Integrating network analysis with differential expression to uncover therapeutic and prognostic biomarkers in esophageal squamous cell carcinoma.

Introduction: Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, we used bioinformatics analysis to identify potential biomarkers and therapeutic targets for ESCC. Methodology: Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained by comprehensively analyzing publicly available RNA-seq datasets from the TCGA and GTEX. Gene Ontology (GO) annotation and Reactome pathway analysis identified the biological roles of the DEGs. Moreover, the Cytoscape 3.10.1 platform and subsidiary tools such as CytoHubba were used to visualize the DEGs' protein-protein interaction (PPI) network and identify hub genes, Furthermore our results are validated by using Single-cell RNA analysis. Results: Identification of 2524 genes exhibiting altered expression enriched in pathways including keratinization, epidermal cell differentiation, G alpha(s) signaling events, and biological process of cell proliferation and division, extracellular matrix (ECM) disassembly, and muscle function. Moreover, upregulation of hallmarks E2F targets, G2M checkpoints, and TNF signaling. CytoHubba revealed 20 hub genes that had a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of four genes, CDK1 MAD2L1, PLK1, and TOP2A, were associated with critical dependence for cell survival in ESCC cell lines, as indicated by CRISPR dependency scores, gene expression data, and cell line metadata. We also identify the molecules targeting these essential hub genes, among which GSK461364 is a promising inhibitor of PLK1, BMS265246, and Valrubicin inhibitors of CDK1 and TOP2A, respectively. Moreover, we identified that elevated expression of MMP9 is associated with worse overall survival in ESCC patients, which may serve as potential prognostic biomarker or therapeutic target for ESCC. The single-cell RNA analysis showed MMP9 is highly expressed in myeloid, fibroblast, and epithelial cells, but low in T cells, endothelial cells, and B cells. This suggests MMP9's role in tumor progression and matrix remodeling, highlighting its potential as a prognostic marker and therapeutic target. Discussion: Our study identified key hub genes in ESCC, assessing their potential as therapeutic targets and biomarkers through detailed expression and dependency analyses. Notably, MMP9 emerged as a significant prognostic marker with high expression correlating with poor survival, underscoring its potential for targeted therapy. These findings enhance our understanding of ESCC pathogenesis and highlight promising avenues for treatment.

Pyrethroids and reproductive function: some endocrine disrupting perspectives from molecular simulations.

Pyrethroids are widely used insecticides with huge applications for household as well as agricultural purposes and contribute to improved product quality and higher yields. In recent decades, the demand for pyrethroids has increased significantly due to advantages such as broad-spectrum efficacy, high insecticidal potential, and lower pest resistance. However, several studies have suggested that human exposure to pyrethroids leads to reproductive problems. Sex hormone-binding globulin (SHBG) is an important hormone transport protein regulating the availability of steroids at their target site. The aim of our study was to investigate the structural interactions of commonly used pyrethroids, cypermethrin and deltamethrin, with ligand binding pocket of SHBG. Cypermethrin and deltamethrin were docked into the steroid binding pocket of SHBG using Schrodinger's induced fit docking (IFD) followed by molecular dynamics (MD) simulation studies. The resultant SHBG-pyrethroid complexes from IFD experiments were subjected to structural analysis including the molecular interactions followed by binding energy estimation. The analysis revealed that both the ligands were tightly bound in the SHBG pocket with high percentage of commonality among the SHBG residues between the indicated pyrethroid ligands and the SHBG native ligand, dihydrotestosterone (DHT). The estimated binding energy values for cypermethrin were less but close to the values calculated for the SHBG native ligand, DHT. However, the estimated binding energy values for deltamethrin were higher compared to the values calculated for SHBG native ligand, DHT. Furthermore, the MD simulation results also revealed the higher stability of SHBG-deltamethrin than SHBG-cypermethrin complex. To sum up, the results suggested that deltamethrin has a greater capability than cypermethrin to prevent sex steroid hormone from binding to SHBG, even though both pyrethroids have this ability. Consequently, this might hamper the circulatory transport of sex steroid hormones and their availability at the target site, subsequently interfering with reproductive function.

Bergenin inhibits growth of human cervical cancer cells by decreasing Galectin-3 and MMP-9 expression.

Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.

Secretory Trefoil Factor 1 (TFF1) promotes gemcitabine resistance through chemokine receptor CXCR4 in Pancreatic Ductal Adenocarcinoma.

