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).

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.

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.

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.

Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve therapeutic outcomes. Conventional treatments, including surgery, chemotherapy, and radiation, have demonstrated limitations in achieving sustained responses. Therefore, the explora-tion of novel approaches encompasses a range of interventions that show promise in enhancing outcomes for patients with lung cancer, particularly those facing advanced or refractory cases. These groundbreaking interventions hold the potential to overcome cancer resistance and offer personalized solutions. Despite the rapid evolution of emerging lung cancer therapies, persistent challenges such as resistance, toxicity, and patient selection underscore the need for continued development. Consequently, the landscape of lung cancer therapy is transforming with the in-troduction of precision medicine, immunotherapy, and innovative therapeutic modalities. Addi-tionally, a multifaceted approach involving combination therapies through the integration of tar-geted agents, immunotherapies, or traditional cytotoxic treatments addresses the heterogeneity of lung cancer while minimizing adverse effects. This review provides a brief overview of the latest emerging therapies that are reshaping the landscape of lung cancer treatment. As these novel treatments progress through clinical trials and integrate into standard care, the potential for more effective, targeted, and personalized lung cancer therapies comes into focus, instilling renewed hope for patients facing challenging diagnoses.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

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.

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.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

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.

Intratumoral heterogeneity can exist along multiple axes: Cancer Stem Cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states and a spectrum of epithelial-hybrid-mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple “attractors”. These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.

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.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and inherited vascular disorder, characterized by the development of arteriovenous malformations (AVMs) in various organs and telangiectasia (small AVM) in the mucocutaneous. The majority of HHT patients have haploinsufficiency of genes involved in the transforming growth factor-beta (TGFβ) signaling pathway, including endoglin (ENG), activin receptor-like kinase 1 (ALK1, also known as ACVRL1), or SMAD4. Active angiogenesis is also required for telangiectasia and AVM development. Anti-angiogenic strategies have been tested in patients and animal models extensively. However, the exact mechanisms for telangiectasia and AVM development remain unclear. In this review, we discuss recent advances in identifying disease mechanisms, and potential therapeutic targets.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we will discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible than others to develop due to ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

The oncologic disease is a big global health issue that causes thousands of deaths annually, and it has a significant impact in the life quality of patients. Prostate cancer (PCa) is the second most diagnosed cancer and the fourth leading cause of cancer-related death in men in the western world. Delineation of pathogenetic pathways and key driver molecular alterations involved in PCa development has provided a roadmap for the evaluation of biomarkers in predicting disease outcome and to identify potential therapeutic targets. Chemotherapeutic agents introduced from the 1990s include the taxanes (paclitaxel, docetaxel and cabazitaxel), which are the most anticancer drugs used for PCa treatment. This review presents the current knowledge about the onset and development of PCa, state-of-art on the use of taxane-based therapy, and their combination with targeting different transmembrane oncoproteins in PCa. The silencing of some transmembrane proteins can improve taxane sensitivity, and therefore, may be a mechanism to improve the ef-fectiveness of these drugs in PCa treatment. This combined therapy needs to be explored as po-tential therapeutic agent for reducing cell proliferation, migration, and invasiveness in PCa.

The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2, are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA) -, gastrin-releasing peptide receptor (GRPR) -, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

Human papillomavirus (HPV) uses the cellular trafficking machinery to reach the cell nucleus and initiate a successful infection. The HPV capsid consists of two proteins: L1 (the major capsid protein) and L2 (minor capsid protein), and L2 is known to be responsible for trafficking the viral genome to the nucleus. From previous studies, we know that many cellular proteins interact with L2 and are involved in the trafficking process at different stages of the infectious entry process. To further investigate how HPV-16 achieves successful viral entry, we have performed a mass spectrometry analysis to identify novel interacting proteins that associate with incoming HPV-16 virions. We show that HPV-16 pseudovirions interact with a group of cellular cargo proteins (COPI), and here we confirm that this is mediated by the direct binding of L2, but not L1, to the COPB1 subunit. We also show that the ability of L2 to interact with COPB1 is conserved in both low- and high-risk HPV types. Furthermore, we also show that the interaction is essential for successful infection entry of multiple HPV types, thereby identifying a novel constituent of the infectious entry pathway of the HPV.

Esophageal cancer is a formidable challenge in the realm of cancer treatment. Conventional methods such as surgery, chemotherapy, and immunotherapy have demonstrated limited success rates in managing this disease. In response, targeted drug therapies have emerged as a promising strategy to improve outcomes for patients. These therapies aim to disrupt specific pathways involved in the growth and development of esophageal cancer cells. This review explores various drugs used to target specific pathways, including cetuximab and monoclonal antibodies (gefitinib) that target the epidermal growth factor receptor (EGFR), trastuzumab that targets human epidermal growth factor receptor 2 (HER-2), drugs targeting the vascular endothelial growth factor receptor (VEGFR), mTOR inhibitors, and cMET inhibitors. Additionally, the article discusses the impact of drug resistance on the effectiveness of these therapies, highlighting factors such as cancer stem cells, cancer-associated fibroblasts, immune-inflammatory cells, cytokines, hypoxia, and growth factors. While drug targeting approaches do not provide a complete cure for esophageal cancer due to drug resistance and associated side effects, they offer potential for improving patient survival rates.

Melanoma is the most aggressive form of skin cancer. In the advanced stage of development it is resistant to currently available therapeutic modalities. Increased invasiveness and metastatic potential depend on a number of proteins involved in various signal transduction pathways. Hippo signaling plays an important role in malignant transformation. Dysfunctions of the Hippo pathway initiate the expression of tumor growth factors and is associated with tumor growth and metastasis formation. This review summarizes the recent achievements in studying the role of the Hippo pathway in melanoma pathogenesis and points to the potential specific targets for anti-melanoma therapy.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S together with cisplatin quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed following identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells.

Accumulating evidences demonstrate that the host genome's epigenetic modificationsare essential for living organisms to adapt extreme conditions.DNA methylation, covalent modifications of histone, andinter-association of non-coding RNAs facilitate the cellular manifestation ofepigenetic changes in the genome. Out of various factors involved in the epigenetic programming of the host, miRNA (microRNA) and LncRNA (Long non-coding RNA) are new generationnon-coding molecules that influence a variety of cellular processes like immunity, cellular differentiation, and tumor development. During tumor development, temporal changes in miRNA/LncRNA rheostat influence sterile inflammatory responses accompanied by the changes in the carcinogenic signalling in the host. At the cellular level, this is manifested by the up-regulation of Inflammasome and inflammatory pathways, which promotes cancer-related inflammation. In view of this, we discuss the potential of lncRNA and miRNA directed interventions in regulating inflammation and tumor development in the host.

