcohol-exposed mice, suggesting that HDPs has a beneficial effect on alleviating alcohol-induced hepatic metabolic disorders.

Zidovudine (AZT) has significantly reduced the mortality and morbidity rates among AIDS patients, but it has been associated with hepatotoxicity. AZT treatment has been linked to disrupted lipid and glucose metabolism, and the enhancement of pro-inflammatory chemokines and other mediators, which can lead to liver steatosis. In contrast, the administration of adenosine (ADO) has proven to be an effective hepatoprotector against both acute and chronic liver damage. Therefore, present study was aimed to investigate the harmful effects of chronic AZT administration and the beneficial effects of the co-administered ADO. Chronic oral AZT administration did not induce hyperglycemia or dyslipidemia, but serum liver marker enzyme activities were increased, as well as evidence of liver steatosis and inflammation. These findings were associated with low insulin and glucagon levels, elevated serum levels of pro-inflammatory cytokines and disruptions in cell redox states in these animals. ADO co-administration attenuated the deleterious effects induced by AZT: blocking the production of inflammatory molecules, increasing serum insulin and glucagon levels, and restoring liver cellular redox state. Then, blood insulin levels seemed to be greatly influenced by the cellular redox state, which was altered by AZT administration. This alteration is likely to be connected to mitochondrial integrity and metabolism.

Understanding the importance of gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat associated with low abundance of Faecalibacterium prausnitzii in humans and further, administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed to target F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD) or low (LFD) fat-diet for 12-weeks in Wistar rats (n=10/group). XOS increased F. prausnitzii growth having only minor impact on the GM composition. When supplemented with HFD, XOS prevented hepatic steatosis. The underlying mechanisms involved enhanced hepatic β-oxidation and mitochondrial respiration. 1H-NMR analysis of caecal metabolites showed that compared to HFD, LFD group had healthier caecal short-chain fatty acid profile and the combination of HFD and XOS was associated with reduced caecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Caecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, our study identifies F. prausnitzii as a possible target to treat NAFLD with XOS. The underlying preventive mechanisms involved improved hepatic oxidative metabolism.

The specific role of nicotinamide adenine dinucleotide (NAD) in hepatic triglyceride (TG) accumulation in alcoholic fatty liver disease (AFLD) were unclear. Poly ADP ribose polymerase (PARP) is a NAD-consuming enzyme and its specific role in the pathogenesis of AFLD is still elusive. In current investigation, we found that chronic alcohol exposure enhanced hepatic PARP expression and activity and lowered hepatic NAD⁺ level. PARP activity inhibitor PJ34 decreased the intracellular TG content in hepatocyte. Moreover, PJ34 suppressed the gene expression of DGAT1 and DGAT2 and elevated the intracellular NAD⁺ level in hepatocyte. These mechanistic observation was validated in alcohol-fed mice injected with PJ34 intraperitoneally. PJ34 injection attenuated hepatic TG accumulation in alcohol-fed mice. Further, the gene expression of hepatic SERBP-1c, DGAT1 and DGAT2 were lowered by PJ34 injection, while the hepatic NAD⁺ level was augmented by PJ34 injection in alcohol-fed mice. At last, the nicotinamide riboside supplementation alleviated hepatic TG accumulation in alcohol-fed mice. These data indicate that applying PARP specific inhibitor PJ34 by intraperitoneal injection attenuated hepatic NAD⁺ depletion and TG accumulation in alcohol-fed mice, which might be a potential candidate for AFLD therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious health problem, and recent evidence indicates that gut microbiota plays a key role in its development. It is known that 2-oleoyl glycerol (2-OG) produced by the gut microbiota is associated with hepatic fibrosis, but it is not known whether this metabolite is involved in the development of hepatic steatosis. The aim of this study was to evaluate how a high-fat sucrose diet (HFS) increases 2-OG production through gut microbiota dysbiosis and to identify whether this metabolite modifies hepatic lipogenesis and mitochondrial activity for the development of hepatic steatosis as well as whether a combination of functional foods can reverse this process. Wistar rats were fed HFS diet for 7 mo. At the end of the study, body composition, biochemical parameters, gut microbiota, protein abundance of lipogenic and antioxidant enzymes, measurement of liver 2-OG, and mitochondrial function were assessed in rats and we studied the effect of HFS with functional foods. In humans with MASLD, we analyzed gut microbiota and serum 2-OG. Consumption of HFS diet in Wistar rats caused oxidative stress, hepatic steatosis and gut microbiota dysbiosis, decreasing α-diversity and increased Blautia producta abundance, which increased 2-OG. This metabolite increased de novo lipogenesis through ChREBP and SREBP-1. 2-OG significantly increased mitochondrial dysfunction. Addition of functional foods to the diet modified the gut microbiota, reducing B. producta and 2-OG levels, leading to a decrease in body weight gain, body fat mass, serum glucose, insulin, cholesterol, triglycerides, fatty liver formation, and increased mitochondrial function. In order to use 2-OG as biomarker, this metabolite was measured in healthy subjects or with MASLD and it was observed that subjects with hepatic steatosis II and III had significantly higher 2-OG than healthy subjects, suggesting that the abundance of this circulating metabolite could be a predictor marker of hepatic steatosis.

