Dysregulation Of Signaling Pathways Research Articles

Exploring Emerging Therapeutic Targets and Opportunities in Neuroendocrine Tumors: Updates on Receptor Tyrosine Kinases

Neuroendocrine tumors (NETs) represent a diverse group of neoplasms originating from neuroendocrine cells, presenting varied clinical behaviors and posing significant challenges in management. This review explores the emerging roles of receptor tyrosine kinases (RTKs) in the pathogenesis and progression of NETs, including vascular endothelial growth factor receptors (VEGFRs), insulin-like growth factor receptors (IGF-1R), RET, epidermal growth factor receptor (EGFR), and ALK. The dysregulation of RTK signaling pathways contributes to key cellular processes such as proliferation, survival, and invasion in NETs. We discuss the potential of targeting RTKs as therapeutic strategies in NETs, with a focus on recent developments in RET inhibitors and the therapeutic implications of RTK alterations.

Epigenetics in Cancer Therapy

Epigenetics regulates parts of the genetic information accessible to cellular machinery, thus contributing to cellular diversity. Disruption of epigenetic harmonisation can lead to dysregulation of signaling pathways and contribute to diseases like cancer. Epigenetic processes are crucial in coordinating the normal growth and preservation of gene activity unique to mammal tissues. Epigenetic studies in current cancer research are vital for early detection through biomarker identification, understanding tumor heterogeneity, predicting treatment responses, and uncovering resistance mechanisms. This knowledge informs targeted therapies, enhances personalized medicine, and improves overall outcomes in cancer patients. This review comprehensively explores epigenetic processes in healthy cells, emphasizing histone modification-lysine acetylation and DNA methylation. The intricate mechanisms governing genetic expression and their dysregulation in cancer progression are also reviewed. Examining prevalent cancer types, this review stresses the pivotal role of epigenetics in understanding and potentially targeting these processes for therapeutic interventions.

Unraveling Dysregulated Cell Signaling Pathways, Genetic and Epigenetic Mysteries of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent and burdensome neurodegenerative disorder that has been extensively researched to understand its complex etiology, diagnosis, and treatment. The interplay between genetic and environmental factors in PD makes its pathophysiology difficult to comprehend, emphasizing the need for further investigation into genetic and epigenetic markers involved in the disease. Early diagnosis is crucial for optimal management of the disease, and the development of novel diagnostic biomarkers is ongoing. Although many efforts have been made in the field of recognition and interpretation of the mechanisms involved in the pathophysiology of the disease, the current knowledge about PD is just the tip of the iceberg. By scrutinizing genetic and epigenetic patterns underlying PD, new avenues can be opened for dissecting the pathology of the disorder, leading to more precise and efficient diagnostic and therapeutic approaches. This review emphasizes the importance of studying dysregulated cell signaling pathways and molecular processes associated with genes and epigenetic alterations in understanding PD, paving the way for the development of novel therapeutic strategies to combat this devastating disease.

Research progress on molecular mechanism of pyroptosis caused by Helicobacter pylori in gastric cancer.

Gastric cancer (GC) is a prevalent malignancy worldwide. Helicobacter pylori (H. pylori), a Gram-negative spiral bacterium, has the ability to colonize and persist in the human gastric mucosa. Persistent H. pylori infection has been identified as a major risk factor for ~80% of GC cases. The interplay between H. pylori pathogenicity, genetic background, and environmental factors collectively contribute to GC transformation. Eradicating H. pylori infection is beneficial in reducing the recurrence of gastric cancer and residual cancer. However, the underlying molecular mechanisms involved in GC remain incompletely understood. Additionally, H. pylori reshapes the immune microenvironment within the stomach which may compromise immunotherapy efficacy in infected individuals. Clinical eradication of H. pylori infection still faces numerous challenges. In this review, the authors summarize recent research progress on elucidating the molecular mechanisms underlying H. pylori infection in GC development. Notably, CagA protein-a carcinogenic virulence factor predominantly expressed by Asian strains of H. pylori-induces inflammation and excessive ROS production within gastric mucosa cells. Dysregulation of multiple pyroptosis signalling pathways can lead to malignant transformation of these cells. MiRNA-1290 plays a crucial role in GC initiation and progression while serving as an indicator for disease progression dynamics. Pyroptosis exhibits dual roles both promoting carcinogenesis and inhibiting tumour growth; thus it holds potential clinical applications for drug-resistant GC treatment strategies. Furthermore, pyroptosis may play a regulatory role within the immune system during gastric cancer development. Lastly, the authors provide an overview on current concepts regarding pyroptosis as well as insights into miRNA-1290's pathogenicity and clinical value within immune mechanisms associated with GC, aiming to serve as reference material for researchers.