The Infierno glacier is located in Aragon (Spain), Pyrenees mountain range, southern slope, the only one in this country that still preserves white glaciers. These are the southernmost glaciers in Europe and are currently in rapid regression. The work analyzes the evolution of the glacier between 2016 and 2022 (taking as "year zero" or starting point, 2015). In addition to the observations on the glacier itself, the variables (precipitation, temperatures, snow volumes and thicknesses) that allow understanding this evolution are studied. The results offer strong regression, with thickness losses in that period of 4.6 m and retreat of its front of 14.9 m. The evolution has frequent trend changes, linked to the interannual climatic irregularity characteristic of this mountain range. The main explanatory factor is the thermal increase. The thermal anomalies with respect to the average reference values have increased, in this period, +0.55° C. The year 2022 has been particularly warm and has recorded the greatest regression of the glacier (between May and August, the thermal anomalies were between +4° C and +2° C). Regarding precipitations, they have irregular tendencies and show a decreasing trend (-9% in the same period of time).

Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning based on deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and we discuss the learning mechanism of MetGen. Additionally, we demonstrate MetGen's interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironment, such as immune response and the metastasis process, which potentially fosters a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the results of traditional immunosuppressive therapy are disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients would eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and there is increasing evidence that gut microbiota and bile acids play an important role in cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Understanding the gut microbiota-bile acid network and corresponding immune functions in PBC provides a new perspective for its treatment strategies. Therefore, we summarize the latest advancements in research of gut microbiota and bile acids in PBC and, for the first time, explore the potential of immune factors related to them as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.

Cancer remains one of the main causes of death in the world due to its increasing incidence and treatment difficulties. Although several progresses have been done in this field, innovative approaches are needed to reduce tumor incidence, progression and spreading. In particular, the development of cancer vaccines is currently ongoing like both preventive and therapeutic strategy. This concept is not new, but few vaccines have been approved in oncology. Antigen-based vaccination emerges as a promising strategy, leveraging specific tumor antigens to activate the immune system response. However, challenges persist in finding suitable delivery systems and antigen preparation methods. Exosomes (EXs) are highly heterogeneous bilayered vesicles which carry several molecule types in the extracellular space. The peculiarity is that they may be released from different cells and may be able to induce a direct or indirect stimulation of immune system. In particular, EX-based vaccines may cause anti-tumor immune attack or produce memory cells recognizing cancer antigens and inhibit disease appearance. This review delves into EXs composition, biogenesis, and immune-modulating properties exploring their role as tool for prevention and therapy in solid tumors. Finally, here we describe future research directions to optimize vaccine efficacy and realize the full potential of EX-based cancer immunotherapy.

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.

Introduction: Signet-ring cells are typically associated with mucin-secreting epithelium thus most commonly found in a gastrointestinal tract, however not exclusively. Primary signet ring cell carcinoma of the prostate is a rare and poorly differentiated, aggressive acinar adenocarcinoma variant with a grim prognosis. Clinical case: In June of 2023 a 54-year-old Caucasian male came to the hospital complaining of lower urinary tract obstructive symptoms with occasional macrohematuria, non-specific body aches, and shortness of breath. A prostate specimen obtained in transurethral resection of the prostate was sent for histopathological examination. After a series of extraprostatic diagnostic workups including fibrogastroduodenoscopy, colonoscopy computed tomography imaging, and immunohistochemical studies, the patient was diagnosed with primary prostatic signet-ring cell adenocarcinoma st. IV. Unfortunately, the patient with the disease this advanced, PE, and third-degree thrombocytopenia was not a candidate for chemotherapy and died of cardiopulmonary insufficiency later that week. Discussion: Prostatic signet-ring cell carcinoma accounts for 0.02% of all prostate adenocarcinoma cases. Due to its nature and epidemiology, a diligent extraprostatic investigation has to be carried out. The disease often presents with unremarkable clinical symptoms and variable serum prostate-specific antigen results which may contribute to its late diagnosis which together with inconsistent immunohistochemical findings and unpredictable response to hormonal treatment pose both diagnostic and therapeutic challenges that negatively affect the prognosis. Conclusion: The study highlights the importance of a multidisciplinary approach and the need for diagnostic and therapeutic consensus within the research community in search of the primary site of the disease which may positively influence the prognosis.

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Optical genome mapping (OGM) is an emerging technology that enables genome-wide detection of all classes of SVs at a high resolution and sensitivity. Identification of cryptic SVs leading to gene disruption or predicted novel gene fusions could be important drivers for cancer development and/or portend a prognostic relevance, which could be used to modify the treatment plan. A cohort of 106 consented cases that had a successful OGM analysis performed were included in the study. Demographic, clinical, laboratory and treatment data were collected. Routine diagnostic and prognostic testing were done on the peripheral blood and bone marrow aspirate as indicated. Additional samples of peripheral blood and/or bone marrow were sent for OGM testing. OGM led to a change in risk stratification in 17/66 (25.75%) of patients with hematological malignancies, the majority of these patients (15/66, 22.72%), having their risk stratification upgraded with a resulting change in treatment of 14 patients. This study highlights the ability of OGM to detect rare, cryptic and clinically relevant variants that potentially impact disease diagnosis, risk stratification and actionable treatment targets.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

The oncogenicity of the human cytomegalovirus (CMV) is debated to this day. In recent years, mounting evidence addresses an anti-cancer effect via T cell-mediated CMV-targeted tumor de-struction. However, the data mostly comes from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. This study examined the correlation between country-specific CMV seroprevalence (n=73) and age-standardized inci-dence rates for 34 tumors using data obtained from the International Agency for Research on Cancer of the World Health Organization. The association between CMV and cancer incidences in 10-year age increments was also analyzed. The study revealed a worldwide inverse correlation between CMV seroprevalence and incidences of 88.2% tumors. Notably, this inverse link persists for all cancers combined (Spearman’s ρ= -0.732, p= 0.001). An antithetical and significant correlation is also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, suggesting a common under-lying mechanism – CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, further in-depth investigation of host-virus interactions is warranted.

Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell – tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise, and highly accurate for the measurement of the drug and the mains metabolites. The lower limit of quantification resulted 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate respectively, was appropriate for the analysis, as demonstrated by the accuracy between 96.8% and 102.4% for plasma and 96.6-102.3% for tumor. The inter-days precision and accuracy determined on quality controls at 3 different levels were in ranges of 6.9%-7.5% and 99.3-101.0% and 0.96-1.91% and 102.3-105.8% for plasma and tumour, respectively.