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue, characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients, satisfying the 2013 ACR/EULAR classification criteria, were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), ac-tivity index, video-capillaroscopy, echocardiography, and lung function data were ana-lyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis and steatosis. Specifically, values ≥ 238 CAP ≤ 259 dB/m were considered consistent with mild steatosis (S1), 260 ≥ CAP ≤ 290 dB/m with moderate steatosis (S2) and ≥291 dB/m with severe steatosis (S3) Results The median age of patients was 51 years, with a median disease duration of 6 years. Median LS was 4.5 (2.9–8.3) kPa; 41 patients (69.5%) had no evidence of fibrosis (F=0), 16 (27.1%) displayed LS values between 5.2 and 7 kPa; only 2 patients (3.4%) had LS values >7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 39 patients (66.1%) did not show evidence of steatosis (CAP values <238 dB/m); 9 patients (15.2%) showed values consistent with mild (S1) steatosis (CAP value ≥238 ≤259 dB/m); 8 patients (13.5%) had moderate (S2) steatosis (CAP value ≥260 ≤290 dB/m); 3 patients (5.1%) were deemed to have severe steatosis (S3) due to CAP values ≥291 dB/m. Conclusions Only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Likewise, the prevalence of significant steatosis was low (5.1%) and depending on the same variables associated with fatty liver in the general population. TE was shown to be an easy and valuable method for detection and screening of liver fibrosis in SSc patients with no additional risk factors for liver disease.

Huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare reagent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical reagents.

The comparative efficacy and safety between lenvatinib and hepatic artery infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) are still unclear. This multicenter historical cohort study enrolled 244 patients who were treated with HAIC (n = 173) or lenvatinib (n = 71) between 2012 and 2020. Propensity score matching (PSM) was performed, and 52 patients were selected per group. Clinical outcomes and safety were compared. Objective response rate (ORR) was not different between the two groups (26.0% vs. 23.1%, P = 0.736). Before PSM, HAIC group had a higher proportion of Child-Pugh B and portal vein tumor, whereas lenvatinib group had more patients with extrahepatic metastases, which was adjusted after PSM. There were no differences in progression-free survival (PFS) and overall survival (OS) after PSM (HAIC vs. lenvatinib, median PFS, 3.6 vs. 4.0 months, P = 0.706; median OS 10.8 vs. 7.9 months, P = 0.106). Multivariate Cox-regression showed that alpha-fetoprotein ≤ 1000 ng/mL was only associated factor for OS after PSM in all patients (hazard ratio = 0.421, P = 0.011). Subgroup analysis for patients with high tumor burden beyond the REFLECT eligibility criteria revealed that HAIC group (n = 29) had a significantly longer OS than did lenvatinib group (n = 30) (10.0 vs. 5.4 months, P=0.004). More patients in HAIC group achieved better liver function than those in lenvatinib group at the time of best responses. There was no difference in the incidence of grade 3 and 4 adverse events between the two groups. Therefore, lenvatinib is comparable to HAIC in terms of ORR and OS in unresectable HCC meeting REFLECT eligibility criteria.