Paternal aging impacts expression and epigenetic markers as early as the first embryonic tissue lineage differentiation

BackgroundAdvanced paternal age (APA) is associated with adverse outcomes to offspring health, including increased risk for neurodevelopmental disorders. The aim of this study was to investigate the methylome and transcriptome of the first two early embryonic tissue lineages, the inner cell mass (ICM) and the trophectoderm (TE), from human blastocysts in association with paternal age and disease risk. High quality human blastocysts were donated with patient consent from donor oocyte IVF cycles from either APA (≥ 50 years) or young fathers. Blastocysts were mechanically separated into ICM and TE lineage samples for both methylome and transcriptome analyses.ResultsSignificant differential methylation and transcription was observed concurrently in ICM and TE lineages of APA-derived blastocysts compared to those from young fathers. The methylome revealed significant enrichment for neuronal signaling pathways, as well as an association with neurodevelopmental disorders and imprinted genes, largely overlapping within both the ICM and TE lineages. Significant enrichment of neurodevelopmental signaling pathways was also observed for differentially expressed genes, but only in the ICM. In stark contrast, no significant signaling pathways or gene ontology terms were identified in the trophectoderm. Despite normal semen parameters in aged fathers, these significant molecular alterations can adversely contribute to downstream impacts on offspring health, in particular neurodevelopmental disorders like autism spectrum disorder and schizophrenia.ConclusionsAn increased risk for neurodevelopmental disorders is well described in children conceived by aged fathers. Using blastocysts derived from donor oocyte IVF cycles to strategically control for maternal age, our data reveals evidence of methylation dysregulation in both tissue lineages, as well as transcription dysregulation in neurodevelopmental signaling pathways associated with APA fathers. This data also reveals that embryos derived from APA fathers do not appear to be compromised for initial implantation potential with no significant pathway signaling disruption in trophectoderm transcription. Collectively, our work provides insights into the complex molecular mechanisms that occur upon paternal aging during the first lineage differentiation in the preimplantation embryo. Early expression and epigenetic markers of APA-derived preimplantation embryos highlight the susceptibility of the future fetus to adverse health outcomes.

Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets.

Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation.

The Senescent Heart-"Age Doth Wither Its Infinite Variety".

Cardiovascular diseases are a leading cause of morbidity and mortality world-wide. While many factors like smoking, hypertension, diabetes, dyslipidaemia, a sedentary lifestyle, and genetic factors can predispose to cardiovascular diseases, the natural process of aging is by itself a major determinant of the risk. Cardiac aging is marked by a conglomerate of cellular and molecular changes, exacerbated by age-driven decline in cardiac regeneration capacity. Although the phenotypes of cardiac aging are well characterised, the underlying molecular mechanisms are far less explored. Recent advances unequivocally link cardiovascular aging to the dysregulation of critical signalling pathways in cardiac fibroblasts, which compromises the critical role of these cells in maintaining the structural and functional integrity of the myocardium. Clearly, the identification of cardiac fibroblast-specific factors and mechanisms that regulate cardiac fibroblast function in the senescent myocardium is of immense importance. In this regard, recent studies show that Discoidin domain receptor 2 (DDR2), a collagen-activated receptor tyrosine kinase predominantly located in cardiac fibroblasts, has an obligate role in cardiac fibroblast function and cardiovascular fibrosis. Incisive studies on the molecular basis of cardiovascular aging and dysregulated fibroblast function in the senescent heart would pave the way for effective strategies to mitigate cardiovascular diseases in a rapidly growing elderly population.

Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells.

Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet-based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.

MiR-26a-5p inhibits the proliferation of psoriasis-like keratinocytes in vitro and in vivo by dual interference with the CDC6/CCNE1 axis.

Psoriasis is a chronic inflammatory proliferative dermatological ailment that currently lacks a definitive cure. Employing data mining techniques, this study identified a collection of substantially downregulated miRNAs (top 10). Notably, 32 targets were implicated in both the activation of the IL-17 signaling pathway and cell cycle dysregulation. In silico analysis revealed that one of these miRNAs, miR-26a-5p, is a highly conserved cross-species miRNA. Strikingly, the miR-26a-5p sequences in humans and mice are identical, and mmu-miR-26a-5p was found to target the same 7 cell cycle targets as its human counterpart, hsa-miR-26a-5p. Among these targets, CDC6 and CCNE1 were the most effective targets of miR-26a-5p, which was further validated in vitro using a dual luciferase reporter system and qPCR assay. The therapeutic assessment of miR-26a-5p revealed its remarkable efficacy in inhibiting the proliferation and G1/S transition of keratinocytes (HaCaT and HEKs) in vitro. In vivo experiments corroborated these findings, demonstrating that miR-26a-5p effectively suppressed imiquimod (IMQ)-induced psoriasis-like skin lesions in mice over an 8-day treatment period. Histological analysis via H&E staining revealed that miR-26a-5p treatment resulted in reduced keratinocyte thickness and immune cell infiltration into the spleens of IMQ-treated mice. Mechanistic investigations revealed that miR-26a-5p induced a cascade of downregulated genes associated with the IL-23/IL-17A axis, which is known to be critical in psoriasis pathogenesis, while concomitantly suppressing CDC6 and CCNE1 expression. These findings were corroborated by qPCR and Western blot analyses. Collectively, our study provides compelling evidence supporting the therapeutic potential of miR-26a-5p as a safe and reliable endogenous small nucleic acid for the treatment of psoriasis.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Oxidized/unmodified-polyethylene microplastics neurotoxicity in mice: Perspective from microbiota-gut-brain axis

Microplastics (MPs) are inevitably oxidized in the environment, and their potential toxicity to organisms has attracted wide attention. However, the neurotoxicity and mechanism of oxidized polyethylene (Ox-PE) MPs to organisms remain unclear. Herein, we prepared oxidized low-density polyethylene (Ox-LDPE) and established a model of MPs exposure by continuously orally gavage of C57BL/6 J mice with LDPE-MPs/Ox-LDPE-MPs for 28 days with or without oral administration of Lactobacillus plantarum DP189 and galactooligosaccharides (DP189&GOS). The experimental results indicated that LDPE-MPs or Ox-LDPE-MPs caused several adverse effects in mice, mainly manifested by behavioral changes, disruption of the intestinal and blood–brain barrier (BBB), and simultaneous oxidative stress, inflammatory reactions, and pathological damage in the brain and intestines. Brain transcriptomic analysis revealed that the cholinergic synaptic signaling pathways, which affect cognitive function, were significantly disrupted after exposure to LDPE-MPs or Ox-LDPE-MPs. Real-time quantitative polymerase chain reaction and Western Blotting results further demonstrated that the critical genes (Slc5a7, Chat and Slc18a3) and proteins (Chat and Slc18a3) in the cholinergic synaptic signaling pathway were significantly down-regulated after exposure to LDPE-MPs or Ox-LDPE-MPs. These alterations lead to reduced acetylcholine concentration, which causes cognitive dysfunction in mice. Importantly, the DP189&GOS interventions effectively mitigated the MPs-induced cognitive dysfunction and intestinal microbiota alteration, improved intestinal and BBB integrity, attenuated the oxidative stress and inflammatory response, and also saw a rebound in the release of acetylcholine. These results indicated that LDPE-MPs and Ox-LDPE-MPs exert neurotoxic effects on mice by inducing oxidative stress, inflammatory responses, and dysregulation of cholinergic signaling pathways in the mouse brain. That probiotic supplementation is effective in attenuating MPs-induced neurotoxicity in mice. Overall, this study reveals the potential mechanisms of neurotoxicity of LDPE-MPs and Ox-LDPE-MPs on mice and their improvement measures, necessary to assess the potential risks of plastic contaminants to human health.

