In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th) was published. The importance of understanding the molecular genetics of thyroid tumors as revealed by large-scale genomic analyses such as The Cancer Genome Atlas (TCGA). Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on tumor cell-of-origin and clinical risk. This paper outlines following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDN) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The Framework for benign lesions have revised. The WHO 5th introduces new categories such as "developmental abnormalities" and "thyroid follicular nodular disease" in benign FDN. 3. Low-Risk Tumors include NIFTP, TT-UMP, and HTT. 4. PTC histological variants are reclassified as "subtypes" in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to shared genetic and prognostic features. 7. Hürthle cell adenoma/carcinoma is renamed oncocytic thyroid adenoma/carcinoma. 8. Other miscellaneous tumors are classified into salivary gland-type carcinomas of the thyroid, thyroid tumours of uncertain histogenesis, thymic tumours within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on genetic abnormalities together with histomorphology, aiding in accurate pathological diagnosis and treatment selection, including molecular-targeted therapies.

The thyroid gland secretes essential hormones for the growth regulation and the metabolic activity of the body. Thyroid dysfunction includes many conditions that can indirectly affect dental treatments. Therefore, the practitioner must be aware of these pathologies and their signs and symptoms in order to elaborate specific dental treatment plans, thus avoiding any per- and/or postoperative complications. Moreover, the dentist can help in the screening of undiagnosed thyroid dysfunction among patients.

The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection, and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley Rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and were killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis and evaluation of biological effects was performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function and cancer and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples are needed for validation.

Thyroidectomy has been post-operatively managed by hormone replacement therapy in order to satisfy the reference ranges of thyroid stimulating hormone (TSH) and thyroxine (T4) levels. While medication and standardized reference ranges have proven to be effective, many patients continue to report unintentional weight gain despite adequate amounts of treatment and levels of TSH and T4. Physicians, over the years, have become complacent to these “normal” ranges, and have ignored the metabolic consequences that are affecting thyroidectomy patients. This paper aims to redefine the approach to post-thyroidectomy clinical care by: challenging the current standardized hormonal range values, exploring the gaps in thyroid hormone conversion, investigating the metabolic pathways of T3, considering the influence of inflammatory markers, and proposing the future for patient-centered management.

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR) shuttles upon ligand binding and homodimerization from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors(TR), retinoic acid receptors (RAR), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXR) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and deprivation alone or with chemotherapy is the standard therapy for PCa. RAR activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TR support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.

This review explores the nuanced decision-making surrounding postoperative radiotherapy for diffuse low-grade glioma (DLGG) patients, emphasizing the need for personalized treatment to balance the benefits of tumor control with the risks of long-term side effects. Radiotherapy is a cornerstone of DLGG treatment, offering significant improvements in progression-free survival, but its potential for cognitive decline and vascular lesions necessitates careful consideration of individual patient factors. The review delves into the complexities of radiotherapy timing, revealing that while early radiotherapy enhances progression-free survival, it does not significantly impact overall survival and may lead to earlier onset of cognitive decline. Conversely, delayed radiotherapy may mitigate cognitive decline but may result in shorter progression-free survival and the onset of neurological symptoms. The review advocates for a patient-centered approach, emphasizing the importance of weighing individual risks and benefits, and highlights the potential of artificial intelligence in predicting cognitive decline and the need to revisit previous research findings in light of the 2021 WHO (World Health Organization) classification update, underscoring the evolving nature of DLGG treatment and the ongoing quest for optimal therapeutic strategies.

Purpose: This study aimed to investigate useful preoperative clinical and hematologic variables in predicting malignancy in patients with the atypia of undetermined significance (AUS) nodules, and to suggest a machine learning-based prediction model. Methods: We enrolled 280 patients who underwent surgery for the AUS nodules at Wonju Severance Christian Hospital between 2018 and 2022. We evaluated preoperative hematologic indices, including Delta Neutrophil Index (DNI), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR), as well as preoperatively identifiable clinical variables such as age and sex at diagnosis, history of radiation exposure, familial history of thyroid cancer, primary tumor size, and the 2016 Korean Thyroid Imaging Reporting and Data System (K-TIRADS) classification. Results: A total of 116 patients (41.4%) were finally diagnosed with various types of thyroid malignancy, excluding 32 patients (11.4%) with thyroid cancer incidentally identified. Age at diagnosis (p = 0.012), primary tumor size (p = 0.048), and the K-TIRADS classification (p = 0.003) were independent risk factors to predict the diagnosis of malignancy in patients with AUS nodules younger than 55 years, not in those aged of 55 years or older. Adding the NLR to these risk factors significantly improved the predictability for malignancy in the same patient group (p < 0.001). Conclusions: The inclusion of NLR in the ma-lignancy prediction model enhances the predictive accuracy for malignancy in younger patients with AUS nodules. This finding suggests that incorporating NLR into preoperative assessment could refine management strategies and improve decision-making for surgical interventions.

Because of ambiguous and widely debated observations concerning incidence trend and management of TC, we performed this analysis. We drew attention to some events, such as “cancer screening activity,” introduction of noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) to TC types, possibility of papillary thyroid microcarcinoma (PTMC) active surveillance (AS), occurrence of personalized medicine in TC management and finally COVID-19 pandemic time. Because of the opinion that all changes have been made mostly by PTC, we compared it to the rest of types of TC in terms of incidence, clinical and pathological characteristics and treatment. The prevalence of TC significantly increased from 5.15% in 2008 to 13.84% in 2015 and then significantly decreased to 1.33% in 2022 when the pandemic lasted (p<0.0001). A similar trend was observed for PTC, when the incidence significantly increased to 13.99% in 2015 and then decreased to 1.38% in 2022 (p<0.0001). At that time, the NIFTP category was introduced, and observation of PTMC began. The prevalence of FTC and MTC also increased until 2015 and then decreased. Significant differences in age, types of surgery, necessity of reoperation, pTNM, between PTCs and other types of TCs were observed. The average age was significantly lower in PTC patients than in patients with the remaining types of TC (p<0.0001). Four milestones, including NIFTP introduction, the possibility of PTMC AS, personalized cancer medicine and the COVID-19 pandemic, may have influenced the general statistics of TC.

Cytologic diagnosis of extra‐adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high rate of diagnostic error. We present a case of a peripancreatic mass identified by radiology as a gastrointestinal stromal tumor. Endoscopic ultrasound‐guided fine needle aspiration (FNA) of the mass showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei arranged singly and in loose clusters. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin) and negative for CD117. A diagnosis of a neoplasm with a neuroendocrine tumor (NET) was made on FNA cytology. The subsequent surgical resection of the tumor revealed peripancreatic paraganglioma with immunohistochemistry positive for synaptophysin, chromogranin, and S100. The latter delineates the sustentacular cells. Although paraganglioma is a well recognized tumor, a detailed comparison of peripancreatic paraganglioma versus pancreatic/gastrointestinal NET is still lacking.

Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.

EUS–TA in unresectable pancreatic cancer requires not only a tissue diagnosis but also tissue collection in anticipation of comprehensive genomic profiling. However, the optimal puncture target remains controversial. Therefore, the Primary and Metastatic Lesions in Pancreatic Cancer (PRIMATE) study was designed to clarify the optimal target by comparing the success rates for meeting OncoGuide NCC Oncopanel (NOP) analysis criteria on pre-check primary and metastatic lesion specimens obtained during the same EUS–TA session in patients with invasive pancreatic ductal adenocarcinoma. In this ongoing prospective study, two specimens, each from primary and metastatic lesions, are obtained by EUS–TA (typically using a 19G fine-needle biopsy needle) in patients with invasive pancreatic ductal adenocarcinoma. The primary endpoint is the proportion of EUS–TA specimens that meet NOP analysis criteria during pre-check (i.e., tumor cellularity ≥ 20% and tissue area ≥ 4 mm2), which are then compared between primary and metastatic lesions. This study has been approved by the National Cancer Center Institutional Review Board (Research No. 2022-168). The results of this study will be reported at an international conference and published in an international peer-reviewed journal. The trial registration number is UMIN 000048966.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine therapy is a cornerstone in DTC management, but sometimes it became useless when cancer cells develop refractoriness. Radioactive Iodine Refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used, it has a demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. FA-Pi, PSMA, SSTR tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed to re-induce RAI accumulation in DTC cells. Results appeared promising, despite not excellent. Conclusions: RAIR-DTC yet represent a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation with post-therapy whole body scan (PT-WBS) is the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents oblige physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

The genome sequencing technologies reveal the molecular mechanisms of differentiated thyroid cancer (DTC). Unlike somatic mutation analysis from thyroidectomy samples, germline mutations showing genetic susceptibility to DTC are less understood. The study aimed to assess the prevalence of germline mutations predisposing to DTC in a cohort of Polish individuals based on their whole genome sequencing (WGS) data. We analyzed sequencing data from 1076 unrelated individuals, released openly for academic and clinical research as The Thousand Polish Genomes database (https://1000polishgenomes.com). The list of genes chosen for further analysis was based on the review of previous studies. The cohort contained 104 variants located within the coding and noncoding DNA sequences of 90 genes selected by ClinVar classification as pathogenic and potentially pathogenic. The frequency of variants in the Polish cohort (our study) was compared to the frequency estimated for the non-Finnish European population, obtained from the gnomAD database (gnomad.broadinstitute.org). Statistically significant variants included 23 genes. Even though the Polish population is genetically similar to other European populations, there are significant differences in variant frequencies contributing to the disease development and progression, such as RET, CHECK2, BRCA1, SLC26A4 or TERT. Further studies are needed to identify genomic variants associated directly with DTC.

Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

Background: Colorectal cancer (CRC) patients experienced multiple chemotoxicity affecting treatment compliance, survival, and quality of life (QOL). Prior research shows clinician-reported chemotoxicity (i.e., grading scales or diagnostic codes) predicts rehospitalization and cancer survival. However, a comprehensive synthesis of clinician-reported chemotoxicity is still lacking. Objectives: We conducted a systematic review and meta-analysis to determine the chemotoxicity's prevalence and risk factors in CRC. Methods: A systematic search from 2009 to 2024 yielded 30 studies for review, with 25 included in the meta-analysis. Results: Pooled prevalences of overall, non-hematological, and hematological moderate-to-severe toxicities were 45.7%, 39.2%, and 25.3%, respectively. The most common clinician-reported chemotoxicities were gastrointestinal (GI) toxicity (22.9%) and neuropathy or neutropenia (17.9%). Significant risk factors at baseline were malnutritional status, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low QOL. Age was associated with neutropenia (β: -1.44) and GI toxicity (β:1.85) (Ps 65 y.o.) had higher prevalences of overall (OR: 1.14) and GI (OR: 1.65) toxicities, but a lower prevalence of neutropenia (OR: 0.65) than younger adults (Ps

The aim of the present study was to investigate the incidence of breast (females), prostate, testicular and thyroid cancer in the Italian National Priority Contaminated Sites (NPCSs), served by cancer registries, where the presence of endocrine disruptors (EDs), reported to be linked to these tumors, was documented. Evidence of carcinogenicity of EDs present in NPCs was assessed based on evaluation by international scientific institutions/committees. Standardized Incidence Ratios (SIRs) were computed for each NPCS and cancer site with reference to the time window 1996-2005. Excess incidence of one or more cancer site at study was found in twelve out of fourteen NPCSs. Significantly increased SIRs were found for breast cancer in eight NPCSs, for prostate cancer in six, for thyroid cancer (both gender) in four and for testicular cancer in two. Non significantly increased SIRs were found in five NPCSs for testicular cancer and in two for thyroid cancer (males). Even if increased incidence of one or more cancer sites at study were found in several NPCSs, the ecological study design and the multifactorial etiology of the considered tumors do not allow reaching conclusions in terms of causal links with environmental contamination. In light of the observation of some excesses in SIRs, continuing epidemiological surveillance is warranted.

Introduction: Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Although the incidence is decreasing in developed countries, treatment results are still unsatisfactory. The standard treatment for locally advanced gastric cancer (LAGC) is gastrectomy with perioperative chemotherapy. Aim: Assessment of selected microRNAs (miRNAs) in chemoresistance in archival material from LAGC. Material and method: The research group consisted of archival material from 10 patients with LAGC. Histological material from each patient was used from a biopsy performed during gastroscopy and after surgery preceded by 4 cycles of neoadjuvant chemotherapy (NAC) according to the FLOT or FLO regimen. The expression of selected miRNAs was assessed in the tissue material, such as miRNA-21-3p, miRNA-21-5p, miRNA-106a-5p, miRNA-122-3p, miRNA-122-5p, miRNA-143-3p, miRNA-143-5p, miRNA-203a-3p, miRNA-203-5p, miRNA-551b-3p, miRNA-551b-5p and miRNA-574-3p. miRNA expression was assessed by quantitative chain reaction polymerase reverse transcriptase (qRT-PCR). The response to NAC was assessed by computed tomography of the abdomen, chest and histopathology after gastrectomy. The statistical analyses were performed using GraphPad Prism 9.The significance limit was set at p

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Background: Fine-needle aspiration cytology (FNAC) is widely used to diagnose and monitor thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is the standard for interpreting FNAC specimens. The risk of malignancy in Bethesda III nodules also known as Atypia of Undetermined Significance (AUS) varies significantly throughout several studies published worldwide. This retrospective study examines the risk of cancer in thyroid FNAC categorized as Bethesda III, as identified in the final histopathology of thyroidectomy specimens at a single endocrine surgery center. Methods: This retrospective cohort analysis included 1038 consecutive patients who underwent elective thyroid surgery with complete follow up data between January 2020 and March 2024. Preoperative data on clinical and pathological characteristics have been collected. The final histopathology report from the thyroidectomy specimen was compared to the results of the preoperative FNAC on nodules that were judged to be Bethesda category III. Statistical methods were performed using SPSS version 29. Results: A total of 670 ultrasound-guided FNACs (64.5%) performed during the study period were included in the final analysis. The study population was predominantly female, represented by 79.6% of patients with a mean age of 42.5 (SD 12.1), while 20.4% were male and significantly older with mean age 45.13 years (p = 0.02). The FNAC inadequacy rate was 5.1%, which was associated with a high risk of malignancy (6 out of 34, 17.6%). Out of the total sample size of 170 patients classified as group III, 57 were found to have malignancies in final surgical histopathology, representing 33.5% of the cases within this category. The secondary gender-related outcome analysis showed that female patients classified under the Bethesda II category had a significantly higher risk of malignancy, with a rate of 21.2%, compared to males who had a malignancy rate of 3.4% in the same Bethesda category (p = 0.001, chi square test). However, female had more better prognostic non-invasive tumors than male (p = 0.02, chi square test). Conclusion: The study's results indicate that Bethesda categories II and III are associated with a higher risk of malignancy in comparison to the reports of the first and third editions of the TBSRTC, particularly for female patients classified under category II.

Differentiated thyroid cancer (DTC), comprising of papillary and follicular thyroid cancers, is the most prevalent type of thyroid malignancy. Accurate prediction of DTC is crucial for improving patient outcomes. Machine learning (ML) offers a promising approach to analyze risk factors and predict cancer recurrence. In this study, we aimed to develop predictive models to identify patients at an elevated risk of DTC recurrence based on 16 risk factors. We developed six ML models and applied them to a DTC dataset. We evaluated the ML models using Synthetic Minority Over-Sampling Technique (SMOTE) and with hyperparameter tuning. We measured the models’ performance using precision, recall, F1 score, and accuracy. Results showed that Random Forest consistently outperformed the other investigated models (KNN, SVM, Decision Tree, AdaBoost, and XGBoost) across all scenarios, demonstrating high accuracy and balanced precision and recall. The application of SMOTE improved model performance and hyperparameter tuning enhanced overall model effectiveness.

Background: We screened key genes involved in the dedifferentiation process of thyroid cancer by analyzing differentially expressed genes in anaplastic thyroid carcinoma (ATC) using Gene Expression Omnibus (GEO) database. Methods: We analyzed differentially expressed genes in ATC from GEO database and constructed a co-expression network using Weighted Gene Co-expression Network Analysis (WGCNA) . Cytoscape was used to calculate top ten key genes based on their gene scores. DEPDC1 was selected as interest gene for further validation, including examination of its prognostic relationship with thyroid cancer, correlation analysis with thyroid differentiation markers, immune cell infiltration, and tumor microenvironment. The impact of DEPDC1 on cancer cell migration, invasion, and proliferation was validated through downregulation and overexpression of DEPDC1 gene in thyroid cancer cell lines c643 and BCPAP. Results: We identified top 10 key genes in ATC: AURKA, TPX2, RACGAP1, MELK, DLGAP5, DEPDC1, KIF2C, NCAPG, CCNB1, and PBK. DEPDC1 showed a strong correlation with the prognosis of thyroid cancer. The odds ratio (OR) for overall survival was 3.5 (P=0.016) in individuals with high DEPDC1 expression, and the OR for disease-free survival was 2.6 (P=0.003). Additionally, the analysis revealed a significant negative correlation between the expression of DEPDC1 and thyroid differentiation markers. Gene Ontology enrichment analysis demonstrated that DEPDC1 co-expressed genes were enriched in cellular processes, cell cycle pathways, and dynamic protein groups. Matrix and immune scoring indicated tumor microenvironment and immune scores were associated with DEPDC1 expression. TIMER2.0 online analysis revealed a strong correlation between DEPDC1 expression and immune cell infiltration in papillary thyroid carcinoma. After downregulation of DEPDC1 expression, the invasion, migration, and proliferation abilities of tumor cells were significantly reduced. Conversely, overexpression of DEPDC1 exhibited the opposite effect. Conclusion: DEPDC1, a newly identified dedifferentiation gene in thyroid cancer, inversely correlated with the degree of differentiation. High expression of DEPDC1 promotes cancer progression and leads to poor prognosis in thyroid cancer.

Bladder cancer (BC) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in bladder cancer (BCa) and elucidated the mechanisms in three-dimensional (3D) spheroid and tumoroid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49, respectively), and tumoroids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine) induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids, and tumoroids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 targets cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of bladder cancer with small-molecule inhibitors TTI101 and SH5-07 via suppression of CSCs and STAT3 signaling.

The pervasive use of plastic for milk packaging has raised significant health concerns, despite its advantages in terms of cost-effectiveness, convenience, and durability. The potential correlation between cancer and plastic packaging is one of these concerns. This mini-review examines the health implications of plastic materials used in milk packaging, with a particular emphasis on their carcinogenic hazards. This work endeavors to summarize the current state of knowledge regarding the influence of plastic components on human health and underscore the importance of ongoing research in this field by utilizing insights from a comprehensive review article. Harmful chemicals have been observed to leach into milk from plastics used in milk packaging, including high-density polyethylene (HDPE), low-density polyethylene (LDPE), and polyethylene terephthalate (PET), particularly under conditions of protracted storage and heat. Bisphenol A (BPA), phthalates, and styrene are among the most prevalent leachates. These chemicals have been associated with a variety of health issues, such as an elevated risk of cancer, and are recognized for their endocrine-disrupting properties. BPA and phthalates, in particular, have the potential to disrupt hormone function, which may result in breast cancer, prostate cancer, and other hormone-related malignancies.This review emphasizes the significance of comprehending the precise components of plastics utilized in milk packaging and their potential health consequences. It advocates for more rigorous research to completely elucidate the long-term health impacts of these materials by emphasizing the current state of knowledge and regulatory initiatives. Additionally, it underscores the necessity of innovative packaging technologies to guarantee consumer protection and mitigate the risk of exposure to carcinogenic substances.

In recent years, numerous approaches have been developed to comprehend the molecular altera-tions underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumour cells from apoptosis, triggering invasion and metastasis through enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumour angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as met-astatic lesions, exhibit overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, para-crine, intracrine, and neuroendocrine processes, including the regulation of tumour burden. Con-sequently, the secretion of SP from TC results in increased SP levels in plasma, which are signifi-cantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumour action. They impair cancer cell proliferation on one side and induce apoptosis of tumour cells on the other side. Furthermore, it has been demonstrat-ed that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment.

During HIV-1 virus assembly the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag-Psi interactions, there is almost no information on kinetic aspects of this interaction. We have investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX2 technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3’ two of the three Psi stem-loops than with monomeric RNA containing the 5’ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly.

The genetic causes of the differentiated, highly treatable and mostly non-fatal papillary thyroid cancer (PTC) are not yet fully known. The widely accepted PTC etiology blames altered sequence or/and expression level of certain biomarker genes. However, our previous studies found that the PTC biomarkers played significantly lower roles than the personalized PTC Gene Master Regulators. Our publicly accessible gene expression data from the cancer nodule and the surrounding normal tissue of surgically removed PTC tumor were re-analyzed to determine the transcriptomic effects on the genomic fabrics responsible for the DNA replication, repair and transcription. Tumor results were compared to the gene expression profiles of the papillary (BCPAP) and the anaplastic (8505C) human thyroid cancer cell lines. The analyses were carried out from the Genomic Fabric Paradigm (GFP) perspective that provides the most theoretically possible comprehensive characterization of the transcriptome and its alterations in disease. The study indicated that, in addition to regulating numerous genes, changes in the homeostatic control of transcript abundances and remodeling of the gene networks had major contributions to the PTC occurrence, resilience and proliferation. Therefore, the molecular mechanisms responsible for gene expression control and inter-coordination should also be considered when designing personalized anti-cancer gene therapies.