Fructose consumption has been growing exponentially and, concomitant with this, the increase in the incidence of obesity and associated complications has followed the same behavior. Studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars. In this context, the liver seems to be a key organ for understanding the deleterious health effects promoted by fructose consumption. Fructose promotes complications in glucose metabolism, accumulation of triacylglycerol in the hepatocytes and alterations in the lipid profile, which, associated with an inflammatory response and alterations in the redox state, will imply a systemic picture of insulin resistance. However, physical exercise has been indicated for the treatment of several chronic diseases. In this review, we show how each exercise protocol (aerobic, strength or a combination of both) promote improvements in the obesogenic state created by fructose consumption as an improvement in the serum and liver lipid profile (HDL increase and decrease TG and LDL levels) and a reduction of markers of inflammation caused by an excess of fructose. Therefore, it is concluded that the practice of aerobic physical exercise, strength or a combination of both is essential for attenuating the complications developed by the consumption of fructose.

Abstract: Nonalcoholic fatty liver disease, characterized by the lipid accumulation within hepatocytes exceeding 5% of liver weight, is strictly related to metabolic disorders and to obesity and diabetes and represents a health emergency worldwide. Being not available any standard therapy for NAFLD, a key role is ascribed to lifestyle intervention including phytonutrient intake to prevent NAFLD development and progression. We have used a rat model of NAFLD to evaluate the effect of dietary supplementation with red tomato and golden tomato, patented mix of fruit with different degrees of ripeness, particularly rich in naringenin and chlorogenic acid, after steatosis development. We have assessed the ef-fects on body weight, metabolic profile, and hepatic steatosis and a correlation between the amelioration of all the parameters and the liver gene expression was evidenced. We found that the genes mainly up regulated by tomatoes administration were HNF4, Lepr and GK, able to condition metabolic homeostasis. Our results suggest that there is a role for red and golden tomatoes, dietary intake as a nutraceutical approach of NAFLD prevention and therapy.

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms behind these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12-weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

The study evaluates the toxic effects of acute and sub-acute oral administration of methanol extracts of Geophila obvallata in rats. During acute study, a dose of 1600, 2900 and 5000 mg/kg bw of extract was orally administered to rats. Rats were observed for signs of toxicity for two weeks. During sub-acute study (28 days), the extract, at doses of 100, 500 and 1000 mg/kg bw were administered orally to rats while control rats were given only tap water. At the end of the study, samples were collected for analyses. In acute toxicity studies, the extract did not induce death after single dose administration. Hence, the LD50 was estimated above 5000mg/kg. The results of sub-acute toxicity study show that no significant changes were observed in the body weights, organ weights, kidney function and organ histology. There were significant changes in hematology and biochemical indices investigated at elevated doses of 500 and 1000 mg/kg bw compared to the control. GOE may be considered non-toxic at a dose of 100 mg/kg with promising applications in drug therapy.

Liver is structurally organized into zonation where LSECs endothelial cells play a crucial role during chronic liver injury and early stages of fibrosis. Fibrosis can be reversed if diagnosed early at molecular level in zonation before progressing to advanced stages like bridging fibrosis. This study identified zonation marker genes using scRNA-seq and spatial transcriptomics molecular profiling technologies in normal and diseased fibrotic human liver. DGE analysis is performed over LSECs and identified the top 20 expressed genes in periportal, perivenous, and intermediate acinar zones. Multi-omics and scRNA-seq analysis over Visium images and ECs liver cells figured out OIT3, DNASE1L3, CLEC4G, LYVE1, FCN2, CRHBP as commonly expressed mid-lobular zonation-specific genes. Also, this study detected STAB2, F8, AQP1, TEK, TIMP3, TIE1, CTSL genes as expressed in DILI and NASH ECs populations. The connection between LSECs marker genes in zone 2 and liver fibrosis holds significant promise for advancing our understanding in developing new therapeutic strategies for fibrosis reversal and designing computational molecular biomarkers in NASH and DILI fibrotic liver diseases.