Gemcitabine is the first-line treatment option for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, the frequent adoption of resistance to gemcitabine by cancer cells poses a significant challenge in treating this aggressive disease. In this study, we focused on analyzing the role of trefoil factor 1 (TFF1) in gemcitabine resistance in PDAC. Analysis of PDAC TCGA and cell line datasets indicated an enrichment of TFF1 in the gemcitabine-resistant classical subtype and suggested an inverse correlation between TFF1 expression and sensitivity to gemcitabine treatment. The genetic ablation of TFF1 in PDAC cells enhanced their sensitivity to gemcitabine treatment in both in vitro and in vivo tumor xenografts. The biochemical studies revealed that TFF1 contributes to gemcitabine resistance through enhanced stemness, increasing migration ability of cancer cells, and induction of anti-apoptotic genes. We further pursued studies to predict possible receptors exerting TFF1-mediated gemcitabine resistance. Protein-protein docking investigations with BioLuminate software revealed that TFF1 binds to the chemokine receptor CXCR4, which was supported by real-time binding analysis of TFF1 and CXCR4 using SPR studies. The exogenous addition of TFF1 increased the proliferation and migration of PDAC cells through the pAkt/pERK axis, which was abrogated by treatment with a CXCR4-specific antagonist AMD3100. Overall, the present study demonstrates the contribution of the TFF1-CXCR4 axis in imparting gemcitabine resistance properties to PDAC cells.

The future of cancer treatment: combining radiotherapy with immunotherapy.

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other's beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell's genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.

Therapeutic implications of signaling pathways and tumor microenvironment interactions in esophageal cancer.

Esophageal cancer (EC) is significantly influenced by the tumor microenvironment (TME) and altered signaling pathways. Downregulating these pathways in EC is essential for suppressing tumor development, preventing metastasis, and enhancing therapeutic outcomes. This approach can increase tumor sensitivity to treatments, enhance patient outcomes, and inhibit cancer cell proliferation and spread. The TME, comprising cellular and non-cellular elements surrounding the tumor, significantly influences EC's development, course, and treatment responsiveness. Understanding the complex relationships within the TME is crucial for developing successful EC treatments. Immunotherapy is a vital TME treatment for EC. However, the heterogeneity within the TME limits the application of anticancer drugs outside clinical settings. Therefore, identifying reliable microenvironmental biomarkers that can detect therapeutic responses before initiating therapy is crucial. Combining approaches focusing on EC signaling pathways with TME can enhance treatment outcomes. This integrated strategy aims to interfere with essential signaling pathways promoting cancer spread while disrupting factors encouraging tumor development. Unraveling aberrant signaling pathways and TME components can lead to more focused and efficient treatment approaches, identifying specific cellular targets for treatments. Targeting the TME and signaling pathways may reduce metastasis risk by interfering with mechanisms facilitating cancer cell invasion and dissemination. In conclusion, this integrative strategy has significant potential for improving patient outcomes and advancing EC research and therapy. This review discusses the altered signaling pathways and TME in EC, focusing on potential future therapeutics.

Deep learning-based identification of esophageal cancer subtypes through analysis of high-resolution histopathology images.

Esophageal cancer (EC) remains a significant health challenge globally, with increasing incidence and high mortality rates. Despite advances in treatment, there remains a need for improved diagnostic methods and understanding of disease progression. This study addresses the significant challenges in the automatic classification of EC, particularly in distinguishing its primary subtypes: adenocarcinoma and squamous cell carcinoma, using histopathology images. Traditional histopathological diagnosis, while being the gold standard, is subject to subjectivity and human error and imposes a substantial burden on pathologists. This study proposes a binary class classification system for detecting EC subtypes in response to these challenges. The system leverages deep learning techniques and tissue-level labels for enhanced accuracy. We utilized 59 high-resolution histopathological images from The Cancer Genome Atlas (TCGA) Esophageal Carcinoma dataset (TCGA-ESCA). These images were preprocessed, segmented into patches, and analyzed using a pre-trained ResNet101 model for feature extraction. For classification, we employed five machine learning classifiers: Support Vector Classifier (SVC), Logistic Regression (LR), Decision Tree (DT), AdaBoost (AD), Random Forest (RF), and a Feed-Forward Neural Network (FFNN). The classifiers were evaluated based on their prediction accuracy on the test dataset, yielding results of 0.88 (SVC and LR), 0.64 (DT and AD), 0.82 (RF), and 0.94 (FFNN). Notably, the FFNN classifier achieved the highest Area Under the Curve (AUC) score of 0.92, indicating its superior performance, followed closely by SVC and LR, with a score of 0.87. This suggested approach holds promising potential as a decision-support tool for pathologists, particularly in regions with limited resources and expertise. The timely and precise detection of EC subtypes through this system can substantially enhance the likelihood of successful treatment, ultimately leading to reduced mortality rates in patients with this aggressive cancer.