Guardians of Immunity: Toll-Like Receptor Signalling in the Onset and Progression of Multiple Sclerosis, Sketching an Immunopathological Scheme

Background: Multiple Sclerosis (MS) is a chronic autoimmune disorder of the central nervous system, characterized by inflammation, demyelination, and neurodegeneration. The role of toll-like receptors (TLRs) in MS pathogenesis, specifically through MYD88-dependent and -independent pathways, has become a focal point of research. Understanding these pathways offers insights into the mechanisms driving MS and potential therapeutic targets. Objective: This review aims to synthesize current knowledge on the role of TLR signaling in the onset and progression of MS, focusing on the dysregulation of MYD88-dependent and -independent pathways and their implications for disease pathogenesis and therapy. Methods: A systematic search of PubMed, Scopus, Web of Science, and Google Scholar databases was conducted to identify studies related to TLR signaling in MS. Keywords related to "toll-like receptors," "multiple sclerosis," "MYD88-dependent pathway," "MYD88-independent pathway," and "immune response" were used. The evidence synthesis was qualitative, integrating findings from both human and animal studies. Results: The review highlights the central role of NF-kB in mediating the effects of TLR signaling on the inflammatory cascade in MS. Dysregulation in TLR signaling pathways can lead to increased expression of pro-inflammatory cytokines and compromise the blood-brain barrier, exacerbating MS pathogenesis. The evidence points towards the dual role of TLR pathways in promoting inflammatory responses and potentially offering protective mechanisms against the disease. Conclusion: TLR signaling pathways play a crucial role in the immunopathology of MS, with both MYD88-dependent and -independent pathways contributing to disease progression. Targeting these pathways presents a promising therapeutic strategy, emphasizing the need for further research to develop effective treatments.

An Overview of Therapeutic Targeting of Nrf2 Signaling Pathway in Rheumatoid Arthritis.

Rheumatoid arthritis (RA), an autoimmune condition that has a significant inflammatory component and is exacerbated by dysregulated redox-dependent signaling pathways. In RA, the corelationship between oxidative stress and inflammation appears to be regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Furthermore, it has been shown that transcriptional pathways involving Nrf2 and NFκB significantly interact under conditions of oxidative stress and inflammation. Because pathologic cells in RA have a higher chance of surviving, Nrf2's influence on concomitant pathologic mechanisms in the disease is explained by its interaction with key redox-sensitive inflammatory pathways. The current review not only updates knowledge about Nrf2's function in RA but also highlights the complex interactions between Nrf2 and other redox-sensitive transcription factors, which are essential to the self-sustaining inflammatory processes that define RA. This paper also reviews the candidates for treating RA through Nrf2 activation. Finally, future directions for pharmacologic Nrf2 activation in RA are suggested.

The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review.

JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions.