This study aimed to compare the prognosis and characteristics of patients with advanced hepatocellular carcinoma treated with first-line atezolizumab plus bevacizumab (AB) combination therapy and hepatic artery infusion chemotherapy (HAIC). We retrospectively assessed 179 and 72 patients treated with HAIC and AB combination therapy, respectively, between January 2018 and January 2023. The progression-free survival of patients treated with HAIC was significantly superior than that of patients treated with AB (P&lt;0.05), but there was no significant difference in overall survival and objective response rate (ORR) between the two groups (P=0.1056 and P=0.137, respectively). After propensity score matching (PSM), our data revealed that there was no significant difference in PFS between patients who received AB combination therapy and HAIC therapy (P=0.8888). However, patients who received AB combination therapy had significantly better overall survival than those who received HAIC therapy (P=0.0133). In addition, after PSM, significant differences in ORR and disease control rate were not observed. In conclusion, our propensity score study reveals that patients treated with AB therapy have a significantly longer OS than those treated with HAIC.

Management of synchronous colorectal cancer with liver metastases (SCLM) is still on debate, regarding timing, indications and complications of the 3 strategies: classic approach (first tumor resection), simultaneous resection and reverse approach (liver first). A retrospective single-centre evaluation of synchronous approach was accomplished, focusing on surgical technique, indications and perioperative complications. Between 2017 and 2020, 31 SCLM patients benefited from synchronously colorectal and hepatic approach: segmental colectomies/rectal resections, simultaneously with liver metastasectomies (associated with radiofrequency ablation). Post-therapeutic imaging monitoring was performed from every 3 to 6 months. There were no perioperative complications related to the combination of the two procedures, low morbidity and zero postoperative mortality. The follow-up period was from 10 to 40 months: 13 patients had no evidence of recurrence, 10 patients had hepatic metastases in regression, 4 of them had signs of peritoneal carcinomatosis and 4 patients showed progression of liver disease; all patients were on chemotherapy. During follow-up 4 patients died. Experience shows that the simultaneous approach of recto-colic and hepatic resections in colo-rectal cancers is a safe procedure, with low morbidity, the limits being dictated by the size of the liver metastases. The results at long-distance must be drawn by further consistent trials.

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes mostly xenobiotic metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

: The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM from lung adenocarcinoma at our institute for 5 years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.

Background/Objectives: Different approaches are required in treating patients with multiple pulmonary lesions. A multistage procedure may increase the risk of complications and patient discomfort. This study provides an initial experience with single-stage management of multiple lung lesions using percutaneous ablation with thoracoscopic resection in a hybrid operating room (HOR). Methods: We retrospectively evaluated patients who underwent combined ablation and resection in a HOR between May 2022 and July 2024. All patients received a single anesthesia via endotracheal tube intubation. Clinical data, operative findings, and pathological characteristics of the lung nodules were recorded. Results: A total of 23 patients were enrolled in this study. Twenty patients underwent unilateral procedures, and the other three patients underwent bilateral procedures. Ablations were performed before lung resection in 22 patients; only one patient underwent surgery first. The median global operating room time was 227.0 min. The median total radiation dose (dose area product) was 14076 μGym2. The median hospital postoperative length of stay was 2 days. Conclusion: The single-stage procedure of percutaneous ablation with thoracoscopic resection under general anesthesia in a HOR is feasible and safe. This procedure is an alternative method for managing multiple pulmonary lesions.

Liver is structurally organized into zonation where LSECs endothelial cells play a crucial role during chronic liver injury and early stages of fibrosis. Fibrosis can be reversed if diagnosed early at molecular level in zonation before progressing to advanced stages like bridging fibrosis. This study identified zonation marker genes using scRNA-seq and spatial transcriptomics molecular profiling technologies in normal and diseased fibrotic human liver. DEG analysis is performed over LSECs and identified the top 20 expressed genes in periportal, perivenous, and intermediate acinar zones. Multi-omics and scRNA-seq analysis over Visium images and ECs liver cells figured out OIT3, DNASE1L3, CLEC4G, LYVE1, FCN2, CRHBP as commonly expressed mid-lobular zonation-specific genes. Also, this study detected STAB2, F8, AQP1, TEK, TIMP3, TIE1, CTSL genes as expressed in DILI and NASH ECs populations. The connection between LSECs marker genes in zone 2 and liver fibrosis holds significant promise for advancing our understanding in developing new therapeutic strategies for fibrosis reversal and designing computational molecular biomarkers in NASH and DILI fibrotic liver diseases.