Papillary thyroid carcinoma (PTC) accounts for approximately 85%-90% of all thyroid cancers. BRAFV600E mutation is a highly specific target for papillary thyroid carcinoma (PTC) and may have a reciprocal causative relationship with iodide-metabolizing genes. Here, we performed a review of studies published in the past 10 years to determine the relationship between iodine intake and BRAFV600E mutation in patients with PTC. We searched the MEDLINE, PubMed, and EMBASE databases for studies published from 2009 to 2019; seven partially matched the selection criteria and were suitable for review, and five passed all selection criteria. We divided the patients into three groups by iodine intake: low (urinary iodine concentration [UIC] &lt;100 μg/L), adequate (UIC 100–200 μg/L), and high iodine intake groups (UIC ≥200 μg/L). Between-group analysis revealed no significant differences in the odds ratio of the prevalence of BRAFV600E mutation between the high and adequate/low iodine intake groups and between the adequate and low iodine intake groups. To further analyzed the results of studies, they exhibited U-shaped curves in the relation of deficient and excessive dietary iodine intake in BRAFV600E mutation. The results might suggest that iodine intake slightly influences the prevalence of BRAFV600E mutation in patients with PTC despite the heterogeneity of studies. Further research should explore potential mechanisms underlying the associations between iodine intake and BRAF mutation in PTC. The systematic review was registered in PROSPERO (CRD42021279462).

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

This article provides a literature review on tubal carcinoma to offer an updated insight into its preventative strategies, diagnosis, treatment, and oncological surveillance. In addition to the search string utilized, the authors' focus extended to key scientific studies, consensus statements, guidelines, and relevant case reports essential for the proper clinical management of the disease, providing a methodologically well-structured literature review combined with the practical expertise in the oncological field. The article also includes two emblematic clinical cases that emphasize the importance of understanding the physiopathology and the current state of the art in the anatomopathological advancements of tubal/ovarian/peritoneal carcinoma, often assimilated into a single clinical entity.

Cancer treatment is a significant focus in medicine owing to the increasing global incidence. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with the supplementation of natural products may confer benefits to cancer patients by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Pain is frequently reported during cancer disease, and still remains poorly controlled in 40% of patients. Recent developments in oncology have helped to better control pain. Targeted treatments may cure cancer disease and significantly increase survival. Thereby, a novel population of patients (cancer survivors) has emerged, also enduring chronic pain (27.6% moderate to severe pain). The present review discuss the different options currently available to manage pain in (former) cancer patients in the light of progress made in the last decade. Major progress in the field are recent development of a chronic cancer pain taxonomy now included in International Classification of Diseases (ICD-11) and update of WHO analgesic ladder. Until recently, cancer pain management has mostly relied on pharmacotherapy, opioids being considered as mainstay. The opioids crisis has prompted the reassessment of opioids use, both in cancer patients and cancer survivors. The review focuses on the current utilization of opioids, on the neuropathic pain component often neglected and on techniques and non-pharmacological strategies available which help to personalize patient’s treatment. Cancer pain management is now closer to the management of chronic non-cancer pain i.e. “an integrative pain care” aiming to improve patient’s quality of life.

With the burgeoning growth of online retail, the issue of counterfeit products has become a significant threat to both consumer trust and brand integrity, posing challenges to sustainable market practices. Online retail platforms are promoted to redesign their channel structures and enhance brand traceability to tackle counterfeits using blockchain technology. To investigate the interactions between blockchain technology and the channel structures of online retail platforms, we design a game theory model incorporating a manufacturer with(out) blockchain participation selling products via an online retail platform that operates an agency channel and/or a reselling channel. We show that the critical trade-off of blockchain participation comprises the brand assurance effect of the blockchain, the channel competition intensification effect, and the blockchain adoption cost. The platform is capable of strategically designing the channel structure to encourage (while discouraging) blockchain participation by the manufacturer. Our analysis highlights the complementarity between blockchain participation and the channel structure. Furthermore, the effect of the consumer’s belief in the reselling channel, the commission fee in the agency channel, and the substitutability between channels are investigated in depth. The research provides valuable insights for online retail platforms and policymakers seeking to foster a sustainable and trustworthy e-commerce ecosystem.

Objective: Breast cancer (BC) is the most common cause of death among females. There are many prognostic systems, the most recent of which are the molecular subtypes. Recently, it was included that thyroid disease is a favorable factor for the patients with BC and that the thyroid hormones have an effect on the disease. Thyroid stimulating hormone (TSH), however, is thought to be unrelated to the cancer aggressiveness. In the current study we aimed to examine the status of the postoperative TSH levels, as well as the impact of the thyroid disease on the cancer aggressiveness. Methods: A retrospective comparative analysis of invasive BC patients was performed between 2017 and 2019 year. 111 patients were selected. They were divided into group A (n=62) and group B (n=49), based on the presence or absence of thyroid disease, respectively. The data was processed with SPSS version 25. Results: There is a significant difference between group A and group B concerning the molecular subtypes, ki-67, and estrogen receptor. The current study supports the fact that TSH is responsible for the aggressiveness of the invasive BC and not the thyroid hormones themselves. Moreover, based on the correlation analyses calcium levels preoperatively are linked to cancer aggressiveness and could be used as future prognostic factors. Conclusion: Indeed, the thyroid disease appears to have more favorable prognosis based on the molecular subtype frequency but more emphasis in future studies should be given to the TSH and its relation to the overall survival of the patients.

This study examines the differential impact of proactive and reactive job crafting behaviors on job well-being, drawing from the perspective of boundary theory. The increasing popularity of work connectivity behavior after-hours (WCBA) after work has attracted widespread attention from scholars on the relationship between WCBA and employee well-being. One view suggests that the impact of WCBA is negative, while another view suggests it is positive. Obviously, the impact of (WCBA) on well-being at work is still contradictory. To clarify the complexity of the impact of WCBA on well-being at work, based on boundary theory, we divided WCBA into proactive WCBA (PC) and reactive WCBA (RC), and examined the double-edged sword effect of WCBA on well-being at work, as well as the mediating mechanisms of job control and work-to-home conflict, and the moderated effects of boundary segmentation preferences. This study uses empirical sampling method to collect data from 125 employees for a period of five days for quantitative research. The results show that, first, PC has an inverted U-shaped effect on job control, and job control is negatively related to well-being at work. Thus the mediating effect of job control is significant. Second, RC has a negative impact on job control, and there is also a negative relationship between job control and well-being at work. Therefore, the mediating effect of job control is significant. Third, PC and RC are positively correlated with work-to-home conflict, and work-to-home conflict has a significant positive impact on well-being at work. Therefore, the mediating effect of work-family conflict is significant. Fourth, the study also found that integration preference moderates the relationship between work-to-home conflict and PC on well-being at work, that is, the mediating effect of work-to-home conflict is stronger for employees with low integration preference. This study enriches our understanding of WCBA, PC and RC from the perspective of proactive and passive employee behaviors. The study also provides a new interpretation of the impact of WCBA on well-being at work and offers valuable insights for the sustainable development in digital social transformation and the application of boundary theory and the theory of empowerment-subjugation in achieving the United Nations Sustainable Development Goals. In addition, the study deepens our understanding of the heterogeneous regulatory role played by work-family integration preferences in influencing well-being at work under different types of WCBA.

Introduction/Aim: Central sensitivity to thyroid hormones refers to the sensitivity of the hypothalamic-pituitary-thyroid (HPT) axis to changes in circulating free thyroxine (fT4). The relationship between fT4 levels and iodine intake is complex. The aim of the present study was to assess central sensitivity to thyroid hormones in pregnancy against iodine intake. Materials & Methods: One thousand one hundred two blood and urine samples were collected from pregnant women (with a mean age+SD of 30.4+4.6 years) during singleton pregnancies; women with known/diagnosed thyroid disease were excluded. Specifically, TSH & fT4 and 24-hour urinary iodine excretion (UI) were measured in each trimester and at two months postpartum. The Thyroid Feedback Quantile-based Index (TFQI) was calculated to assess central sensitivity to thyroid hormones. For the statistical analysis of TFQI by time period, analysis of variance (ANOVA) was used, while Pearson's correlation was used to assess TFQI versus UI. Results: The mean TFQI index ranged from -0.06 (first trimester) to -0.07 (two months postpartum), while the corresponding UI was 141 and 172 μg/L, respectively. The TFQI-UI correlation was negative (Pearson r: -0.325, p: 0.04 and r: -0.399, p: 0.023), for UI values over 250 μg/L, in the first and the third trimester of pregnancy, respectively. Discussion: TFQI is a new index reflecting central sensitivity to thyroid hormones. Lower TFQI indicates higher sensitivity to thyroid hormones. In our sample TFQI was inversely related to iodine intake, in the first trimester of pregnancy (the critical period of organogenesis) and the third trimester (the critical period of fetal growth). Thus, the observed changes in TFQI may reflect different ways of central action of thyroid hormones, according to the phase of pregnancy. The negative association between maternal TFQI (indicative of central sensitivity to thyroid hormone) and urine iodine levels during the third trimester of pregnancy may reflect the combined influence of maternal and fetal thyroid function. Our results are intriguing and have the potential to enhance our comprehension of the changes in the HPT axis’ function via variations in central sensitivity to thyroid hormones and its interplay with nutritional iodine status during pregnancy.

For monitoring of chimeric antigen receptor (CAR) T-cell therapies antigen-based CAR detection methods are usually applied. However, for each target-antigen a separate detection system is required. Furthermore, when monitoring CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods producing false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment, promise an universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19 targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection by using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel the sensitivity was significant lower compared to antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel or Ide-cel, respectively. Cilta-cel (containing an monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but not universal applicable.