Extracellular vesicles as tools and targets in therapy for diseases.

Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.

Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.

CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond.

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.

Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk. METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR. RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004). CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

The potential modulation of gut microbiota and oxidative stress by dietary carotenoid pigments.

Gut microbiota plays a crucial role in regulating the response to immune checkpoint therapy, therefore modulation of the microbiome with bioactive molecules like carotenoids might be a very effective strategy to reduce the risk of chronic diseases. This review highlights the bio-functional effect of carotenoids on Gut Microbiota modulation based on a bibliographic search of the different databases. The methodology given in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) has been employed for developing this review using papers published over two decades considering keywords related to carotenoids and gut microbiota. Moreover, studies related to the health-promoting properties of carotenoids and their utilization in the modulation of gut microbiota have been presented. Results showed that there can be quantitative changes in intestinal bacteria as a function of the type of carotenoid. Due to the dependency on several factors, gut microbiota continues to be a broad and complex study subject. Carotenoids are promising in the modulation of Gut Microbiota, which favored the appearance of beneficial bacteria, resulting in the protection of villi and intestinal permeability. In conclusion, it can be stated that carotenoids may help to protect the integrity of the intestinal epithelium from pathogens and activate immune cells.

Gut microbiota plays an essential role in regulating the immune checkpoint therapyCarotenoids are promising molecules in the alteration of gut microbiotaCarotenoids activate the immune cells resulting in a low incidence of oxidative stress.

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments.

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Long non-coding RNAs modulate tumor microenvironment to promote metastasis: novel avenue for therapeutic intervention.

Cancer is a devastating disease and the primary cause of morbidity and mortality worldwide, with cancer metastasis responsible for 90% of cancer-related deaths. Cancer metastasis is a multistep process characterized by spreading of cancer cells from the primary tumor and acquiring molecular and phenotypic changes that enable them to expand and colonize in distant organs. Despite recent advancements, the underlying molecular mechanism(s) of cancer metastasis is limited and requires further exploration. In addition to genetic alterations, epigenetic changes have been demonstrated to play an important role in the development of cancer metastasis. Long non-coding RNAs (lncRNAs) are considered one of the most critical epigenetic regulators. By regulating signaling pathways and acting as decoys, guides, and scaffolds, they modulate key molecules in every step of cancer metastasis such as dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Gaining a good knowledge of the detailed molecular basis underlying lncRNAs regulating cancer metastasis may provide previously unknown therapeutic and diagnostic lncRNAs for patients with metastatic disease. In this review, we concentrate on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis, the cross-talk with metabolic reprogramming, modulating cancer cell anoikis resistance, influencing metastatic microenvironment, and the interaction with pre-metastatic niche formation. In addition, we also discuss the clinical utility and therapeutic potential of lncRNAs for cancer treatment. Finally, we also represent areas for future research in this rapidly developing field.

Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.

BACKGROUND: Osteosarcoma is a type of bone cancer that predominantly affects young individuals, including children and adolescents. The disease progresses through heterogeneous genetic alterations, and patients often develop pulmonary metastases even after the primary tumors have been surgically removed. Ubiquitin-specific peptidases (USPs) regulate several critical cellular processes, such as cell cycle progression, transcriptional activation, and signal transduction. Various studies have revealed the significance of USP37 in the regulation of replication stress and oncogenesis. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was analyzed to investigate USP37 expression. RNA sequencing was utilized to assess the impact of USP37 overexpression and depletion on gene expression in osteosarcoma cells. Various molecular assays, including colony formation, immunofluorescence, immunoprecipitation, and DNA replication restart, were employed to examine the physical interaction between USP37 and PCNA, as well as its physiological effects in osteosarcoma cells. Additionally, molecular docking studies were conducted to gain insight into the nature of the interaction between USP37 and PCNA. Furthermore, immunohistochemistry was performed on archived tissue blocks from osteosarcoma patients to establish a correlation between USP37 and PCNA expression. RESULTS: Analysis of the TCGA database revealed that increased expression of USP37 was linked to decreased progression-free survival (PFS) in osteosarcoma patients. Next-generation sequencing analysis of osteosarcoma cells demonstrated that overexpression or knockdown of USP37 led to the expression of different sets of genes. USP37 overexpression provided a survival advantage, while its depletion heightened sensitivity to replication stress in osteosarcoma cells. USP37 was found to physically interact with PCNA, and molecular docking studies indicated that the interaction occurs through unique residues. In response to genotoxic stress, cells that overexpressed USP37 resolved DNA damage foci more quickly than control cells or cells in which USP37 was depleted. The expression of USP37 varied in archived osteosarcoma tissues, with intermediate expression seen in 52% of cases in the cohort examined. CONCLUSION: The results of this investigation propose that USP37 plays a vital role in promoting replication stress tolerance in osteosarcoma cells. The interaction between USP37 and PCNA is involved in the regulation of replication stress, and disrupting it could potentially trigger synthetic lethality in osteosarcoma. This study has expanded our knowledge of the mechanism through which USP37 regulates replication stress, and its potential as a therapeutic target in osteosarcoma merits additional exploration.