Predictive biomarkers for immune checkpoint inhibitors (ICI), such as PD-L1 expression (TPS), remain limited in clinical applications. Improved novel ICI predictive biomarkers are urgently needed. We evaluated a live single-cell functional liquid biopsy cytokine profiling platform to track immunotherapy treatment response and outcomes. Peripheral blood mononuclear cell samples of healthy donors and NSCLC patients undergoing ICI-based therapies were collected longitudinally pre-/post-treatment under IRB-approved protocols. Samples were enriched for CD4+ and CD8+ T-lymphocytes and analyzed on the IsoLight platform. The single T-cells were captured in microchambers on IsoCode chips for cytokines profiling. Functional polyfunctionality data from 55,775 single cells were analyzed using the IsoSpeak software, kappa coefficient, and Kaplan-Meier survival plots. We found a significant difference between responders and non-responders in CD8+ T-cells’ changes in overall polyfunctionality and polyfunctional strength index (ΔPSI). ΔPSI score in CD8+ T-cells performed better than PD-L1 TPS and, when combined with PD-L1 TPS, strongly correlated with early ICI treatment response with a kappa coefficient of 1.0 (p=0.003). High CD4+ T-cells ΔPSI predicted a strong trend of improved PFS (3.9-fold) and OS (3-fold). In conclusion, single peripheral T-cell polyfunctionality dynamics analysis is a promising liquid biopsy profiling platform as NSCLC ICI predictive biomarker regardless of oncogene-addiction status.

Recombinant α1-microglobulin (A1M) is proposed as protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but, the radioprotecting action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 hours or 7 days. Differential protein expression was analyzed with tandem mass spectrometry. Dosimetric estimation was based on 177Lu activity in kidney. PHLDA3 was the most prominent radiation responsive protein in kidney tissue. In general, no statistically significant difference in expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation induced protein expression early after exposure, and late effects should be further studied.

(1)Background: Among new anti-angiogenetic agents being developed and everchanging guidelines indications, the question of benefits/safety ratio remains unclear. (2)Methods: we have conducted a systematic review and meta-analysis of 25 randomized controlled trials (15487 patients), evaluating overall survival – OS, progression free survival– PFS and toxicity (grade ≥3 adverse effects, type and number of all adverse effects. (3)Results: analysis showed improvement of pooled-PFS (HR 0.72, 95%CI 0.66–0.78, I2 = 77%, P<0.00001) regardless of treatment settings (first-line - HR 0.83, 95%CI 0.77-0.90, P<0.00001, recurrent cancer – HR 0.61, 95%CI 0.54-0.68, P<0.00001 or maintenance – HR 0.82, 95%CI 0.67-1.00, P=0.04) and type of anti-angiogenetic drug used (VEGF inhibitors, VEGF-R inhibitors or angiopoietin inhibitors). Improved OS was also observed (HR 0.95, 95%CI 0.91–0.99, P=0.02). OS benefits were only observed in recurrent platinum-sensitive or platinum-resistant cancers. Grade≥3 adverse effects were increased across all trials. Anti-angiogenetic therapy increased the risk of hypertension, infection, thromboembolic/ hemorrhagic events, gastro-intestinal perforations but not the risk of wound related issues, anemia or posterior leukoencephalopathy syndrome. (4)Conclusions: Although angiogenesis inhibitors improve PFS, there is little to no OS benefits. Given the high risk of severe adverse reactions a careful selection of patients is required for obtaining the best results possible.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

Androgenetic alopecia, the most common cause of hair loss affecting both men and women, is typically treated using pharmaceutical options such as minoxidil and finasteride. While these medications work for many individuals, they are not suitable options for all. To date, the only non-pharmaceutical option that the United States Food and Drug Administration has cleared as a treatment for androgenetic alopecia is low-level laser therapy (LLLT). Various clinical trials utilizing LLLT devices of various types are available. However, a myriad of other physical treatments for this form of hair loss are reported in the literature. This review evaluated the effectiveness of microneedling, pulsed-electromagnetic field (PEMF) therapy, low-level laser therapy (LLLT), fractional laser therapy, and non-ablative laser therapy for the treatment of androgenetic alopecia (AGA). It also explores the potential of multimodal treatments combining these physical therapies. LLLT has the majority of evidence in the literature as a physical therapy for androgenetic alopecia. However, other physical treatments, such as non-ablative laser treatments, and multimodal approaches, such as PEMF-LLLT, seem to have the potential to be equally or more promising and merit further exploration.

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including but not limited to imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neu-rostimulation including acupuncture. Lastly, we also touch upon the disease’s different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.

Cardiac amyloidosis is caused by amyloid fibrils that deposit in the myocardial interstitium, causing restrictive cardiomyopathy and eventually death. The electromechanical, inflammatory, and autonomic changes due to amyloid deposition result in arrhythmias. Atrial fibrillation is by far the most common arrhythmia. Rate control strategy is generally poorly tolerated due to restrictive filling physiology and heart rate dependance, favoring adoption of rhythm control strategy. Anticoagulation for stroke prophylaxis is warranted irrespective of CHA2DS2Vasc score in patients with favorable bleeding profile; data on left appendage closure devices is still insufficient. Ventricular arrhythmias are also not uncommon and the role of implantable cardioverter-defibrillator in cardiac amyloidosis is controversial. There is no evidence of improvement in outcomes when used for primary prevention in these patients. Bradyarrhythmia is most commonly associated with sudden cardiac death in cardiac amyloidosis. Pacemaker implantation can help provide symptomatic relief but does not confer mortality benefit.

New antimicrobial approaches are essential to counter antimicrobial resistance. The drug development pipeline is exhausted with emergence of resistance resulting in unsuccessful trials. The lack of an effective drug developed from the conventional drug portfolio has mandated the introspection into the list of potentially effective unconventional alternate antimicrobial molecules. Alternate therapies, that are clinically explicable forms include monoclonal antibodies, antimicrobial peptides, aptamers and phages. Clinical diagnostics optimizes the drug delivery. In the era of diagnostic-based applications, it is logical to draw diagnostic based treatment for infectious diseases. Selection criteria of alternate therapeutics in infectious disease include detection, monitoring of response and resistance mechanism identification. Integrating these diagnostic applications is disruptive to the traditional therapeutic development. The challenges and mitigation methods need to be noted. Applying the goals of clinical pharmacokinetics that include enhancing efficacy and decreasing toxicity of drug therapy this review analyses the strong correlation of alternate antimicrobial therapeutics in infectious diseases. The relationship between drug concentration and the resulting effect defined by the pharmacodynamic parameters are also analyzed. This review analyzes the perspectives of aligning diagnostic initiatives into the use of alternate therapeutics with a particular focus on companion diagnostic applications in infectious diseases.