Tertiary lymphoid structures (TLSs) have become the focus of antitumor immunity. However, the prognostic significance of TLSs in epithelial ovarian cancer (EOC) treated with primary debulking surgery (PDS) or interval debulking surgery (IDS) remains unelucidated. This retrospective study examined the prognostic value of TLSs in tumor tissues obtained during PDS and IDS. Pathological specimens were collected from patients with EOC who underwent PDS or IDS between 2017 and 2020 at the National Cancer Center Hospital East. The correlation of tumor-infiltrating lymphocyte frequency, TLS presence, and PD-L1 expression with progression-free survival (PFS) and overall survival (OS) and the correlation between TLS and PD-L1 expression were analyzed. Overall, 25 specimens (15 from PDS and 10 from IDS) were analyzed. The presence of TLS was associated with a significantly longer OS in patients who underwent PDS but not in patients who underwent IDS. No correlation was identified between TLS and PFS in patients with PDS or with IDS. However, TLS was positively correlated with PD-L1 positivity. The prognostic impact of TLS, specifically in pre-chemotherapy specimens, and a positive correlation between TLS and PD-L1 indicate the potential of TLS as a meaningful biomarker for understanding antitumor immunity and developing immunotherapy for EOC.

Brazil has ideal conditions for the large-scale use of cabotage cargo transportation: a vast coastline with almost 7,400 km, approximately 70% of the population resident in a coastal range of up to 200 km from the coast and a strong concentration of activities economic along the coast. However, there is an absolute domain of road modal for the transportation of goods, and cabotage is underused. The purpose of the study was to raise the main barriers that negatively impact the performance of Brazilian cabotage. To this end, it was used to bibliographic and documentary research, based on studies already published in journals, doctoral theses, master's dissertations, congress annals, technical reports and research on government-related government agencies sites, navigation companies and entities related to cabotage. The main barriers that contribute to the low use of cabotage in Brazil were identified and analyzed, as well as possible alternatives of solution for sustainable development of this mode of transport. Such a study will certainly serve as subsidies for the definition of public policies aimed at better use of Brazilian cabotage, as well as to encourage navigation companies to invest more in the transport of goods by cabotage, in order to contribute to the reduction of trucks on highways Brazilian and for environmental preservation.

This study investigates the impact of circular economy (CE) strategies on organizational resilience (OR) within the metal industry, focusing on a case study of a forging department in a large man-ufacturing company. The idea of the paper is to link the macroeconomic topic of circular economy (CE) with microeconomic and practical activities in the organization, exploring how CE principles can improve resource efficiency, sustainability, and organizational resilience. A systematic literature review and case study methodology were used to assess the relationship between CE and OR. The findings reveal that companies with higher circularity demonstrate better resilience, both in normal operations and during crises. Specifically, in the case study, the closure of the forging department, following a detailed analysis using the Inputs-Mediators-Outputs (IMO) model, emerged as the most sustainable option, yielding financial, environmental, and operational benefits. This decision aligned with the company’s long-term goals of energy efficiency and carbon neutrality. The research highlights the significance of integrating CE strategies with business processes to not only achieve sustainability but also to build a more adaptable and resilient organization. Future research should explore broader applications of this framework across different industries to strengthen the links between circular economy practices and organizational resilience.

Recognizing the need to enhance immune cells' ability to target and eliminate tumor cells by focusing on tumor-associated antigens is crucial for the success of immunotherapy. Numerous cell-based therapies, such as CAR-T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, CAR-NK cell therapy, and T-cell receptor (TCR)-based therapies, are currently undergoing clinical and pre-clinical evaluation across various cancer types. However, a significant challenge lies in managing the inflammatory responses that are harmful to cancer patients. To overcome this, developing advanced strategies to target tumor cells precisely while preserving immune balance in cancer patients is imperative. One promising approach involves using modified tumor-associated macrophages (TAMs), which constitute approximately 50% of the tumor microenvironment (TME) and play a pivotal role in tumor progression. CAR-Macrophage (CAR-M) therapy is an emerging potential asset of immunotherapy for a wide range of tumors.

Epidemiological studies have shown a strong association between high body mass index (BMI) and papillary thyroid cancer (PTC). We assessed the clinical and histopathological features of PTC in patients with a higher BMI and compared them to analogous parameters in PTC patients with a normal BMI. We retrospectively analyzed 5,021 medical records of patients admitted and surgically treated for thyroid tumors in one center between 2008 and 2018. Finally, we extracted data from 523 adult patients with PTC and stratified patients into two groups according to BMI: Group 1 with BMI < 25 kg/m² and Group 2 with BMI ≥25 kg/m². Data stratification was performed to estimate the association of overweight and obesity with clinical and histopathological features of PTC in both univariate and multivariate binary logistic regression analyses. Overall, compared to patients with a normal BMI, overweight and obese patients had a greater risk of minimal extrathyroidal extension (minimal ETE), multifocality and bilaterality of PTC (p<0.001 for all). Analysis did not show that BMI was significantly associated with more advanced tumor-node-metastasis (TNM) stage (p=0.894). Obesity and overweight were significantly associated with higher aggressiveness of PTC. When considering various management options for PTC patients, these findings regarding overweight and obesity should be taken into consideration during the decision-making process.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2 and neuroendocrine carcinoma: NEC) on the basis of Ki-67 proliferation index and mitotic count according to the 2010 WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic backround together with preclinical studies to develop new agents, including those already under investigation for SCLC, will be needed to improve the prognosis.

At present, farmland abandonment（FA）is a severe phenomenon in China, imposing a serious restriction on agricultural production. In this context, it is of great significance to explore the logical relationship between high-standard farmland construction (HSFC) and FA to optimize land resource allocation and guarantee national food security. Based on 838 samples of farmers in the main rice production area of the Yangtze River Basin in China, this paper employs the Tobit model, the mediating effect model, and the moderated mediating effect model to analyze the impact of HSFC on FA at the micro level. The results show that (1) HSFC inhibits FA, and FA proportion decreases by 1.14% for every 1% increase in HSFC proportion, and the robustness test and endogeneity treatment also yield consistent conclusions. (2) Agricultural socialization services (ASS) play a positive mediating role in the influence path. HSFC promotes farmers' purchase of ASS, which in turn inhibits FA. (3) The agricultural labor transfer distance (ALTD) plays a positive moderating role in the relationship between HSFC and FA. The farther the distance, the more likely HSFC can promote farmers' purchase of ASS and inhibit FA. The results provide enlightenment on how to precisely implement HSFC policy, that is, to inhibit FA by improving the construction of high-standard farmland and the post-construction management as well as protection system. Moreover, this study helps guiding the development of ASS and optimizing the institutional environment for agricultural labor transfer, creating conditions for agricultural scale management.

To decrease privacy risks, consumers may choose to misrepresent when they are asked to offer personal information. This paper examines the impact of consumer misrepresentation on a monopolistic firm and consumers with an economic model. The results show that consumer misrepresentation may benefit the firm but hurt consumers. In addition, consumers misrepresentation may encourage the firm to provide higher personalized service level in certain scenarios, such as, when the unit cost of personalized service is low. Thirdly, when consumers misrepresent, and the firm only covers part of the market, a greater unit value of consumer’s privacy information will reduce the firm’s profit, but a greater unit cost of personalized service increases the firm’s profit.

Ulleung County, one of the most medically vulnerable areas in South Korea, requires public attention because of the high incidence of liver cancer. This study was conducted as a part of the Ulleung Liver Cancer Prevention and Management Project. The purpose of this study was to estimate the community prevalence of hepatitis B and C viruses and to identify the associated risk factors. The Project’s interagency workgroup established a procedure for conducting blood sampling and health behavior surveys at the Ulleung Public Community Health Center. A total of 1,792 residents aged 40 years and older voluntarily participated in the study between 2019 and 2022. The hepatitis B surface antigen (HBs Ag) and hepatitis C virus antibody (anti-HCV) positive rates in Ulleung were 7.19% and 1.37%, respectively. Low education level and lifetime smoking were associated with HBsAg positivity, whereas cupping therapy at non-medical institutions was associated with anti-HCV positivity. The odds of HBs Ag positivity were lower among those with tattoos than among those without. There was a difference in the risk factors associated with hepatitis B and C viral infection. While a high HBs Ag positivity rate alone may not fully explain the high incidence of liver cancer in Ulleung, it may be a contributing factor.

Background: The incidence of various types of cancer, for example papillary thyroid carcinoma (PTC), is on the rise. Since therapeutic success depends greatly on early diagnosis, reliable diag-nostic biomarkers must be identified and easy-to-apply tools for detecting them must urgently be standardized. Here, we contribute to solving this medical challenge by assessing miRNAs sus-pected of promoting carcinogenesis in extracellular vesicles (EVs) that can be routinely obtained via liquid biopsy. We profit from current progress in cancerology that provides innovations in liquid biopsy and EVs analysis along with identification of miRNAs and chaperone system (CS) components implicated in carcinogenesis. Methods: We measured in EVs obtained from circulat-ing blood plasma from PTC patients the levels of three miRNAs implicated in thyroid cancer, miR-1, miR-206, and miR-221, and most likely involved in the regulation of two members of the CS, Hsp60 and CCT. EVs were isolated from the plasma of patients with PTC and controls with benign goiter (BG), and from the culture medium of a PTC cell line (MDAT32) and were duly characterized. Results: The levels of miRNAs determined by RT-qPCR were consistently higher in PTC patients and decreased down to control levels after thyroidectomy. Bioinformatics showed that the miRNAs target genes were associated to the molecular pathogenesis of PTC. Conclusions: Thus, our exploratory study reaffirms the potential in clinics of the selected miRNAs in EVs as useful biomarkers of PTC easily accessible via liquid biopsy, which is minimally invasive and amenable to periodic repetition, an improvement compared to the established fine-needle aspirate biopsy.

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those above the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level are reviewed in the neoadjuvant, surgical, adjuvant and metastatic settings of colon and rectal cancers. Immunotherapy is shown as an effective option treatment in older adults that have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Under the new pattern of “double carbon” development, good ESG performance is the best way to promote the sustainable development of enterprises, and the ESG investment strategies are directly affected by the strategic vision of managers. Based on the upper echelons theory and stakeholder theory, this paper takes Chinese A-share listed companies from 2011 to 2022 as samples to empirically analyze the impact of managerial myopia on corporate ESG performance. The results show that managerial myopia significantly inhibits corporate ESG performance, mainly by inhibiting corporate green investment and green innovation sustainability. Furthermore, for state-owned enterprises (SOE), heavy polluting enterprises (HPE) and non-high-tech enterprises, the inhibitory effect of manager myopia on ESG performance is stronger. When the enterprise is in the growth stage, the above inhibition effect is more severe. For external governance, the greater the analyst attention and public environmental attention are, the more conducive they are to alleviating the restraining effect of managerial myopia on enterprise ESG performance. Therefore, effectively improving the time cognition level of managers and strengthening external supervision have become important measures for comprehensively optimizing the ESG performance.