MAPK/NF-κB signaling mediates atrazine-induced cardiorenal syndrome and antagonism of lycopene

Atrazine (ATZ) is the most prevalent herbicide that has been widely used in agriculture to control broadleaf weeds and improve crop yield and quality. The heavy use of ATZ has caused serious environmental pollution and toxicity to human health. Lycopene (LYC), is a carotenoid that exhibits numerous health benefits, such as prevention of cardiovascular diseases and nephropathy. However, it remains unclear that whether ATZ causes cardiorenal injury or even cardiorenal syndrome (CRS) and the beneficial role of LYC on it. To test this hypothesis, mice were treated with LYC and/or ATZ for 21 days by oral gavage. This study demonstrated that ATZ exposure caused cardiorenal morphological alterations, and several inflammatory cell infiltrations mediated by activating NF-κB signaling pathways. Interestingly, dysregulation of MAPK signaling pathways and MAPK phosphorylation caused by ATZ have been implicated in cardiorenal diseases. ATZ exposure up-regulated cardiac and renal injury associated biomarkers levels that suggested the occurrence of CRS. However, these all changes were reverted, and the phenomenon of CAR was disappeared by LYC co-treatment. Based on our findings, we postulated a novel mechanism to elucidate pesticide-induced CRS and indicated that LYC can be a preventive and therapeutic agent for treating CRS by targeting MAPK/NF-κB signaling pathways.

Alterations in Adipocytokine Signaling Pathway and Pyroptosis in Neonatal Hypoxic-ischemic Encephalopathy.

The aims of this study are to discover dysregulated adipocytokine signaling pathway and pyroptosis-related genes to predict neonatal hypoxic-ischemic encephalopathy (HIE) occurrence. HIE is an important cause of infant death and long-term neurological sequelae. Current treatment options for HIE are relatively limited and the pathogenesis of HIE remains to be fully explored. This study investigated the alterations of adipocytokine signaling pathway and pyroptosis in neonatal HIE. To reveal the alterations of adipocytokine signaling pathway and pyroptosis relevant to HIE occurrence. Data on neonatal HIE were downloaded from the Gene Expression Omnibus (GEO) database. Pathway analyses of single-sample gene set enrichment analysis (ss- GSEA) and GSEA were performed on the adipocytokine signaling pathway and pyroptosis. Proportions of immune cells in a single sample were also calculated by ssGSEA and CIBERSORT algorithm. The relationship between the adipocytokine signaling pathway and pyroptosis was analyzed according to Pearson correlation analysis. The activities of KEGG pathways changed after the occurrence of HIE, and adipocytokine signaling pathway was activated with related overexpressed genes. For the three energy metabolisms, carbohydrate metabolism was enhanced; lipid metabolism showed increased fatty acids metabolism and decreased ability of fatty acids synthesis; metabolic levels of phosphate and phenylalanine in amino acid metabolism were elevated. Enhanced pyroptosis and relevant overexpressed genes were accompanied by increased immune cells. A positive connection between adipocytokine signaling pathway and pyroptosis was observed. These results indicated that the adipocytokine signaling pathway may promote HIE occurrence by upregulating the expression of pyroptosis-related genes, providing a novel mechanism for HIE.

Molecular mechanism and promising treatments of chronic prostatitis/chronic pelvic pain syndrome: An exploratory bibliometric analysis and literature review of preclinical studies

AbstractBackgroundAs one of the most common diseases in urology, a large number of preclinical studies have been accumulated to explore the etiological mechanism and potential intervention of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).MethodsIn this study, we systematically evaluated the current status of preclinical research on CP/CPPS through bibliometrics analysis using VOSviewer and Citespace. Characteristics of publication such as year, country/region, institution, author, journal, citation, and keywords were analyzed. Based on the bibliometrics analysis results of keywords, we summarized the possible mechanisms and promising treatments for CP/CPPS narratively.ResultsAccording to the results of this study, the most common mechanisms involved in CP/CPPS were as follows: disturbed immune and inflammation mediators, immune cell dysfunction, oxidative stress, dysregulated signaling pathways, apoptosis, gut microbiota, and testosterone metabolism. Chinese Traditional Medicine and extracorporeal shock wave therapy have important potential in the treatment of CP/CPPS.ConclusionFurther translational studies targeting the above mechanisms and validating the objective efficacy of potential treatments indicated by preclinical studies in clinical patients are needed in the future.