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g. intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease that progressively leads to thyroid gland destruction and hypothyroidism. Patients produce antibodies against two thyroid-specific antigens: thyroglobulin and thyroid peroxidase. As a result of the abnormal amount of thyroid hormone produced and its autoimmune etiology, patients with HT display a higher frequency of either autoimmune or non-autoimmune dermatological disorders. On ultrasound examination, HT can be detected by observing an enlarged thyroid gland with hypoechoic parenchymal regions or by observing a small gland indicating atrophy and diffusely heterogeneous parenchyma. Changes in the parenchymal vascularity can be observed as decreased or increased levels of vascularization. Objective: This study aimed to analyze the role of clinical data and ultrasound evaluation of patients with HT in suggesting an association with dermatological disorders. Patients and methods: Complete dermatological and endocrinological assessments as well as ultrasonography of the thyroid and lymphnodes were performed in HT patients. Results: The data obtained showed that a family history of thyroid disease, increased diameter of the inferior thyroid artery, and the presence of cervical lymphadenopathy were more frequent in the group of patients with dermatological diseases. Taken together, our results suggest the usefulness of ultrasound in determining a possible association between HT and dermatological disorders.

The affordable production of valuable antioxidant extracts from plant resources depends on the availability of enabling technologies, such as hydrodynamic cavitation (HC), characterized by unrivalled effectiveness, efficiency, and scalability in the extraction of natural products. As sources of phytochemicals showing biological effects on human health, including anti-cancer properties, pomegranate (Punica granatum L.) fruits were processed using HC. Fractions collected during the process (M1-M5) were lyophilized (L), filtered (A), or used as such (C), for identifying their best conservation practice. Biochemical profile and in vitro antioxidant power were investi-gated by spectrophotometric and chromatographic assays. The antiproliferative effect of L-M3, resulting from just 15 minutes of extraction, was tested on human breast cancer line (AU565-PAR) and peripheral blood mononuclear (PBMCs) cells from healthy donors. M3-M4 fractions from L and C series revealed the highest antiradical activity and phenolic content. Cell growth, death, and redox state were assessed, showing that the pomegranate extract M3 significantly reduced tumor cell proliferation and intracellular oxygen reactive species. No effect on PBMCs was de-tected. Thus, the use of antioxidants isolated using HC as adjuvants in anticancer therapies might be advantageous and affordable; moreover, since oxidative stress contributes to cancer devel-opment, its reduction might be the leading mechanism.

Cancer stem cells play a crucial role in tumor initiation, metastasis and therapy resistance. Cellular heterogeneity and plasticity challenge the isolation of cancer stem cells. The impact of intratumoral cellular heterogeneity in the context of treatment resistance using a label-free approach remains understudied. Here, we use the sedimentation field-flow fractionation technique to separate, without labeling, cell subpopulations of colorectal cancer cell lines and primary cultures according to their biophysical properties. One of the three cell subpopulations sorted by SdFFF exhibits cancer stem cell traits, including high tumorigenicity in vivo, and a higher frequency of tumor-initiating cells compared to the other subpopulations. In vitro two- and three-dimensional chemosensitivity assays emphasize the therapeutic relevance of this cancer stem cell-like subpopulation due to its chemoresistance. Therefore, our findings highlight a label-free cell sorting approach to reveal intratumoral cellular heterogeneity and its implication in therapy resistance. This approach enables the study of the individualized response of each sorted cell subpopulation by breaking down the tumor, thus offering new perspectives for personalized therapy.

Chimeric antigen receptor and T-cell receptor (CAR-T/TCR) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1,007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR industry may be a robust response to success and failure of competitor products.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. One of the undisputed values of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make any conclusion on this topic hard. Current guidelines suggest considering micrometastasis (MIC) as a node-positive disease, while isolated tumor cells (ITC) as a node-negative disease, with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, prognostic and therapeutic role of LVM and underline the present and future challenges we are facing. We hope this review will guide further research, giving robust evidence on LVM and their impact on clinical practice.

Background: Cell proliferation and the cell cycle are fundamental to tumor development, with mitosis playing a crucial role in cell division. Understanding the complexities of the cell cycle and mitosis is critical for cancer research, especially in the context of developing therapeutic strategies. Objective: This review highlights mitotic poisons as potential anti-cancer pharmacotherapeutics, particularly their structural and functional group diversity presenting opportunity for semi-synthesis of new derivatives with multi-target mechanisms relevant for cancer pharmacotherapeutics. Also, the review explores naturally occurring mitotic poisons and inhibitors of microtubule-dependent molecular motors as promising cancer pharmacotherapeutics. Methods: A comprehensive review of literature from 2004 to 2023 was conducted, covering studies on cell proliferation, mechanism of cell cycle regulation, mitosis, cytokinesis, and anti-cancer drug development. The published literature was collected primarily from PubMed, Scopus, Medline, Web of Science Core Collections, Google Scholar and other relevant scientific databases using keywords including but not limited to mitotic poisons and cancer, sources of mitotic poisons, mechanism of mitotic poisons, targets of mitotic poisons and structural diversity of mitotic poisons. The efficacy and limitations of various mitotic poisons and their impact on different cancer types were examined. Recent advancements in targeted therapeutic interventions for various cancers were also explored. Results: The effectiveness and limitations of mitotic poisons, including Taxanes, Epothilones, Colchicine, Vinca alkaloids, Berberine, Laulimalide, and Pseudolaric acid B, were highlighted. Drugs targeting mitotic kinases such as CDKs, Aurora kinases, PLK1, and WEE1 inhibitors were reported. Inhibiting kinesin motor proteins such as Eg5 and KIF15 to interfere with spindle formation and cell division were discussed, along with specific genomic alterations in KIF genes and the discovery of KIFC1 as potential for future research and drug development. Conclusion: Targeting microtubules and mitotic kinases, along with inhibiting kinesin motor proteins, show promise for cancer pharmacotherapeutics. The combination of targeted therapies, patient stratification based on biomarkers (such as low alpha-1 acid glycoprotein and high p63 expression), and exploration of alternative natural sources of mitotic poisons and analogues can significantly advance cancer pharmacotherapy to improve patient outcomes.

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously [1]. In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

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.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

Cholestasis is a condition defined as an abnormal decrease of bile flow due to progressive pathological states or cholestatic liver diseases that affect the biliary tree at intrahepatic and extrahepatic level. It induces complications such as cirrhosis, liver failure, malignancies, pruritus, fatigue, bone disease and nutritional deficiencies that merit close follow-up and specific interventions to improve quality of life. Furthermore, cholestasis can progress to end-stage liver disease and represents an entity with high morbidity and mortality; and economic burden, Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. This review addresses the pathophysiology of cholangiopathies, a general view of current treatments and their molecular targets, and a specific review of those groups of drugs. The objective is to provide clinicians with an overview of the current treatment of cholangiopathies based on evidence on its efficacy and safety.

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverses established arterial wall thickening, stiffening and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from better understanding of pulmonary vascular gene expression programs. In this review potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. Progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

This review explores the transformative role of induced pluripotent stem cells (iPSCs) and organoids in advancing neuropathology research. Focused on Alzheimer's disease, epilepsy, Parkinson's disease, and spinal cord injury, iPSCs offer patient-specific disease modeling with regenerative therapy potential. The versatility of iPSCs, their ability to differentiate into the main neuronal cell types, and their integration into three-dimensional organoid models enable the recreation of complex tissues in vitro. Improvement of organoid and iPSCs generation protocols and the selection of appropriate donor cell types are highlighted as crucial steps toward the application of these new technologies to overcome tumorigenic potential and other challenges. iPSCs demonstrate promise in regenerative therapies, as evidenced by successful applications in animal models.

This study focuses on the potential medicinal properties of Campsis radicans L. extracts and its aim is to investigate the antioxidant and antiproliferative effects of these extracts on the human colon adenocarcinoma cell line (HT-29). Cytotoxic activity in the HT-29 cell line was evaluated, and the 3-dimensional structures of phenolic compounds were obtained using the GC-MS method. Docking simulations were performed with AutoDock Vina, targeting proteins that are crucial in the apoptotic pathway (Bax, Bcl-2, and Caspase-3). Drug similarities and ADMET estimates of the phenolic compounds were obtained from databases. The highest antioxidant activity of Campsis radicans L. plant was observed in ethanol and water extracts, with notable inhibition capacities. While the total phenolic content was highest in ethanol, water, and ether extracts respectively the total flavonoid content was highest in ethanol, then ether, and water extracts. Certain elements were undetectable in mineral determination, and others exceeded the toxic doses for plants. The water extract exhibited dose-dependent cytotoxic activity in the HT-29 cell line, with an IC50 value of 4.47 mg/mL. Molecular docking results revealed the binding of phenolic molecules to the active sites of apoptotic pathway proteins. The findings suggest that Campsis radicans L. plant possesses cytotoxic properties, significant phenolic and flavonoid content, and a high antioxidant capacity. These properties make it a potential candidate for treatment use, emphasizing its potential therapeutic value in the HT-29 cell line. Further research and exploration on the identified phenolic compounds could contribute to the development of novel therapeutic agents.

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the HER2 target in the presence of pertuzumab was in-vestigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and con-sistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the im-portance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.

Mutations in epidermal growth factor receptor (EGFR) occur in about 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) have been developed, targeting EGFR activity. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. These models are particularly effective in identifying optimal responders to specific treatments, thereby enhancing therapeutic efficacy. We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, representing two distinct generations of EGFR TKIs, to accurately simulate the drugs’ distribution within the primary tumor and metastatic sites following oral administration. These models were integrated with a pathophysiological mechanistic model of EGFR-mutant LUAD, enabling the representation of the effects of both gefitinib and osimertinib on EGFR activation-induced signaling pathways. This comprehensive model outputs detailed evolutions of the primary tumor and each metastatic site, facilitating the evaluation of patient progression in alignment with RECIST guidelines (version 1.1). Notably, the model encapsulates the heterogeneity within the tumor, through the representation of various subclones, each characterized by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002 and FLAURA clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. The model adeptly replicated the time to progression observed in real clinical trials in EGFR-mutant LUAD patients receiving gefitinib or osimertinib as first-line therapy. In addition, the model was able to reproduce the results from a retrospective study comparing gefitinib and osimertinib, a study that was not used to inform the model. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a vital investigational tool for deriving pertinent insights and informing treatment strategies, particularly in identifying optimal responders to various generations of EGFR TKIs. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the required patient cohort size in such trials, optimizing resource utilization.

Cervical cancer is one of the ailments that endangers the health of women all over the world and causes infertility. Fortunately, this disease can be avoided. Both the results and participation rates of the current preventative strategy remain poor. Hence, preventative or early detection methods remain challenging and open. In gynecology and computer science fields, few studies on identifying cervical cancer are based on behavior risk factor and machine learning. Moreover, various social and behavioral aspects might often make it more difficult to detect cervical cancer especially in low‑ and middle‑income countries (LMICs). Accordingly, focus on predicting the presence of cervical cancer through behavioral risk factors is the basic structure of this research. We proposed an approach to classify cervical cancer from a social-behavioral perspective using logistic regression to predict cervical cancer. We got significantly improved outcomes than the existing methods. Moreover, we used feature engineering to formulate less dimensionality as a pre-processing step and optimized parameters to be prepared for classification phase. The results proved that using the logistic regression with regularization type L1 had a promising performance. The accuracy of Logistic Regression (LR) L1 was 97.2%. Such results support the proposed work as a reliable classification predictive tool.

High hopes were associated with the new anti-angiogenic medicament, bevacizumab, which due to the possibility of binding to isoform A of vascular endothelial growth factor (VEGF), inhibited the creation of new blood vessels. However, not only blood vessels are responsible for the tumor cells' spread. During the process of tumor growth, lymphangiogenesis is mediated by other isoforms of the VEGF family, specifically VEGF-C and VEGF-D, which are independent of the bevacizumab action. Therefore, based on the mechanism of bevacizumab action and the processes of angio- and lymphangiogenesis, we formed three hypotheses: 1) if the lymph nodes in the primary ovarian cancers are metastatic, the outcome of bevacizumab treatment is worsened; 2) concerning the second-line treatment, bevacizumab will act in a weakened manner if the recurrence occurs in lymph nodes compared to local recurrences; 3) patients treated by bevacizumab are more likely to have recurrences in lymph nodes. These hypotheses raise the issue of the existing gap of knowledge, which concerns the effect of bevacizumab on the metastatic lymph nodes.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration-resistance is often developed during the course of treatment, though its influences require further understanding. This study explores the human microbiome for its implications in castration-resistance and metastasis in prostate cancer. RNA sequencing data was downloaded for bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These sequences were mapped to bacterial sequences to yield species-level abundance approximations. Numerous species were found to correlate to the expression of known markers of castration-resistance, including AR, PI3K, and AKT. Castration-resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for relation to these species. EGFR and SLC3A2 were widely downregulated with greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration-resistance and stemness in prostate cancer. By considering the microbiome’s importance in these factors, we may better understand the highly aggressive and highly invasive nature of prostate cancer, allowing for needed improvement in the treatment of this disease.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