Penile cancer (PeCa) is a rare urological malignancy characterized by significant geographic variations in both incidence and mortality rates. Due to its rarity and the consequent lack of randomized trials, current management is based on retrospective studies and small prospective trials. In addition, the diagnostic pathways and treatment strategies exhibit substantial heterogeneity, differing significantly between less developed and well-developed countries. The prognosis of PeCa is determined by the presence and extent of regional lymph node (LN) involvement. Therefore, early detection and treatment of LN metastasis is paramount to ensure better outcomes. In recent decades, the overall survival for PeCa has increased, mainly due to advancements in imaging techniques and risk stratification. We aim to provide an overview of the current role of PET CT imaging in the management of patients with PeCa.

The collaboration of multimodal transport documents is the foundation for conducting multimodal transport operations. Blockchain technology can effectively address trust issues and information sharing difficulties in current multimodal transport document collaboration. However, in current blockchain-based electronic document research, the bottleneck problem lies in the collaboration of multiparty in multimodal transport under the "one-bill coverage system". We design a blockchain platform architecture for multimodal transport, reshaping collaboration processes for different modes of transport based on the blockchain platform. It proposes a collaboration model for multimodal transport under the "one-bill coverage system" and performs model solving and case analysis. The obtained collaboration strategies are embedded into the platform's application layer. Finally, using Solidity language, it writes smart contracts related to multimodal transport under the "one-bill coverage system " and deploys and executes them on the Remix platform.

Productivity has been modest in construction due to many reasons, especially project-specific operations and fragmentation. The main aim of this research is to map the challenges towards industrialization in construction through a comparative study of the manufacturing industry. An inductive approach and a qualitative method are followed by applying semi-structured inter-views, and node-based thematic analysis. The key elements of industrialization in mature man-ufacturing companies are benchmarked. The findings indicate a specific order of steps for indus-trialization in construction. Data and information management with achieved systematization have been sources of productivity in manufacturing companies. However, the systematization starts from the offering, construction companies need to define their offering, that is the products, and define their respective data. Only accurate and good quality data on products enables the systematization of order delivery processes, which are the engine for a company’s success or failure. Continuous efficiency improvement is only possible with systematized processes and respective data related to the processes. The originality involves clarifying the industrialization of construction companies via products, respective data, and processes considering industrialized manufacturing companies.

Long COVID is a phenomenon in which individuals experience persistent symptoms after recovering from COVID-19. The symptoms are discovered to be unique for every individual and can affect multiple organs systems in the body. This study aims to identify effective natural remedies for long COVID by analyzing hub genes associated with the symptoms of the condition and evaluating the repurposed drugs catered and used for treating the symptoms of long COVID. The most common and prevalent symptoms of long COVID were identified; Fatigue, Shortness of Breath, Loss of Smell, Headache, Brain Fog, Chest Pain, Insomnia, Heart Palpitations, Dizziness, Joint Pain, Depression, Anxiety, Tinnitus, Loss of Appetite. Hub genes for each of the symptoms provided an insight on the key biological pathways of the symptom. Repurposed drugs identified, provided the template to identify the natural compounds with similar structure as a potential therapeutic drug. The natural compounds were retrieved using fingerprint search of the repurposed drugs from the NPASS Database. The findings of this study suggest several natural remedies for each symptom based on the molecular docking of the hub gene and natural compound using iGEMDOCK. The identified natural remedies may hold promise in treating long COVID, but further research is required to explore the efficacy and effectiveness of the proposed natural compounds. The results of the study pose important implications for the development of effective treatments for long COVID.

Xinjiang, as a climate-sensitive region in northwest China, holds significant importance in studying extreme weather events for agricultural production and socioeconomic development. Based on data from 52 meteorological stations and 23 extreme climate indicators in Xinjiang from 1960 to 2021, the 5a moving average, linear trend estimation, climate tendency rate, and GIS spatial analysis methods are used to analyze the distribution and change characteristics of extreme climate. The results revealed that from 1960 to 2021, TXx, TNx, TXn, TNn, FD, ID, TN10p, TX10p, and WSDI showed a significant upward trend, while SU, TR, TN90p, TX90p, and CSDI showed a significant downward trend. What is more, the range of changes in the extreme temperature indexes from 1990 to 2021 is higher than that of 1960 to 1989. The high-value areas of extreme indexes are primarily concentrated in the northern part, while the high-value areas of cold event indexes are mainly distributed in the southern part. The upward/downward trends all accounting for over 80.00% of the entire region. The Rx1day, Rx5day, PRCPTOT, R95p, R99p, R10, R20, and R25 showed a significant growth trend from 1960 to 2021, and the range of change in the extreme precipitation indexes from 1990 to 2021 was lower than that from 1960 to 1989. Moreover, their high-value areas and high climate tendency areas are mainly concentrated in the northern and western parts of Xinjiang, with upward trends all accounting for over 71.00% of the entire region. The research results provide theoretical foundations for formulating climate risk strategies in the northwest region of China.

A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and cytokines interleukin 6 (IL-6), contributing to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K) /protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor -1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes, but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

Dogs population increased exponentially in the past decade while the birth rate decreased gradually, especially in the developed countries. Due to dogs’ characteristics of loyalty and obedience, most pet owners treated their dogs as their family members or companions, therefore they are willing to select and purchase safe, high quality and nutrition dog food to their dogs. However, there is lack of regulation or standard to reinforce the production or distribution of dog food in Hong Kong. Consequently, this paper will first review the relationship between high dog population and declining birth rate, types of dog food and typical ingredients. Secondly, the potential health implications of various “toxic” food ingredients for dog, hazard analysis of dog food and its testing methods will be investigated. Lastly, this paper will summarize worldwide existing standards and regulations, quality and hygiene management system related to dog food safety to provide insights and suggestions to Hong Kong government about the importance and urgency of implementing regulations and policies to oversee the imported and local manufactured dog food.

Long COVID, also referred to as post-COVID-19 condition, describes the lingering after-effects of COVID-19 infection. This complex syndrome encompasses a range of symptoms affecting physical well-being, cognitive function, and mental health. The widespread impact of long COVID extends beyond individual sufferers, placing significant strain on healthcare systems and causing far-reaching socioeconomic consequences. The scale of this multifaceted health crisis is unparalleled in recent history, affecting millions globally and challenging our understanding of post-viral conditions. This study aimed to explore the possibility of targeting G protein-coupled receptors (GPCRs) signaling pathway-related genes as therapeutics for long COVID using computational analysis. Targeting GPCRs and their signaling pathways holds significant promise for long COVID therapeutics, as these receptors are involved in crucial physiological processes including immune regulation, inflammation control, and neurotransmission. All of these are implicated in the diverse and persistent symptoms of long COVID, potentially offering a versatile approach to addressing multiple aspects of the condition simultaneously. This study identified 21 genes associated with GPCRs for further exploration as potential targets. Notably, GPCR genes such as HRAS, KRAS, GNAQ, and GNA11 were determined to be possible therapeutic targets for the pathophysiological mechanisms of long COVID. FDA-approved drugs targeting these genes were identified, including Binimetinib, Cabozantinib, Selumetinib, Panitumumab, Cetuximab, Adagrasib, Tipifarnib, and Sotorasib. Additionally, Naltrexone and Tipifarnib have emerged as potential new treatment options for long COVID. SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport, contributing to the pathophysiology of pulmonary edema in patients with COVID-19. Further research is required to translate the findings into the development of therapeutics and to investigate the relationship between viral infection and GPCR signalling.

This paper aims to assess whether the financial performance of Portuguese companies that publish sustainability reports (SR) differs from the financial performance of companies that do not publish SR. We use two methodological procedures. First, we conducted a univariate analysis to test the differences in the financial performance according to the disclosure of SR. Second, we conducted a multivariate analysis using a multiple linear regression that explains financial performance by the disclosure of SR, as well as control variables such as sector, size, leverage, growth, and liquidity. Findings indicate that financial performance of companies that disclose SR does not significantly differ from the financial performance of companies that do not disclose SR. The results are robust to both methodological procedures, as well as to the sample split by sectors.

This paper presents a comprehensive study on applying machine learning (ML) techniques for real-time credit card fraud detection. With the increasing prevalence of credit card fraud, financial institutions face the challenge of detecting fraudulent transactions promptly and accurately. This research evaluates various ML models, including Logistic Regression, Decision Trees, Random Forests, XGBoost, and Deep Convolutional Neural Networks, for their effectiveness in identifying fraudulent activities. Utilizing PySpark for processing large-scale transaction data, the study highlights the importance of real-time analysis, adaptive learning, and handling imbalanced datasets. Key findings reveal that XgBoost, with its balance of accuracy and complexity, emerged as the most promising model, achieving an accuracy rate of 98% in detecting fraudulent transactions. The paper further discusses the potential of ensemble methods, graph-powered systems, and intelligent sampling in enhancing fraud detection capabilities. Challenges such as overfitting, data access, and the need for real-time analysis are addressed. Future research directions include implementing models in live transaction environments, expanding model applicability across financial platforms, and developing advanced anomaly detection methodologies. This study underscores the pivotal role of machine learning in safeguarding financial transactions against fraud, offering significant implications for consumers, financial institutions, and the broader financial ecosystem.

Thyroid surgery rates have tripled over the past 3 decades making it one of the most frequently performed procedures within general surgery. They are associated with the possibility of serious postoperative complications having a significant impact on the patient's quality of life. The recurrent laryngeal nerve (RLN) palsy and the external branch of the superior laryngeal nerve (EBSLN) palsy are, next to hypoparathyroidism and bleeding after operation, one of the most common complications. The introduction of neuromonitoring into thyroid surgery, enabling both confirmation of anatomical integrity and assessment of laryngeal nerve function, was a milestone that has begun a new era in thyroid surgery. The International Neural Monitoring Study Group made standardization of the technique of RLN and EBSLN monitoring during thyroid and parathyroid surgery which increased prevalence of neural monitoring during thyroidectomy. Current status of IONM and benefits of its use have been presented in this publication.