Excess weight, which is seen as the background cause of most diseases, is gradually becoming the most important problem in the world. The cafeteria diet is robust diet that mimics the western diet and provides rapid weight gain associated with the obesity, diabetes, and cancer. The relationship between obesity and cancer is well known. For this reason, it is of great importance to reveal the first molecular and metabolic alterations that occur before entering the obesity process with any factor to understand the pathology of many diseases and to treat them in the early period. The beneficial effects of probiotics are attributed to their metabolite content with antioxidant properties or the postbiotic metabolites produced by them. In this study, the effects of different dietary practices on the hepatic antioxidant system of rats in developmental period were investigated by real-time PCR, enzyme activity measurements, and quantitative measurements of metabolites. After all, it was observed that CAF caused serious impairments by affecting the hepatic antioxidant system at gene and protein levels, and these impairments were relatively reversed with SCD Probiotics supplementation. In addition, regardless of the CAF diet, the regulatory effect of SCD Probiotics supplementation on the hepatic antioxidant system is remarkable.

Ultrasound (US) is commonly used for the diagnosis of liver masses. Ensemble learning has been widely used for image classification, but its methods have not been fully optimized. This study was performed to investigate the usefulness of ensemble learning and compare a number of ensemble learning techniques using multiple convolutional neural network (CNN)-trained models for image classification of liver masses in US images. The US imaging data set was classified into four categories: benign liver tumor (BLT, 6320 images), liver cyst (LCY, 2320 images), metastatic liver cancer (MLC, 9720 images), and primary liver cancer (PLC, 7840 images). In this study, 250 test images were randomly selected for each class, for a total of 1000 images, and the remaining images were used for training. Sixteen different CNNs were used for to train and test the US images. All four types of ensemble learning—soft voting (SV), stacking (ST), weighted average voting (WAV), and weighted hard voting (WHV)—showed greater accuracy than the single CNN. All four types also showed significantly better deep learning performance than ResNeXt101 alone. For image classification of liver masses using US images, ensemble learning improved the performance of deep learning over a single CNN.

Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions in glucose metabolism, insulin resistance and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin-mimic, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid

Background: This retrospective study evaluates the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. The significant differences of survival between the two groups were only observed in patients with positive EGFR expression. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Abstract: Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion and sterile inflammation. Oral l-glutamine administration has been shown to reduce the frequency of pain crisis in SCD patients, however, the long-term effect of l-glutamine in SCD remains to be determined. To understand the long-term effect of l-glutamine administration in SCD liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice. We here show that chronic l-glutamine administration reduces hepatic hemoglobin-heme-iron level, but fails to ameliorate ischemic liver injury. Remarkably, we find that this failure in resolution of hepatobiliary injury and persistent liver fibrosis is associated with reduced expression of hepatic Kupffer cells post l-glutamine treatment. These findings establish the importance to investigate the long-term effects of l-glutamine therapy on liver pathophysiology in SCD patients.

Although a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) serve as the cleaving protease of vWF-multimers, its role in liver ischemia-reperfusion injury (IRI), as well as partial liver transplantation (pLT), remains unknown. First, ADAMTS13 deficient mice were subjected to IRI to investigate the impact on hepatic IRI. Hepatic IRI significantly decreased serum ADAMTS13 activity, while simultaneously up-regulated intrahepatic vWF expression. Ablation of ADAMTS13 aggravated liver IRI by promoting platelet aggregation and disturbing microcirculation in the liv-er accompanied by exacerbated transaminase release and enhanced pro-inflammatory cytokine/chemokines levels. Adjunctive supplementation of recombinant ADAMTS13 (rADAMTS13) improved hepatic microcirculatory failure observed in ADAMTS13-null mice. Immunohistochemistry revealed massive platelet aggregation within hepatic micro-vasculatures in ADAMTS13-null mice, which was attenuated by rADAMTS13 treatment. Consequently, peripheral platelet counts, transaminase release, and pro-inflammatory cytokines/chemokines levels deteriorated in ADAMTS13-null mice, while ameliorated by rADAMTS13 administration. Notably, rADAMTS13 improved IRI-induced pathologies even in WT mice compared with those without. Next, we tested rADAMTS13 in the rat pLT model. Similarly, in rat pLT, ADAMTS13 supplementation attenuated the aforementioned pathologies observed in the experimental mouse model. In conclusion, ADAMTS13 plays a pivotal role in alleviating both hepatic microcirculation and inflammatory responses, thus providing a novel therapeutic approach against LT-related stress.