Chronic kidney disease (CKD) is actually considered a public health priority according to the increasing number of patients affected by this condition: this casuistry is not only related to specific glomerular, tubular or autoimmune diseases or a consequence of acute kidney injury (AKI) episodes leading to organ failure, but it is tied to the progression of life expectancy and the impact of comorbidities such as cardiovascular disease, diabetes and cancer. CKD and its comorbidities promote low grade inflammatory status with an impact on patients’ clinical conditions, reducing their possibility for kidney transplantation or graft survival and their survival when receiving renal replacement therapies such as hemodialysis (HD) or peritoneal dialysis (PD). CKD is often referred to as an ageing accelerator: innate immune system dysregulation, in the uraemic proinflammatory milieu, is involved in this accelerated senescence phenomena and pentraxins, particularly Pentraxin-3 (PTX-3), are of particular interest in the development of kidney disease. A complete understanding of the mechanism of CKD progression, innate immune system involvement and a proper definition of PTX-3 role in kidney disease, could redefine the approach for diagnosis and a more centered patients’ management to slow down CKD progression over time and reduce its clinical and social impact.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Viral diseases represent a major public health concern and an ever-present risk for developing into a future pandemic. Antiviral antibody therapeutics, either alone or in combination with other therapies, have emerged as valuable preventative and treatment options, including during a global emergency. Here we will discuss polyclonal and monoclonal antiviral antibody therapies, focusing on the unique biochemical and physiological properties that make them well suited as therapeutic agents. We will describe the methods of antibody characterization and potency assessment throughout development, highlighting similarities and differences between polyclonal and monoclonal products as appropriate. In addition, we will consider the benefits and challenges of antiviral antibodies when used in combination with other antibodies or other types of antiviral therapeutics. Lastly, we will discuss novel approaches to the characterization and development of antiviral antibodies and identify areas that would benefit from additional research.

Mycobacterium abscessus is a non-tuberculous mycobacteria notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations e.g. vancomycin-clarithromycin and dual beta-lactam therapy have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as intracellular and/or animal models, most have little if any evidence of effect in humans infections. Clinical studies of M. abscesssus treatments are needed in order to reliably determine the value of their incorporation in therapeutic regimens.

Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1&gt;49% in combination with a negative KRAS result had a median survival of 40 months compared to patients with a positive KRAS result (9 months, p&lt;0.05). In addition, patients diagnosed with adenocarcinoma, PDL1&lt;49% and negative KRAS result had a median survival of 39 months compared to patients with a positive result (28 months, p&lt;0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.

Cancer, characterized by abnormal cell proliferation driven by genetic mutations, remains a significant health challenge. Tailoring effective therapies depends on factors like tumor location, grade, and stage, alongside patient condition. Leveraging Nano-carrier encapsulated drugs offers a promising avenue, as they accumulate preferentially at tumor sites, enhancing therapeutic efficacy while mitigating side effects. Polymeric Nano-carriers, with their customizable properties, further optimize drug delivery efficiency and specificity. Incorporating active targeting ligands such as antibodies, carbohydrates, peptides, folates, and aptamers-onto polymeric nanoparticle surfaces through techniques like functionalization, adsorption, and conjugation plays a pivotal role in directing therapeutic agents to tumor cells. Consequently, polymeric nanoparticles emerge as the carrier of choice for delivering drugs to various tumor types, including breast, colon, lung, prostate, liver, and spleen tumors.

Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques; whereas, in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy will be considered

Prompt removal of misfolded membrane proteins and misassembled membrane protein complexes is essential for membrane homeostasis. However, the elimination of these toxic proteins from the hydrophobic membrane environment has high energetic barriers. Transmembrane FtsH is the only known ATP-dependent protease responsible for this task, unlike other well-studied soluble ATP-dependent proteases. The mechanisms by which FtsH recognizes, unfolds, translocates, and proteolyzes its substrates remain unclear. Here, we report the crystal structures of the Thermotoga maritima FtsH periplasmic domain (PD) in an associative trimeric state at a 1.5-1.95 Å resolution. We also describe the pH-dependent oligomerization states of the isolated PD using dynamic light scattering. These observations help us understand how FtsH recognizes membrane-anchored misfolded proteins.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is highly invasive and easily recurs. For HCC, chemotherapy shows a limited effect. The gold standard for HCC treatment includes curative surgical resection or liver transplantation. However, the recur-rence rate at 5 years after liver resection is estimated at approximately 70% and even at 5 years after liver transplantation, it is 20%. Therefore, improving survival outcomes after curative surgi-cal resection of liver cancer is crucial. This review highlights the importance of identifying risk factors for HCC recurrence following radical surgical resection and adjuvant therapy options that may reduce the recurrence risk and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization and radiotherapy), adjuvant systemic therapy (e.g., small molecule targeted therapy and immunotherapy), and other adjuvant therapies (e.g., chem-otherapy). However, further research is needed to refine the use of these therapies and optimize their effectiveness in preventing HCC recurrence.

Research indicates that painful experiences can significantly affect the fear of cancer recurrence among cancer survivors, which is a distressing concern that influences both physiological and psychological recovery. Yet, the role of potential factors and mechanisms in these relationships is not fully known. This cross-sectional study aimed to advance our comprehension of the associa-tions between total pain and the fear of recurrence in post-treatment cancer patients by examining two potential mediators: psychological flexibility and mentalization. Three hundred and thirty-five participants (aged 22 to 88, 49.1% female) who had finished their cancer treatment completed self-report assessments of total pain, fear of recurrence, psychological flexibility, and mentalization. The serial mediation analysis showed that all dimensions of total pain were positively related to the fear of recurrence indirectly through psychological flexibility and mentalization, in serial. Additionally, gender moderated these serial mediational effects. In line with the psychological flexibility model, personal capacities to face difficult internal/external problems and interpret one’s behaviour in motivational terms can counterbalance patients’ negative emotions and feelings related to the illness.

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those &gt;55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephrotoxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients' recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostructures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010-2020. Numerous publications have been reviewed to provide an essential summation of the nanopolymer types and their essential properties, mechanisms towards efficient drug delivery, as well as active targeting stimuli-responsive strategies that are currently utilized in the doxorubicin transportation field.