Food insecurity remains a significant developmental challenge, particularly in rural areas, despite ongoing efforts to mitigate it. To better understand the persistence of this issue, this study investigates the causes of household food insecurity and the coping strategies employed by households in Zorkor Goo, Zorkor Kanga, and Zorkor Kadaare communities within the Bongo District of Ghana’s Upper East Region. A descriptive cross-sectional survey was conducted, sampling 196 households systematically from these communities. Data were collected through a structured questionnaire covering socio-demographic factors, causes of food insecurity, household coping strategies, and dietary intake. The analysis was performed using SPSS (Version 21.0), with food security status and dietary intake assessed via the FANTA Household Food Insecurity Access Scale (HFIAS) and Food Consumption Score, respectively. The study identified key factors contributing to food insecurity, including soil infertility, poor rainfall patterns, food spoilage, extravagant funerals, large family size, high unemployment, and lack of education. Major coping strategies among households included meal skipping, reducing meal size and frequency, migration, asset sales, and basket weaving. The findings revealed that 96.4% of households were severely food insecure, and over two-thirds (67.3%) exhibited poor dietary consumption. Notably, household employment levels, education, and food consumption scores were significantly associated with food insecurity (P&lt;0.001). These findings underscore the need for targeted interventions addressing the root causes of food insecurity and enhancing household resilience in these communities.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

We study a two-echelon supply chain made up of a supplier and a manufacturer, both of which can reduce their component/product carbon emissions. With the vertical technology spillovers, we explore the optimal decisions of centralized and decentralized supply chains with price dependent demand and propose coordination strategy for the decentralized supply chain. Considering the cost contraction effectiveness of the technology spillovers, the centralized and decentralized game theoretic models of a two-echelon supply chain are developed to investigate optimal decisions of pricing and carbon emissions reduction. Through a systematic comparison and numerical analysis, we show that the profits of both players and the entire supply chain improve with the effect of technology spillovers increasing. Carbon emissions reduction will be taken by various protective measures so that the supplier and the manufacturer who do not innovate can hardly share the results of innovating via the “free-riding” methods when the technology spillover is relatively small. We also propose a revenue-cost sharing contract through bargaining to enhance the performance of the decentralized supply chain.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

Using the data of China's A-share non-financial listed enterprises from 2015 to 2022 as a sample, this study empirically tests the impact of ESG rating disagreement on corporate debt financing cost. The results show that ESG rating disagreement significantly increases the debt financing costs of enterprises, and this result still holds after a series of robustness tests such as replacing the dependent and independent variables and PSM approach. Meanwhile, the heterogeneity analysis reveals that non-state-owned enterprises and enterprises in non-heavily polluting industries are more sensitive to ESG ratings disagreement. In addition, mechanism analysis shows that corporate financing constraints mediate the relationship between ESG rating disagreements and debt financing costs. The findings of this study provide important evidence for understanding the impact of ESG rating disagreement on the costs of debt financing, enrich the meaning of ESG rating disagreement, and reveal the significance of unifying ESG rating standards.

Amidst the escalating demands for efficient Intelligent Transportation Systems (ITS) management, the significance of accurate Origin-Destination (OD) data prediction has emerged as a paramount concern, given its indispensable role in the ITS domain. This paper introduces a groundbreaking integrated model, creatively fusing the unique strengths of Graph Convolutional Network (GCN), Residual Neural Network (ResNet), and Long Short-Term Memory Network (LSTM) into a single architecture, which we name GraphResLSTM, to exploit road segment average speed data for OD prediction. Compared with conventional road segment traffic volume data, average speed data is more readily available, significantly reducing the data accessibility barrier for OD prediction. We underscore the critical role of selection of key road segments and employs a combination of Entropy Weight Method and Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) to identify 41 representative road segments from the experimental road network. In the experimental phase, we simulate 86400000 seconds of traffic conditions, generating a total of 1440000 data records. Utilizing these simulated data, we design and conduct comparative experiments between models as well as data types. The results demonstrate that both the GraphResLSTM model and road segment average speed data outperform other models and data types notably in OD prediction tasks.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role, and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Background: Molecular genetic events are among the numerous factors affecting the clinical course of papillary thyroid carcinoma (PTC). Recent studies have demonstrated that aberrant expression of miRNA, as well as different thyroid-related genes, correlate with the aggressive clinical course of PTC and unfavorable treatment outcome, which opens up new avenues for using them in personalization of the treatment strategy for patients with PTC. In the present work, our goal was to assess the applicability of molecular markers in preoperative diagnosis of aggressive variants of papillary thyroid cancer. Methods: The molecular genetic profile (expression levels of 34 different markers and BRAF mutation) was studied for 108 cytology specimens collected by fine-needle aspiration biopsy in patients with PTC having different clinical manifestations. Results: Statistically significant differences with adjustment for multiple comparisons (p &lt; 0.0015) for clinically aggressive variants of PTC were obtained for four markers: miRNA-146b, miRNA-221, FN1, and CDKN2A. Weak statistical correlation (0.0015&lt; р&lt;0.05) was observed for miRNA-31, -375, -551b, -148b, -125b, mtDNA, CITED1, TPO, HMGA2, CLU, NIS, SERPINA1, TFF3, and TMPRSS4. Conclusions: The recurrence risk of papillary thyroid carcinoma can be preoperatively predicted using miRNA-221, the fibronectin and cyclin-dependent kinase inhibitor 2A genes.

By introducing environmental mediator, for avoiding randomness in selecting indicators and subjectivity in deciding interaction path coefficients to reveal interaction mechanism among forest industry, ecology and environmental capacity, structural Pressure–State–Impact–Response (PSIR) and quantitative Structural Equation Modeling (SEM) are utilized with data on thirty–one provinces of China. We can find that: (i) forest industry has a negative influence on ecology, whereas ecology has a positive influence on industry; (ii) the destructive influence that industry has on ecology is much greater than the positive effect ecology has on industry; and (iii) environmental capacity plays a partial mediating role between industry and ecology. According to these results we can conclude that: (i) forest industry and ecology are not in a symbiotic relationship and have not reached a level of ecological security; (ii) the interaction between industry and ecology is in a period of transition from antagonistic to beneficial; and (iii) industry dominates ecology. However, we prospect the following advice: (i) methods of forest industry should be changed; (ii) new modes of industrial integration and circular economy should be developed; and (iii) the ability of the environment to sustain itself should be enhanced. The level of forest ecological security to discuss the symbiotic mechanism of industry and ecology will propose to be measured in future.

Our aim is at three feels: i) study safe haven properties of sectoral CDS; ii) study hedging effectiveness and measure the diversification benefits of introducing them in both Conventional and Islamic stock markets portfolios and iii) compare these results with VSTOXX, Gold and Bitcoin indices. To do this, we estimate time varying hedge ratio using (A)DCC and GOGARCH models and then deduce hedging effectiveness.. We follow the same methodology for each sub-period and each refit to test the effect of bubble crypto currency and COVID-19 pandemic on hedging effectiveness. Empirical results show the superiority of industrial CDS sectoral index to hedge both conventional and Islamic stock markets whether long or short term despite that their performances were reduced slightly during the second and third periods. VSTOXX and Others sectoral CDS indices offers Hedging performances that are generally better than Bitcoin and gold.

Despite being stored at 113 K and atmospheric pressure, LNG cold potential is not exploited to reduce green ships’ energy needs. An innovative system based on three Organic Ranking Cycles integrated into the regasification equipment is proposed to produce additional power and recover cooling energy from condensers. A first-law analysis identified ethylene and ethane as suitable working fluids for the first and the second ORC making available freshwater and ice. Propane, ammonia and propylene could be arbitrarily employed in the third ORC for air-conditioning. An environmental analysis that combines exergy efficiency, ecological indices and hazard aspects for marine environment and ship’s passengers, indicated propylene as safer and more environmentally friendly. The exergy analysis confirms more than 20% of the LNG potential can be recovered from every cycle to produce a net clean power of 76 kW, whereas 270 kW can be saved by recovering condensers' cooling power to satisfy some ship needs. Assuming the sailing mode, a limitation of 162 kg in LNG consumptions was determined, avoiding the emission of 1584 kg of CO2 per day. Marine thermal pollution is reduced by 3.5 times by recovering the working fluids' condensation heat for the LNG pre-heating.

Big Data and blockchain technology are coming together to revolutionize how decisions are made in a decentralized way across various industries. This review looks at how these technologies, along with distributed systems, can improve data security, transparency, and real-time processing, making decision-making more efficient and informed. The integration enhances data security with unchangeable records, increases transparency and traceability, and supports real-time data analysis. However, there are challenges to overcome, including scalability, data privacy, interoperability, regulatory compliance, and high costs. By examining case studies such as Estonia's healthcare system, IBM and Walmart's Food Trust, and the Brooklyn Microgrid project, we explore the practical applications and benefits of combining Big Data with blockchain. Despite these hurdles, the review finds that the ongoing advancements and innovative solutions in these technologies offer significant promise. They are set to drive the adoption and effectiveness of decentralized decision-making, ultimately leading to better efficiency and outcomes across multiple sectors.

Background. The Stanford Health Assessment Questionnaire-Disability Index (HAQ) is widely used to measure functional ability in persons with Rheumatoid Arthritis (RA). The instrument was developed with limited involvement from persons with RA, and their perception of the instrument has not been studied in depth. The aim of this study was to explore how persons with RA experience the use of the HAQ in care. Methods. Forty persons with RA were purposefully recruited to participate in semi-structured interviews. The interviews were then analyzed qualitatively using thematic analysis. Results. The participants questioned the relevance of the HAQ but nevertheless experienced that the instrument had a profound effect on their understanding of health and how care is delivered. The analysis resulted in three themes: Problems with individual items, meaning of the summative score, and effects on care and health perceptions. Conclusions. To make the HAQ relevant to persons with RA, it needs to be revised or to include an option to select items most meaningful to the respondent. To ensure relevance, the HAQ update should preferably be co-created by researchers, clinicians and persons with RA.

Recycling waste products is an environmental-friendly activity that can bring benefits to accompany, saving manufacturing costs and improving economic efficiency. For the beer industry, recycling bottles can reduce manufacturing costs and reduce the industry's carbon footprint. This paper presents a model for a multi-objective collection-distribution center location and allocation problem in a closed loop supply chain for the beer industry, in which the objective is to minimize total costs and transportation pollution. Uncertainties in the form of randomness and fuzziness are jointly handled in this paper to ensure a more practical problem solution, for which returned bottle sand unusable bottles are considered fuzzy random variables. A heuristic algorithm based on priority-based global-local-neighbor particle swarm optimization (pb-glnPSO) is applied to ensure reliable solutions for this NP-hard problem. A case study on a beer operation company is conducted to illustrate the application of the proposed model and demonstrate the priority-based global-local-neighbor particle swarm optimization.

The wellness economy has developed rapidly recently, particularly in wellness tourism. Wellness tourism transforms sustainable strategy through the availability of extended multi-actor engagement in service innovation to further the tourism experience. Therefore, when operating a wellness tourism destination, it is necessary to encourage multi-actor engagement in service innovation to achieve sustainable development. This paper introduces a mixed research method with the SWOT-AHP-QSPM, as it qualitatively analyzes the advantages, disadvantages, opportunities, and threats, constructs an evaluation index system, conducts quantitative analysis using the analytic hierarchy process, determines the index weight and weighted score, and calculate the sustainable development strategy, which is appropriate for wellness development of Chongqing Tea Mountain and Bamboo Forest National Forest Park. Purposive field surveys and personal interviews were conducted in Chongqing forest tourism destinations, involving 356 effective respondents. The research reveals that multi-actor engagement significantly enhances sustainable development. These findings bridge service innovation knowledge gaps and provide valuable insights for forest tourism destination management and sustainable policy strategies to elevate multi-actor engagement in forest sites.

Gross strap muscle invasion (gSMI) in patients with differentiated thyroid cancer (DTC) was defined as high-risk recurrent group in the 2015 American Thyroid Association guidelines. However, controversy persists because several studies suggested gSMI had little effect on disease outcome. Herein, a systematic review and meta-analysis was conducted to investigate impact of gSMI on outcome of DTC. Methods: A systematic search of electronic databases (PubMed, EMBASE, Cochrane Library, and MEDLINE) for studies published until February 2020 was performed. Case-control studies and randomized controlled trials that studied the impact of gSMI on outcome of DTC were included. Results: Six studies (all retrospective studies) involving 13639 patients met final inclusion criteria. Compared with no extrathyroidal extension (ETE), patients with gSMI were associated with increased risk of recurrence (P=0.0004,OR, 1.46; 95% CI: 1.18 to 1.80) and lymph node metastasis (LNM) (P<0.00001,OR 4.19;95% CI. 2.53 to 6.96). For mortality (P=0.34,OR 1.47;95% CI:0.67 to 3.25), ten-year disease-specific survival (P=0.80, OR 0.91;95% CI:0.44 to 1.88) and distant metastasis (DM) (P=0.21, OR 2.94;95% CI. 0.54 to 15.93), there was no significant difference between gSMI and no ETE group. In contrast with maximal ETE, patients with gSMI were associated with decreased risk of recurrence (P<0.0001,OR, 0.58; 95% CI: 0.44 to 0.76) , mortality (P=0.0003,OR 0.20;95% CI:0.08 to 0.48), LNM (P=0.0003,OR 0.64;95% CI. 0.50 to 0.81) and DM (P=0.0009,OR 0.28;95% CI. 0.13 to 0.59). Conclusions: DTC patients with gSMI had a higher risk of recurrence and LNM than those without ETE. However, in contrast with maximal ETE, a much better prognosis was observed in DTC patients with only gSMI. The findings of our meta-analysis provide supportive evidence for the validity of the T category changes in the 8th edition American Joint Committee on Cancer system. The actual impact of gSMI should be re-evaluated and revised in the recurrent risk stratification system in the future.

In the extended malfatti problem, the numbers of circles in the triangle are triangle numbers, because the tangency properties among the internal circles and 3 sides of the triangle have special type of structure. That is, the corner circle tangent to two sides of the triangle and two boundary circles, the boundary circles tangent to one side of the triangle and 4 other circles, and the inner circles always tangent to 6 other circles. The circles we find in extended general Malfatti’s problem has the property that the smallest radius and the largest radius for the circle has big difference. In this paper, we proposed algorithms to solve the problem that the tangency properties among circles and sides of triangle is not fixed, so that the number of circles in the triangle is not necessary a triangle numbers. The purpose of this change is try to find the radii of the circles in the triangle is within a small range.

It has been empirically observed that the upper tail of the firm size distribution follows either the Pareto distribution or the Zipf distribution, with both patterns being explained by Gibrat’s law (Gabaix, 1999). This article analyzed firm revenue data from China, spanning from 2005 to 2013, to examine the whole range of the firm size distribution. Our empirical analysis revealed that firm revenue data over these years is well fitted by a three-parameter generalized Pareto distribution, with the fitted parameters indicating a dichotomy: The size distribution of large-sized firms, namely the upper tail, is asymptotically characterized by a Pareto distribution or a Zipf distribution, whereas the size distribution of smaller and medium-sized firms is approximated by an exponential distribution. This finding suggests that Gibrat’s law should be extended to account for the emergence of a generalized Pareto distribution.

Driving factors of smart city construction are exploratively studied by grounded theory method based on text sources from journal papers in SCI and CSSCI databases. Initial scale of driving factors about smart city construction is obtained on the basis of above analyses. This paper modifies measuring items of the initial scale with a small sample pretest and reliability test, then forms final items by exploratory factor analysis. According to the above scale, questionnaires are designed to obtain empirical data, and confirmatory factor analysis is used to verify further validity and reliability of the scale. The results show that driving factors of smart city construction include three main dimensions: problem-oriented factors, business- or technology-driven factors and endogenous development requirements.

Natural gas hydrate, also known as combustible ice and mainly composed of methane, it is identified as the potential clean energy in the 21th century. Due to its large reserves, gas hydrate can ease problems caused by energy resource shortage and has gained attention around the world. In this paper, we focus on the exploration and development of gas hydrate as well as discussing its status and future development trend in China and abroad, then we analyze its opportunities and challenges in China from four aspects: resource, technology, economy and police with five forces model and PEST method. The results show, China has abundance gas hydrate resource; however the backward technologies and inadequate investment has seriously hindered the future development of gas hydrate, so China should establish relevant cooperation framework and intuitional arrangement to attract more investment as well as breaking through technical difficulties to make gas hydrate commercialization as soon as possible.

1) Background: When women receive a diagnosis of a gynecologic malignancy, they can have questions about their diagnosis or treatment that can result in voice queries to virtual assistants. Recent advancement in artificial intelligence (AI) has transformed the landscape of medical information accessibility. The Google virtual assistant (VA) outperformed Siri, Alexa, and Cortana in voice queries presented prior to the explosive implementation of AI in early 2023. The efforts presented here focus on determining if advances in AI in the last 12 months improved the accuracy of Google VA responses related to gynecologic oncology. (2) Methods: Previous questions were utilized to form a common basis for queries prior to 2023 and responses in 2024. Correct answers were obtained from the UpToDate medical resource. Responses related to gynecologic oncology were obtained using Google VA, as well as the generative AI chatbots Google Bard/Gemini and Microsoft Bing-Copilot. (3) Results: The AI narrative responses varied in length and positioning of answers within the response. Google Bard/Gemini achieved an 87.5% accuracy rate, while Microsoft Bing-Copilot reached 83.3%. In contrast, the Google VA’s accuracy in audible responses improved from 18% prior to 2023 to 63% in 2024. (4) Conclusion: While the accuracy of the Google VA has improved in the last year, it underperformed Google Bard/Gemini and Microsoft Bing-Copilot so that there is considerable room for further improved accuracy.

The impact of the agriculture net carbon effect is crucial for climate change mitigation, yet research on this topic in China is currently insufficient. In this study, the carbon balance ratio (CBR) is used to characterise the net carbon effect of agriculture, and the spatial Durbin model and threshold regression model were used to empirically analyse the CBR with a sample of 30 provincial-level regions in China from 2004 to 2019. The aim was to investigate the mechanism of the influence of the land management scale (SCALE) of farming on the CBR. The results of the study indicate that national farming generally has a net sink effect, with large changes in interannual fluctuations; the expansion of SCALE has an obvious role in increasing sinks and reducing emissions, and has a positive spatial spillover effect on CBR, with significant spatial heterogeneity. Furthermore, as the SCALE expands, the direction of the influence of rural residents’ income and education level on CBR changes in the opposite direction, showing a significant non-linear relationship characteristic. However, in most areas, the SCALE threshold has not yet been reached, suggesting that the improvement in education levels can still offset the negative impact of economic income growth in the short term. The study recommends paying attention to the role of farmers’ human capital, changing production methods, and implementing carbon peaking and carbon neutrality goals to enhance the net sink effect of the farming industry, which would be achieved by increasing land management scale.

Brand trust holds significant importance in the Mongolian cashmere industry. This study examines the primary predictors of customer brand trust among Mongolian cashmere users. Our research includes a survey with 800 participants and 20 individual interviews conducted among both Mongolian cashmere users and non-users. We utilized an online platform to reach participants, employing convenience sampling. The study investigates the relationship between various factors and brand trust within the context of Mongolian cashmere brands. Through a combination of in-dividual interviews and statistical analysis, we test six hypotheses. The findings indicate that higher brand quality, a strong reputation, greater transparency, effective issue resolution, commitment to environmental and social responsibility, and pre-purchase research on such commitments positively impact brand trust. Key insights gleaned from the interviews emphasize the importance of quality, reputation, transparency, customer service, and environmental responsibility in shaping consumer trust. These results offer valuable implications for cashmere brands aiming to bolster consumer trust and foster loyalty.

Abstract. Introduction: BMD study gives partial information on bone health in patients with TSH suppression therapy due to Differentiated Thyroid Cancer (DTC). TBS, a new parameter of bone microarchitecture is propose for bone quality study. This study analyze their long-term use in patients with DTC. Methods: BMD was measured by DXA and TBS with iNsigth software in 145 postmenopausal DTC patients. Vertebral Fractures (VFs) with a semi-quantitative x-ray method. Results: BMD at the end study was not different from initial. TBS decreased from 1.35±0.1 to 1.27±0.1 (p=0.002). PTH, Osteocalcin, and BAP were increased, suggesting increased bone remodeling. There was an increase in osteoporosis and osteopenia (40.6% and 16.5% to 46.6% and 18.6%); 31% had partially degraded and 15.1% degraded TBS changed to 48,9% and 24,8% at the end study. VFs in 30 patients, was not different in age, BMI, calcium and alcohol ingestion, smoking, radioiodine, or thyroid parameters vs. without VFs. Odds ratio for VFs increased with osteopenia (OR 2.63). Combination of TBS plus TBS did not improve discrimination. Conclusions: TBS was lowered while BMD did not differ. Percentage of osteoporosis and osteopenia and of partially degraded and degraded TBS was higher at the end study. Predominant discordance rate was found in partially degraded microarchitecture, in which the proportion of osteopenia was higher than normal or osteoporotic patients. AUC of TBS plus BMD did not improve discrimination. TBS, radioactive iodine, and sedentary lifestyle were the main differential data for patients with DTC and VFs.

The PAX8/PPARγ rearrangement, producing the PAX8–PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble docking-based compound screening. Specifically, we investigated which pocket structure should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand binding pocket on the PPARγ side of the PPFP is common to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to PPFP for 97 drug or drug-like compounds with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ, registered in the DrugBank database. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics-Poisson–Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.