Single-Cell Molecular Profiling of Head and Neck Squamous Cell Carcinoma Reveals Five Dysregulated Signaling Pathways Associated With Circulating Tumor Cells.

To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization. Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied. Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers - not yet being fully adopted in HNSCC treatment algorithms. Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies. Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.

Nucleosome profiling at AR binding sites (ARBS) to provide a prognostic tool for metastatic castration-resistant prostate cancer (mCRPC).

42 Background: Prostate cancer is the second leading cause of cancer death for men in the U.S., and metastatic castration-resistant prostate cancer (mCRPC) is the most advanced form. In previous work, we have reported prognostic significance of PTEN-PI3K-AKT pathway and DNA damage response aberrations detected in cell-free DNA (cfDNA) of mCRPC. Here we utilized nucleosome profiling pattern at androgen receptor (AR) binding sites to further investigate AR signaling pathway dysregulation of mCRPC. Methods: Using the next-generation sequencing PredicineScore liquid biopsy assay (low-pass whole genome sequencing, LP-WGS), we profiled cfDNA fragment coverage centered around AR binding sites (ARBS). For 118 mCRPC patient samples, we quantified sample-level ARBS nucleosome profiling abnormality score (ARBS score) by comparing its centric fragment coverage with normal plasma background using standard Z-score. ARBS score was correlated with clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: By comparing ARBS nucleosome profiling and normal plasma background, we found that mCRPC plasma samples had significant ARBS nucleosome depletion, reflective of transcription factor binding and persistent AR signaling. Notably, ARBS nucleosome depletion was prostate cancer specific, and did not occur in other examined cancer types. ARBS score was highly correlated with tumor fraction (R=0.82), indicating that high tumor fraction mCRPC sample had higher AR binding. Importantly, we found that high ARBS score (>2) in pre-treatment samples (n=86) was associated with significantly shorter OS and lower PSA RR compared with low ARBS (≤2) group for patients receiving AR pathway inhibitor (ARPI) or taxane chemotherapy (13.4 vs. 19.4 months, p=7.3×10-3, 45.7% vs. 77.5%, p=5.2×10-3). By integrating genome-wide DNA methylation profiling, we further found that ARBS was hypo-methylated in mCRPC patients, and identified a strong negative correlation between DNA methylation beta value and ARBS score (R=-0.83). Conclusions: ARBS nucleosome profiling abnormality inferred from LP-WGS can serve as a key prognostic tool for mCRPC patients. Patients with high ARBS score had worse clinical outcomes, highlighting the potential clinical utility of cfDNA fragmentomics analysis for mCRPC patient stratification. Integration of mutation, copy number variation and fragmentomics profiling of ARBS may further enhance our understanding of molecular aberrations and treatment outcomes in mCRPC.

Liver Metastasis in Advanced Ovarian Cancer after Chemotherapy: A Case Report

Ovarian cancer is the most lethal disease among gynecologic malignancies; about 1/4 of ovarian cancer patients are in stage IV when diagnosed. Based on the data of Globocan, there were 295,414 newly diagnosed ovarian cancer patients and 184,799 deaths registered in 2018. For ovarian epithelial cancer patients with stage IV disease, the mean overall survival (OS) is around 20 months, and the 5 year-OS is about 20%. About 1 in 5 patients with advanced-stage ovarian cancer have hepatobiliary involvement. The study on HGSOC aims to understand the molecular and genetic features, diagnosis, and prognosis of HGSOC, as well as its response to therapy. The method involves analyzing the genetic traits, chromosomal instability, and dysregulation of signaling pathways associated with HGSOC, as well as the detection of stemness and EMT levels in response to chemotherapy and radiation therapy. The results highlight the unique characteristics of HGSOC, such as nearly universal mutation in and dysfunction of p53, genomic instability, and the role of cancer stem cells and EMT in chemo- and radiation resistance. The implication of the study is the need for a better understanding of the molecular basis of HGSOC for improved diagnosis, prognosis, and treatment strategies.