Background: this interventional pilot study aimed to evaluate the short-term (3 years) efficacy of focal laser ablation (FLA) in treating the index lesion of low-intermediate risk prostate cancer, along with assessing the safety of the procedure (ClinicalTrials.gov ID NCT04045756). Methods: forty patients aged between 46 and 86 with histologically proven organ-confined prostate cancer and low to intermediate progression risk were included. FLA was performed under percutaneous fusion magnetic resonance/ultrasound guidance in a Day Hospital setting under local anesthesia. Patients underwent regular clinical assessments, PSA measurements, post-procedure MRI scans, and biopsies at 36 months or if positive findings were detected earlier. Statistical analyses were conducted to assess trends in PSA levels and cavity dimensions over time. Results: forty patients were initially included, with 15 lost to follow-up. At 36 months, a mean PSA reduction of 60% was observed, and 80% of MRI scans showed no signs of in-field clinically significant residual/recurrent cancer. Biopsies at 36 months revealed no malignant findings in 20 patients. No deterioration in sexual function or urinary symptoms was recorded. Conclusions: FLA appears to be safe, feasible and effective in the index lesion treatment of low-intermediate risk prostate cancer, with a high rate of tumor eradication and preservation of quality of life.

Background: Circulating rare cells participate in breast cancer evolution as systemic components of the disease and thus, are a source of theranostic information. Exploration of cancer-associated rare cells is in its infancy. We determined the validity of a rare-cell detection platform and demonstrated the usefulness of a certain rare cell subset as a novel approach to characterize the breast cancer system. Methods: Linearity of the Rarmax® platform was established using a spike-in approach. The platform includes red blood cell lysis, leukocyte depletion and high-resolution fluorescence image recording. Rare cell analysis was conducted on 28 samples (before and after surgery) from 14 patients with breast cancer, 20 healthy volunteers and 9 non-cancer control volunteers. In-depth identification of rare cells, including circulating tumor cells, endothelial-like cells, erythroblasts and inflammation-associated cells, was performed using a phenotype and morphology-based classification system. Results: The platform performed linearly over a range of 5-950 spiked cells, with an average recovery of 84.6%. Circulating epithelial and endothelial-like cell subsets have been demonstrated to be associated with or independent of cancer with tumor presence. Furthermore, certain cell patterns may be associated with treatment-related adverse effects. The sensitivity in detecting tumor-presence and cancer-associated abnormality before surgery was 50% and 85.7%, respectively and the specificity was 100% and 96.6%, respectively. Conclusion: The present study supports the idea of a cancer-associated rare cell abnormality to represent tumor entities as well as systemic cancer. The latter is independent of the apparent clinical cancer.

Dengue is one the most significant mosquito-borne viral diseases globally, with its prevalence extending across tropical and subtropical regions, exerting a considerable financial strain on health systems. Despite decades of research leading to the development of a vaccine implemented in endemic countries, its usage remains restricted to a fraction of the population at risk of contracting dengue. Due to these limitations, there is a growing focus on research aimed at unraveling the cellular mechanisms crucial for Dengue virus (DENV) infection to pinpoint potential host targets. Multiple studies propose a pivotal role of cytoskeletal remodeling in DENV infection. Specifically, DENV alters the organization of actin to facilitate viral entry, replication, and release. In this study, we investigated the involvement of the protein c-Abl, a kinase crucial in actin dynamics, in the context of DENV infection. Our findings suggest that either silencing or pharmacological inhibition of the kinase c-Abl leads to accumulation of dengue ENV protein in vitro, associated with actin remodeling. These results illuminate cellular mechanisms that could serve as potential therapeutic alternatives for dengue management.

Regenerative Medicine and Tissue Engineering are interdisciplinary fields that combine cell biology, material science, and bioengineering to develop therapies for tissue repair and regeneration. This field has made significant advances in recent years, particularly in the use of stem cells and biomaterials. Advancements in cell-based therapies have involved the use of cells to repair or replace damaged tissues and organs. Tissue engineering involves using scaffolds and growth factors to promote tissue regeneration. However, a major challenge in this field is the formation of adhesions, which can cause complications, such as intestinal obstruction and chronic pain. Adhesion barriers are used to prevent adhesion of tissues and organs during recovery, thereby reducing the risk of complications. Anti-adhesion materials, such as polysaccharides, proteins, and synthetic polymers, are used to create a physical barrier between tissues and prevent adhesion. These materials can be used alone or in combination, but their effectiveness varies.

Conventional cancer clinical trials can be time-consuming and expensive, often yielding results with limited applicability to real-world scenarios and presenting challenges for patient participation. Real-world data (RWD) studies offer a promising solution to address evidence gaps and provide essential information about the effects of cancer treatments in real-world settings. Defining RWD based on its original intent, which is the collection of data at the point of care for clinical purposes, can distinguish it from conventional clinical trial data. RWD can be generated using experimental designs that resemble those used in conventional clinical trials, but with several advantages, such as improved efficiency and a better balance between internal and external validity. RWD can support pharmacovigilance, insights into disease progression, and the development of external control groups. Prospective RWD collection enables evidence generation based on pragmatic clinical trials (PCTs) that support randomized study designs and expand clinical research to the point of care. To ensure the quality of real-world studies, it is crucial to implement auditable data abstraction methods and develop new incentives to capture clinically relevant data electronically at the point of care. The treatment landscape is constantly evolving, with the integration of front-line immune checkpoint inhibitors (ICIs), either alone or in combination with chemotherapy, affecting subsequent treatment lines. Real-world effectiveness and safety in underrepresented populations, such as the elderly, patients with poor performance status (PS), hepatitis, or human immunodeficiency virus-infected patients, are still largely unexplored. Similarly, the cost-effectiveness and sustainability of these innovative agents are important considerations in the real world.

The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances and the therapeutic effects of metabolic ketogenic therapy remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.

The emergence of bispecific antibodies has transformed cancer immunotherapy, highlighting increased clinical efficacy, especially in hematological malignancies. These innovative molecules uniquely target two distinct tumor antigens or separate epitopes simultaneously, demonstrating potent antitumor activity across various cancers. Despite their promise, challenges like rapid drug clearance, off-target effects, and cytokine release syndrome hinder their widespread therapeutic application. Recent engineering advancements in bispecific antibody systems aim to overcome these challenges, broadening therapeutic coverage. This review offers insights into the latest clinical and preclinical progress in bispecific immunotherapy, outlining key challenges faced by the technique, and exploring emerging strategies to address these obstacles.

Background: Iron chelation medications (desferoxamine, desferasirox, desferiprone) are used to manage iron overload. These medications are partially excreted via the kidneys, desferoxamine and desferiprone excretes primarily in the urine, and desferasirox had about 8% excreted in the urine. Their use in severe kidney disease and dialysis patients is caution as “avoided” concerning adverse effects; however, there are reports safe use. This manuscript reviews the literature in this population. Data Sources: Pubmed: desferasirox, deferiprone, deferoxamine, kidney disease, ESKD, Dialysis. Case reports and case series that described experiences with using iron chelation medications in ESKD patients are included. Data also gathered from reading-related sources. Results: This is a review of desferoxamine, desferasirox, and deferiprone use in kidney disease from 1976 to the present time. Table 1 provides a summary of findings. These are mostly reports and brief descriptions of the experiences used in severe kidney disease and dialysis, but lack of randomized control trials and small number of participants. Conclusions: Iron chelation medications are important for treating iron overload but concerns with adverse effects. Due to limited medications available to treat iron overload in patients with severe kidney disease, their safe use has been reporting in the literature. This is an area that warrants further research.

Neovascular age-related macular degeneration (nAMD) accounts for one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardised frequent administration of anti-VEGF injections only improves the vision in approximately 30%-40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has discovered novel therapeutic targets and angiogenic signalling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signalling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NLRP3 inflammasome inhibition, targeted intraceptor nanoparticle therapy, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed to anti-VEGFs for the treatment of nAMD.

Introduction: Lymph-nodal prostate cancer oligometastases are differently treated according to their site: pelvic are locoregional lymph-nodes, instead para-aortic lymph-nodes are considered as distant metastases. Aim of the study was a comparison between para-aortic and pelvic oligometastases treated with stereotactic body radiation therapy (SBRT). Material/methods: This is a retrospective analysis. De-novo metastatic or extra-nodal disease were excluded. Univariate and multivariate analyses were performed; pattern of recurrence was evaluated too. A propensity score matching (PSM) was applied to create comparable cohorts. Primary end-point was the progression-free survival (PFS). Secondary end-points were biochemical relapse-free survival (BRFS), ADT-free survival (ADTFS), polymetastases-free survival (PMFS), local progression-free survival (LPFS) and pattern of relapse. Results: 240 lymph-nodal oligometastases in 164 patients (127 pelvic and 37 para-aortic) were treated. Median PFS was 20 and 11 months in pelvic and para-aortic patients respectively (p=0.042). The difference was not confirmed at the multivariate analysis (p=0.06). Median BRFS was 16 and 9 months respectively in pelvic and para-aortic group (p=0.07). No statistically significant differences for ADTFS or PMFS were detected. The cumulative 5-years LPFS was 90.5%. At PSM no statistically significant differences for all the study end-points were detected. Conclusions: Patients affected by para-aortic disease might have PFS comparable to pelvic disease; local control is high in both cohorts. Our results support the use of SBRT also to para-aortic metastases.

The application of artificial intelligence to point-of-care testing (POCT) disease detection has become a hot research field, in which breath detection which detects the patient's exhaled VOCs combined with sensor arrays of Convolutional Neural Network (CNN) algorithms as a new lung cancer detection is attracting more researchers' attention. However, due to low accuracy, high complexity computation and large number of parameters make the CNN algorithms difficult transplant to the embedded system of POCT devices. A lightweight neural network (LTNet) in this work is proposed to deal with this problem, and meanwhile, achieve high-precision classification of acetone and ethanol gases, which are respiratory markers for lung cancer patients. Compared to currently popular lightweight CNN models such as EfficientNet, LTNet has fewer parameters (32K) and its training weight size is only 0.155 MB. LTNet achieved an overall classification accuracy of 99.06% and 99.14% in the own mixed gas dataset and the University of California (UCI) dataset, which are both higher than that of the five existing models’, and it also offers the shortest training (844.38s and 584.67s) and inference time (23s and 14s) in the same validation set. Compared to the existing CNN models, LTNet is more suitable for resource-limited POCT devices.

Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In this review, we discuss specific examples of how variations in glycan structure and glycoengineering impacts the stability, safety, and clinical efficacy of protein-based drugs that are already in the market as well as those that are still in preclinical development. We also highlight the impact of glycosylation on next generation biologics such as T cell-based cancer therapy and gene therapy.

PURPOSE: Breast cancer tumors frequently have intratumor heterogeneity. Tumors with high intratumor heterogeneity have caused therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to poor prognosis for HER2-targeted adjuvant therapies resistance in primary breast cancers. METHODS: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with HER2 gene copy number within a tumor sample. Those heterogeneity classified each tumor into the biphasic grade graph (high heterogeneity [HH]) group and the monophasic grade graph (low heterogeneity [LH]) group. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. RESULTS: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: P < 0.001 (HH:63% vs LH:91% at 10 years), and OS: P = 0.012 (HH:78% vs LH:95% at 10 years). CONCLUSION: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach of heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.

Abstract: Cancer cells are originated by normal cells and with those share the need to be fed. Metabolic reprogramming in cancer cells is not yet fully understood although there is a vast literature suggesting that huge amounts of both energy and substrates are require for synthesis of components of new neoplastic cells so that any macronutrient may be efficiently utilized. Recently, in vitro data show that EAA supplementation promoted colon cancer cells apoptosis by enhanced autophagy. Therefore, in this study we tested in vivo the effects of matched macronutrients standard laboratory diet (control) versus EAA rich modified diet (EAArmd) in mice injected with colon cancer cells. Results of the first set of 12 animals, 6 controls and 6 EAArmd-fed, showed that controls mice develop cancer volume cancers 5 times larger and heavier than EAArmd-fed. If confirmed, these results would open new scenarios for the cancer integrate therapies.

The uterine leiomyoma is the most common benign tumor in women of childbearing age. It may lead to problem of conception or complications during gestational period. The methods of treatment can be surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (Ulipristal acetate, Leuprolide acetate, Cetrorelix, Goserelin, Mifeprestone). Both approaches are efficient, but are incompatible with pregnancy planning. Therefore, there is a call for medical practice in developing therapeutical means of preventing leiomyoma onset in patients planning on pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeuticals of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the MED12, HMGA2 and FH genes should be considered when developing or prescribing drugs. E.g. synthetic inhibitors and vaccines based on matrix metalloproteinases MMP11 and MMP16 are expected to be effective only for the prevention of the occurrence of MED12-dependent nodules.