Background: In high-risk breast cancer patients with skin infiltration the administration of a uniform dose to superficial tissues is fundamental in order to reduce local skin relapse. A personalized bolus may prevent the potential standard bolus’ inadequate dose distribution due to air gaps between the bolus and the skin. In this pilot study, we introduced in clinical practice the use of a personalized 3D printed bolus filled with ultrasound transmission gel. Methods: Seven patients undergoing radiotherapy after mastectomy were selected. 3D printed bolus dosimetric assessment was performed with MOSFET dosimeters on an anthropomorphic phantom and subsequently on three selected cases with increasing bolus shape irregularity. Acute/late toxicity and local control was assessed. Results: Overall, for the clinical cases the percentage median difference between measured and calculated doses was -2.7% (-7.0%÷4.9%). Median follow-up was 21 months. After two years, one patient showed G2 pain, one patient manifested G1 telangiectasia, one patient showed G1 hyperpigmentation, and two patients had no relevant toxicity. Conclusions: Personalized 3D-printed bolus filled with ultrasound gel may easily reproduce the standard bolus’ consistency providing an accurate coverage of the target area with tolerable acute/late toxicity grades. This is a pilot study and further investigations are needed.

The sustainable development of resource-based cities has long been a focal point for both governmental policies and academic research. A wealth of academic literature identifies the 'resource curse' as a critical barrier to sustainable development in these urban areas. Despite extensive studies, a consensus on effective strategies to circumvent or resolve this challenge remains elusive. Recent empirical data reveals a noticeable pattern of economic growth differentiation in China's resource-based cities. Why do some resource-based cities experience economic decline while others achieve sustainable economic growth? Therefore, this paper analyzes the reasons for the divergence of economic growth in resource cities from the perspective of heterogeneity. The results of the study show that the phenomenon of the resource curse is conditional, and the heterogeneity of demo-graphic changes, geographic location and institutional environment has a significant impact on the economic growth of resource cities. These factors are investigated to elucidate the observed diversification and heterogeneity in the economic growth of resource-based cities. Building upon this analysis, the paper proposes a framework for differentiated sustainable development pathways tailored to the unique contexts of these cities. This approach not only contributes to the current understanding of the 'resource curse' but also offers novel insights for future research aiming to adopt a more nuanced and context-specific perspective in examining sustainable urban development.

Expression of miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA. In addition, expression of tumor suppressor gene RECK is associated with miR-21 overexpression in high-grade cervical lesions. In the present study we analyze the role of miR-21 in RECK gene regulation in cervical cancer cells. To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression using siRNAs. We analyzed the expression of miR-21 and RECK, as well as functional effects on cell proliferation and migration. We found that in cervical cancer cells there was an inverse correlation between miR-21 expression and RECK mRNA and protein expression. SiRNAs to miR-21 increased luciferase reporter activity in construct plasmids containing the RECK-3′-UTR microRNA response elements MRE21-1, MRE21-2, and MRE21-3. The role of miR-21 in cell proliferation was also analyzed and cancer cells transfected with siRNAs exhibited a markedly reduced cell proliferation and migration. Our findings indicate that miR-21 post-transcriptionally down-regulates the expression of RECK to promote cell proliferation and cell migration inhibition in cervical cancer cell survival. Therefore, miR-21 and RECK may be potential therapeutic targets in gene therapy for cervical cancer.

Background: Several trace minerals have been shown to be associated with thyroid cancer. However, there is a paucity of data on the characteristics of thyroid nodules in different mineral rich regions of the Democratic Republic of Congo (DRC). The objective of this study is to establish the spectrum of thyroid nodules in different regions of the most mineral wealthy country in the world. Method: We conducted a cross-sectional study, performing descriptive statistics and logistic regression with a p value < 0.05 deemed of statistical significance. We enrolled 529 patients diagnosed with thyroid nodules between 2005 and 2019 in two of the richest provinces in minerals (Katanga and South Kivu) and the capital city, Kinshasa. Results: The mean age was 44.2±14.6 years with a female predominance, with a female to male ratio of 5.4. 66.5% of patients had a family history of thyroid disease. 74 patients had simple nodules, whereas 455 had multiple nodules. 87.7% of patients with nodules were euthyroid. The nodules mostly presented a solid structure (72.2%), hypoechogenicity (84.5%), a macronodule (59.8%), calcification (14.4%) and lymphadenopathy (15.5%). 22.3% of these nodules had a malignant character. The independent factors associated with this malignancy were age ≥60 years (aOR=2.81), Katanga as province of origin (aOR=8.19), solid echostructure (aOR=7.69), hypoechogenicity (aOR=14.19), macronodule (aOR=9.13), calcification (aOR=2.6) and the presence of adenopathy (aOR=6.94). Conclusion: By the way of this first of its kind study, we demonstrated that thyroid nodules were more likely to be malignant if found in patients originating from mineral rich region of Katanga. This high frequency of malignancy in mineral rich regions requires measures aimed at early detection in this population, lower threshold for suspicion of malignancy and adequate training of doctors involved in the management of these patients. This study paves the way for future, more extensive and well-funded studies to better understand the relationship of heavy metals and thyroid cancer incidence in the richest country in heavy metals in the world.

Under the development mode of deep blending of emerging technologies, major projects are important for enhancing China's comprehensive national strength and independent innovation capability. Based on the social benefits of major projects, and considering the influence of reputation factors, an evolutionary game model composed of a general contractor and subcontractor of major projects is established. This paper studies the influence of various factors including the income distribution coefficient of collaborative innovation, and MATLAB simulation software is analyzed the influence of factors on an evolutionary path. The results show that a reasonable income distribution coefficient can promote the game behavior of both parties to the direction of active collaborative innovation; The reduction of innovation cost and the improvement of spillover technology absorption capacity can make innovation subjects tend to choose active collaborative innovation strategies. In addition, reputation loss above a specific threshold can effectively inhibit free-riding behavior and encourage innovation subjects to choose active collaborative innovation strategies. The research results provide reference for promoting major projects' technology innovation.

The intelligent elderly care model places new demands on the skills of aging caregivers. The identification and development of forward-thinking, high-potential nursing talent is essential for advancing the intelligent elderly care sector. Multi-benchmarking selection and competitive analysis is used to evaluate and identify nursing personnel in the rehabilitation treatment center of a hospital in Hefei City. Using proxy evaluation and democratic evaluation model, three types of benchmarks such as single item benchmark, individual benchmark and group benchmark were identified and selected, and the professional nursing team was constructed based on the evaluation results. Different from the traditional other-directed evaluation, multi-benchmarking selection and competitive analysis is self-directed evaluation, this method is more conducive to the identification of high-potential and digital nursing talents by intelligent elderly service organizations, and facilitates the formation of professional nursing teams with complementary strengths and cross-fertilization, so as to satisfy the diversified and multi-level needs of the elderly for intelligent elderly services.

Aortic valve stenosis and malignancy frequently coexist and share the same risk factors as atherosclerotic disease. Data reporting the prognosis of patients with severe aortic stenosis and cancer are limited. Tailoring the correct and most optimal care for cancer patients with severe aortic stenosis is complex. Cancer patients may be further disadvantaged by aortic stenosis if it interferes with their treatment by increasing the risk associated with oncologic surgery and compounding the risks associated with cardiotoxicity and heart failure (HF). Nowadays, several therapeutic options are available for aortic valve stenosis (surgical valve replacement , transcatheter valve implantation, balloon valvuloplasty, or medical therapy), but in presence of malignancy, the use of one of these versus the others should be decided on a case-by-case approach, depending on cancer stage and associated treatment, expected outcome, comorbidities and after an accurate physical examination and Doppler-echocardiography which are the key tools for diagnosing and evaluating aortic stenosis. The current review considers the available data on the association between aortic stenosis and cancer, and therapeutic options.

In the present research, it has been tried to use the applied research bases in the field of business management with marketing orientation. Since there were wide and diverse spectrums in the field of economic activities in Isfahan province and Isfahan city, the model of economic sectors was used to categorize these activities. In this regard, the specific goals of the research in all five sectors of the model of economic sectors, drawing and prioritizing the components (indices) of the 7P marketing mix model in each of these economic sectors by the related individuals and members of subgroups of guilds and non-governmental organizations in Isfahan province, have been formed, specified and determined. Collecting data for processing and answer the question of this research, after designing a questionnaire in accordance with the AHP model standard, by spending a period of 2 months from September 2022 and ended in November 2022 , from the statistical population has been done.

Against the backdrop of the European Union's commitment to achieve climate neutrality by 2050, efforts to improve energy efficiency are being intensified. The manufacturing industry is a key focal point of these endeavors due to its high final electrical energy demand, while simultaneously facing a growing shortage of skilled workers crucial for meeting established goals. Expert systems (ESs) offer the chance to overcome this challenge by automatically identifying potential energy efficiency improvements and thereby playing a significant role in reducing electricity consumption. This paper systematically reviews state-of-the-art approaches of ESs aimed at improving energy efficiency in industry, with a focus on manufacturing. The literature search yields 1668 results, of which 62 articles published between 1987 and 2024 are analyzed in depth. These publications are classified according to the system boundary, manufacturing type, application perspective, application purpose, ES type, and industry. Furthermore, we examine the structure, implementation, utilization, and development of ESs in this context. Through this analysis, the review reveals research gaps, pointing toward promising topics for future research.

Graph visualization has evolved significantly over time, offering various methods to effectively represent complex data structures. This study introduces a novel force-directed algorithm for 3D data visualization, specifically tailored for commonly used datasets in linked data visualization. Leveraging the power of graph theory and methods, the algorithm aims to address the challenge of creating visually appealing and easily interpretable visualizations, which often necessitate advanced user interaction. By utilizing 3D space and the Unity Engine, the research successfully visualizes data and develops interactive visualizations, overcoming limitations of basic force-directed implementations. The main contribution of presented research is in the force-directed algorithm with springs and controlled placement as a visualization technique that combines the use of springs and attractive forces to stabilize a graph in a 3D environment. The combination of these two techniques also helps prevent the formation of a single large cluster within the graph, enhancing the overall visualization quality.

The increasing availability of longitudinal data (repeated numerical observations of same units at different times) requires the development of flexible techniques to automatically detect common errors in such data. Besides obvious and easily identifiable cases, such as missing or out-of-range data, large longitudinal dataset often present problems not easily traceable by the techniques used for generic datasets. In particular, elusive and baffling problems are i) inversion of one or more values from one unit to another; ii) anomalous jumps in the series of values, iii) errors in the timing of the values due to a recalculation operated by the data providers to compensate previous errors. This work proposes a statistical-mathematical approach based on a system of indicators that is able to capture the complexity of the described problems by working at the formal level, regardless of the specific meaning of the data. The proposed approach identifies suspect erroneous data and is applicable in a variety of contexts. We implement this approach in a relevant database of European Higher Education institutions (ETER) by analyzing Total academic staff, that is one of the most important variables, used in empirical analysis as proxy of size and also considered by policy makers at European level.