Cyclin-dependent kinases in cancer: Role, regulation, and therapeutic targeting.

Regulated cell division is one of the fundamental phenomena which is the basis of all life on earth. Even a single base pair mutation in DNA leads to the production of the dysregulated protein that can have catastrophic consequences. Cell division is tightly controlled and orchestrated by proteins called cyclins and cyclin-dependent kinase (CDKs), which serve as licensing factors during different phases of cell division. Dysregulated cell division is one of the most important hallmarks of cancer and is commonly associated with a mutation in cyclins and CDKs along with tumor suppressor proteins. Therefore, targeting the component of the cell cycle which leads to these characteristics would be an effective strategy for treating cancers. Specifically, Cyclin-dependent kinases (CDKs) involved in cell cycle regulation have been identified to be overexpressed in many cancers. Many studies indicate that oncogenesis occurs in cancerous cells by the overactivity of different CDKs, which impact cell cycle progression and checkpoint dysregulation which is responsible for development of tumor. The development of CDK inhibitors has emerged as a promising and novel approach for cancer treatment in both solid and hematological malignancies. Some of the novel CDK inhibitors have shown remarkable results in clinical trials, such as-Ribociclib®, Palbociclib® and Abemaciclib®, which are CDK4/6 inhibitors and have received FDA approval for the treatment of breast cancer. In this chapter, we discuss the molecular mechanism through which cyclins and CDKs regulate cell cycle progression and the emergence of cyclins and CDKs as rational targets in cancer. We also discuss recent advances in developing CDK inhibitors, which have emerged as a novel class of inhibitors, and their associated toxicities in recent years.

Current and emerging biomarkers in ovarian cancer diagnosis; CA125 and beyond.

Ovarian cancer (OC) is one of the most common causes of cancer-related death in women worldwide. Its five-year survival rates are worse than the two most common gynecological cancers, cervical and endometrial. This is because it is asymptomatic in the early stages and usually detected in the advanced metastasized stage. Thus, survival is increasingly dependent on timely diagnosis. The delay in detection is contributed partly by the occurrence of non-specific clinical symptoms in the early stages and the lack of effective biomarkers and detection approaches. This underlines the need for biomarker identification and clinical validation, enabling earlier diagnosis, effective prognosis, and response to therapy. Apart from the traditional diagnostic biomarkers for OC, several new biomarkers have been delineated using advanced high-throughput molecular approaches in recent years. They are currently being clinically evaluated for their true diagnostic potential. In this chapter, we document the commonly utilized traditional screening markers and recently identified emerging biomarkers in OC diagnosis, focusing on secretory and protein biomarkers. We also briefly reviewed the recent advances and prospects in OC diagnosis.

Integration of CRISPR/Cas9 with artificial intelligence for improved cancer therapeutics.

Gene editing has great potential in treating diseases caused by well-characterized molecular alterations. The introduction of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based gene-editing tools has substantially improved the precision and efficiency of gene editing. The CRISPR/Cas9 system offers several advantages over the existing gene-editing approaches, such as its ability to target practically any genomic sequence, enabling the rapid development and deployment of novel CRISPR-mediated knock-out/knock-in methods. CRISPR/Cas9 has been widely used to develop cancer models, validate essential genes as druggable targets, study drug-resistance mechanisms, explore gene non-coding areas, and develop biomarkers. CRISPR gene editing can create more-effective chimeric antigen receptor (CAR)-T cells that are durable, cost-effective, and more readily available. However, further research is needed to define the CRISPR/Cas9 system's pros and cons, establish best practices, and determine social and ethical implications. This review summarizes recent CRISPR/Cas9 developments, particularly in cancer research and immunotherapy, and the potential of CRISPR/Cas9-based screening in developing cancer precision medicine and engineering models for targeted cancer therapy, highlighting the existing challenges and future directions. Lastly, we highlight the role of artificial intelligence in refining the CRISPR system's on-target and off-target effects, a critical factor for the broader application in cancer therapeutics.

Natural products as chemo-radiation therapy sensitizers in cancers.

Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer.