As living standards elevate, cancers are appearing in growing numbers among younger individuals globally and these risks escalate with advancing years. One of the reasons is that instability in the cancer genome reduces the effectiveness of conventional drug treatments and chemotherapy, compared with more targeted therapies. Previous research has discovered non-coding RNAs' crucial role in shaping genetic networks involved in cancer cell growth and invasion through their influence on messenger RNA production or protein binding. Additionally, the interaction between non-coding RNAs and oxidative stress, a crucial process in cancer advancement, cannot be overlooked. Essentially, oxidative stress results from the negative effects of radicals within the body and ties directly to cancer gene expression and signaling. Therefore, this review focuses on the mechanism between non-coding RNAs and oxidative stress in cancer progression, which is conducive to finding new cancer treatment strategies.

This study aimed to explore PTPN2 expression levels in Hypopharyngeal Squamous Cell Carcinoma (HPSCC) tissues and their relationship with the clinical characteristics and prognosis of HPSCC patients. PTPN2, a protein tyrosine phosphatase, has recently emerged as a promising target for cancer immunotherapy, and in many previous studies, PTPN2 may have a significant role in the growth, differentiation, metabolism and immune response of head and neck malignant tumors. In this study, PTPN2 expression in Head and Neck Squamous Cell Carcinoma (HNSCC) and other cancer tissues was analyzed using datasets derived from the Sangerbox database. Furthermore, we analyzed data on PTPN2 mRNA levels across various clinical stages of HNSCC (I, II, III, and IV), which was extracted from the Gene Expression Profiling Interactive Analysis (GEPIA) database. Clinical data from patients who underwent surgical resection for hypopharyngeal malignancies at the Third Affiliated Hospital of Zunyi Medical University between January 2013 and January 2024 were also obtained and analyzed. The patient specimens were categorized into two groups (the HPSCC tumor and paracarcinoma tissue groups) and compared for PTPN2 expression using Immunohistochemistry (IHC), Immunofluorescence (IF), and Western Blot (WB) analyses. According to the results, HPSCC patients were mostly elderly males with a history of tobacco and alcohol abuse. Furthermore, the most common site of HPSCC onset was piriform sinuses, and the disease was often diagnosed in the middle or advanced stages. Additionally, HPSCC tissues exhibited PTPN2 upregulation. Moreover, PTPN2 expression did not correlate significantly with patients' gender, Smoking Index (SI), alcohol abuse, tumor diameter, Hypertension (HTN), diabetes, and M stage. On the other hand, it correlated with HPSCC patients' T-stage, N-stage, Overall Survival (OS), and clinical stage. Based on these findings, we deduced that high PTPN2 expression could be involved in HPSCC patients' poor prognosis.

Ixodes scapularis ticks transmit several medically important pathogens including Anaplasma phagocytophilum to humans and animals. In this study, we provide evidence that A. phagocytophilum modulates autophagy molecules for its survival in tick cells. qRT-PCR analysis revealed that A. phagocytophilum infection results in the upregulation of tyrosine phosphatase, shp-2, and serine/threonine-protein kinase, mTOR, in ticks and tick cells. RNAi-mediated knockdown of shp-2 or functional blocking with SHP-2 inhibitor resulted in significantly increased bacterial burden and reduced phospho-mTOR levels in A. phagocytophilum-infected tick cells. In addition, treatment of A. phagocytophilum-infected tick cells with rapamycin (mTOR inhibitor) resulted in significantly increased bacterial burden and reduced phospho-mTOR levels. Furthermore, expression of autophagy molecules such as atg14 and ulk1 were noted to be upregulated in both A. phagocytophilum-infected unfed ticks and tick cells. RNAi-mediated silencing of atg14 or ulk1 affected bacterial growth in tick cells. Collectively, these results not only indicate distinct host and pathogen responses in tick-A. phagocytophilum interactions but also suggest that this bacterium modulates autophagy molecules for its survival in ticks.

In this study, we provide a comprehensive characterization of HPV-positive primary cervical cancers (CC) and HPV-positive head and neck squamous cell carcinomas (HNSCC) through whole genome next-generation sequencing. Human papillomavirus (HPV) infection, recognized as a definitive human carcinogen, is increasingly acknowledged for its role in development of human cancers. HPV-driven cervical cancers are among the leading causes of cancer-related deaths worldwide, while HPV-driven head and neck cancers exhibit distinct biological and clinical characteristics. Recent data has provided convincing evidence that HPV-related cervical cancer, like HPV head and neck cancer also predict better outcomes, with viral integration patterns further predicting disease related outcomes.

We designed an experimental study that encompasses four pairs of HPV-positive patient samples with controls, utilizing state-of-the-art Next Generation Sequencing (NGS) technology including whole genome sequencing, transcriptome sequencing and virus integration.

Multiple mutated genes, including TTN, COL6A3, and FLNA, were identified shared between CC and HNSCC. Additionally, we observed a notable proportion of pathways affected by oncogenic alterations, particularly in the RTK-RAS and NOTCH pathways, in both CC and HNSCC. Furthermore, we discovered a shared down-regulation of the Hedgehog signaling pathway based on transcriptome expression analysis in KEGG. We also identified RUNX2 and TFPI as sites of virus integration, and upstream as well as downstream pathway modulators, and represent potential targets for therapeutic interventions.

Overall, this study showed a thorough comparison between CC and HNSCC from multiple aspects, including gene variations, oncogenic pathways, KEGG enrichment and virus integration sites. However, further studies, which involve larger patient cohorts should be undertaken to further support these findings.

Central nervous system tumors represent the leading cause of cancer-related mortality in children. Conventional therapies of surgery, radiation, and cytotoxic chemotherapy have insufficient efficacy for some pediatric CNS tumors and are associated with significant morbidity, prompting an ongoing need for novel treatment approaches. Identification of molecular alterations driving tumorigenesis has led to a rising interest in developing targeted therapies for these tumors. The present narrative review focuses on recent progress in targeted therapies for pediatric CNS tumors. We outline the key implicated cellular pathways, discuss candidate molecular therapies for targeting each pathway, and present an overview of the clinical trial landscape for targeted therapies in pediatric CNS tumors. We then discuss challenges and future directions for targeted therapy, including combinatorial approaches and real-time drug screening for personalized treatment planning.

RAS proteins, as pivotal signal transduction molecules, are frequently mutated and hyperactivated in various human cancers, closely associated with tumor cell proliferation, survival, and metastasis. Despite extensive research on RAS targeted therapies, developing effective RAS inhibitors remains a significant challenge. Natural products, endowed with unique chemical structures and diverse biological activities through long-term natural selection, have emerged as a vital resource for discovering novel RAS-targeted therapeutic drugs. This review focuses on the latest advancements in targeting RAS with natural products and categorizes these natural products based on their mechanisms of action. Additionally, we discuss the challenges faced by these natural products during clinical translation, including issues related to pharmacokinetics. Strategies such as combination therapy, structural optimization, and drug delivery systems are anticipated to enhance efficacy and overcome these challenges.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with hallmark pathways of metastasis along with classical and non-classical epithelial-mesenchymal transition. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered ligands ephrinB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggests that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Lung cancer is a type of cancer that begins in the lungs and is one of the leading causes of cancer-related deaths worldwide. Herein an attempt to explore the relationship between the properties of indolone derivatives and their anticancer activity was investigated, implementing in silico approaches. Four indolone derivatives with the highest anticancer potential were selected to evaluate their pharmacological properties. The ADMET analysis revealed that these compounds exhibited favourable drug-like properties, meeting nearly all the key pharmacological criteria required for potential therapeutic agents. Molecular docking studies of the most active compounds revealed strong interactions with critical amino acid residues in the PDK1 receptor's binding site, underscoring their potential as effective PDK1 inhibitors. In addition, 200 ns molecular dynamics (MD) simulations of two R and S configurations validated the stability of the ligand-receptor complexes, with minimal structural deviations observed throughout the simulation period. These comprehensive results highlight the potential of the selected indolone derivatives as viable drug candidates and provide a solid foundation for future optimization efforts aimed at developing novel PDK1 inhibitors for cancer therapy.

Over the past two decades, tyrosine kinase inhibitors (TKIs) have rapidly emerged as pivotal targeted agents, offering promising therapeutic prospects for patients. However, as the cornerstone of targeted therapies, an increasing number of TKIs have been found to develop acquired resistance during treatment, making the challenge of overcoming this resistance a primary focus of current research. This review comprehensively examines the evolution of TKIs from multiple perspectives, with particular emphasis on the mechanisms underlying acquired resistance, innovative drug design strategies, inherent challenges, and future directions.

Red grapes contain resveratrol (Resv), a polyphenol with anti-inflammatory, anti-diabetic, and anticancer properties. In this study, in silico molecular docking was used to assess the binding affinity of Resv to target proteins. Resv was encapsulated in PEGylated liposomes (LNPs) using Phospholipon 90G, cholesterol, and DSPE-mPEG2000. The particle size, surface charge, and structural details of the Res-LNPs and the Blank LNPs were determined. The effects of Res-LNPs and pure Resv were examined in vitro in C6 (rat glioma) and U87 MG (human glioblastoma) cell lines to evaluate cell survival, uptake, wound healing, and apoptosis. BBB permeability of the Res-LNPs was assessed using an in vitro BBB model with hCMEC/D3 cells. EGFR and AKT 1 and 2 expression levels in Resv-treated U87 MG cells were analyzed by RT-qPCR. Res-LNPs had a particle size of 155.0 ± 1.62 nm and an encapsulation efficiency (% EE) of 76.62 ± 3.43. FTIR, DSC, and XRD analyses confirmed the complete entrapment of Resv within the LNPs, displaying a unilamellar spherical morphology, as verified by SEM and TEM. In vitro studies on C6 and U87 MG cell lines showed that Res-LNPs significantly improved cell viability, uptake, migration, and apoptosis compared with Resv. An in vitro BBB model demonstrated that Res-LNPs efficiently crossed the BBB and accumulated in brain cancer cells. RT-qPCR results indicated that Resv treatment reduced EGFR and AKT 1 and 2 gene expression in U87 MG cells. These results suggest that Res-LNPs effectively crossed BBB and inhibited EGFR and its downstream pathways in glioma cell lines.

The interactions between platelet-derived growth factor/PDGF receptor and integrin signaling are crucial for cells to respond to extracellular stimuli. Integrin interactions with PDGFR within the lipid rafts activate downstream cellular signaling pathways that regulate cell proliferation, cell migration, cell differentiation, and cell death processes. The mechanisms underlying PDGFR activation mediated receptor internalization, interactions with other cell-surface receptors, particularly extracellular matrix receptors, integrins, and how these cellular mechanisms switch on anchorage-independent cell survival, leading to anoikis resistance are discussed. The role of regulatory molecules such as noncoding RNAs, that can modulate several molecular and cellular processes, including autophagy, in the acquisition of anoikis resistance is also discussed. Overall, the review provides a new perspective on a complex interplay of regulatory cellular machineries involving autophagy, noncoding RNAs and cellular mechanisms of PDGFR activation, PDGFR-integrin interactions, and involvement of lipids rafts in the acquisition of anoikis resistance that regulates glioblastoma progression along with potential future strategies to develop novel therapeutics for glioblastoma multiforme.

The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.

Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration, influenced by a complex interplay of mechanical, biochemical, and molecular cues. Properties of the extracellular matrix (ECM) such as stiffness and alignment guide stem cell fate through mechanosensitive pathways, where forces like shear stress translate into biochemical signals, affecting cell behavior. Aging introduces senescence which disrupts the MuSC niche, leading to reduced regenerative capacity via epigenetic alterations and metabolic shifts. Transplantation further challenges MuSC viability, often resulting in fibrosis driven by dysregulated fibro-adipogenic progenitors (FAPs). Addressing these issues, scaffold designs integrated with pharmacotherapy emulate ECM environments, providing cues that enhance graft functionality and endurance. These scaffolds facilitate the synergy between mechanotransduction and intracellular signaling, optimizing MuSC proliferation and differentiation. Innovations utilizing human pluripotent stem cell-derived myogenic progenitors and exosome-mediated delivery exploit bioactive properties for targeted repair. Additionally, 3D-printed and electrospun scaffolds with adjustable biomechanical traits tackle scalability in treating volumetric muscle loss. Advanced techniques like single-cell RNA sequencing and high-resolution imaging unravel muscle repair mechanisms, offering precise mapping of cellular interactions. Collectively, this interdisciplinary approach fortifies tissue graft durability and MuSC maintenance, propelling therapeutic strategies for muscle injuries and degenerative diseases.

Nowadays, skin cancer is widespread just like a varied malignant cancer which can cause serious health issues. Skin cancer, which encompasses malignant melanoma, basal cell carcinoma, and squamous cell carcinoma, is a prevalent form of cancer among humans. Due to its broad prevalence, financial burden, mortality rates, and cosmetic effects, it is a major public health issue. Skin cancer treatment involves surgery, chemotherapy, and radiation. Recently, personalized treatment in the fields of targeted therapies and precision medicine has been shown to diagnose early detection of every individual tumor by knowing their genetic and molecular characteristics. To target the molecular pathways responsible for tumor growth and reduce the damage to healthy tissue, new targeted therapies have emerged for melanoma, basal cell carcinoma, and squamous cell carcinoma. B-raf serine/threonine kinase (BRAF) and mitogen-activated protein kinase (MEK) inhibitors, immune checkpoint inhibitors, and precision medications have strong response rates to improve patient survival. Targeted therapeutics like nanocarriers have shown promising results by reducing skin irritation and protecting encapsulated therapeutics. These formulations have been shown to improve the transdermal permeability of anticancer drugs. The consideration of employing physical techniques to enhance the permeation of nanocarriers warrants attention to augment the dermal permeation of anticancer agents and facilitate targeted drug delivery within neoplastic cells. Targeted therapies face obstacles like resistance mechanisms and treatment strategy monitoring. Taken together, this review delves into the basic mechanisms of skin cancer, current treatment methods, drug resistance processes, and nano-based targeted techniques for cancer treatment. It will also delineate the challenges and perspectives in pre-clinical and clinical contexts.

Epidermal growth factor receptor (EGFR) controls cell growth, death, and proliferation through a variety of signaling mechanisms. The expression of vascular endothelial growth factor receptor-2 (VEGFR-2) by endothelial cells from malignant tissues triggers a series of signaling pathways that lead to tumor angiogenesis and increase cancer cell survival, proliferation, migration, and vascular permeability. The aim is to find novel inhibitors for EGFR and VEGFR-2 kinases by molecular docking drug-likeness models, pharmacokinetic, interaction analysis, and molecular dynamic simulation. Over 482 ligands were tested against the kinases, there are about 20 compounds that had the best docking scores for the 2 kinases but only compound 2C inhibited them with the highest score values by binding to active sites pocket established through molecular docking study. Secondly, the drug-likeness score of 2C was very good compared to the other compounds. The pharmacokinetics, physicochemical properties, and toxicity of 2C were much better than sorafenib and erlotinib as references. Analysis of interaction showed a strong interaction between 2C and active sites of EGFR and VEGFR-2 kinases illustrated by calculation of halogen bonds, π-Cation Interactions, Hydrogen Bonds, and Hydrophobic Interactions. Finally, the molecular dynamic simulation was also used to assess the stability of the EGFR and VEGFR-2 kinases-2C complexes. The complexes' stability was validated by RMSD, Rg, RMSF, SASA, and several hydrogen bonds analysis. 2C was shown to interact stably with pocket residues after MD simulation. Compound 2C may be a promising way to slow the signaling cascade of proteins that are significant contributors to the spread of cancer.Communicated by Ramaswamy H. Sarma.

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

Neuroblastoma is a devastating disease accounting for ~15% of all childhood cancer deaths. Collagen content and fiber association within the tumor stroma influence tumor progression and metastasis. High expression levels of collagen receptor kinase, Discoidin domain receptor II (DDR2), are associated with the poor survival of neuroblastoma patients. Additionally, cancer cells generate and sustain mechanical forces within their environment as a part of their normal physiology. Despite this, evidence regarding whether collagen-activated DDR2 signaling dysregulates these migration forces is still elusive. To address these questions, a novel shRNA DDR2 knockdown neuroblastoma cell line (SH-SY5Y) was engineered to evaluate the consequence of DDR2 on cellular mechanics. Atomic force microscopy (AFM) and traction force microscopy (TFM) were utilized to unveil the biophysical altercations. DDR2 downregulation was found to significantly reduce proliferation, cell stiffness, and cellular elongation. Additionally, DDR2-downregulated cells had decreased traction forces when plated on collagen-coated elastic substrates. Together, these results highlight the important role that DDR2 has in reducing migration mechanics in neuroblastoma and suggest DDR2 may be a promising novel target for future therapies.

The 2019 outbreak of SARS-CoV-2 has caused a major worldwide health crisis with high rates of morbidity and death. Interestingly, it has also been linked to cancer, which begs the issue of whether it plays a role in carcinogenesis. Recent studies have revealed various mechanisms by which SARS-CoV-2 can influence oncogenic pathways, potentially promoting cancer development. The virus encodes several proteins that alter key signaling pathways associated with cancer hallmarks. Unlike classical oncogenic viruses, which transform cells through viral oncogenes or by activating host oncogenes, SARS-CoV-2 appears to promote tumorigenesis by inhibiting tumor suppressor genes and pathways while activating survival, proliferation, and inflammation-associated signaling cascades. Bioinformatic analyses and experimental studies have identified numerous interactions between SARS-CoV-2 proteins and cellular components involved in cancer-related processes. This review explores the intricate relationship between SARS-CoV-2 infection and cancer, focusing on the regulation of key hallmarks driving initiation, promotion and progression of cancer by viral proteins. By elucidating the underlying mechanisms driving cellular transformation, the potential of SARS-CoV-2 as an oncovirus is highlighted. Comprehending these interplays is essential to enhance our understanding of COVID-19 and cancer biology and further formulating strategies to alleviate SARS-CoV-2 influence on cancer consequences.

Aberrant phosphorylation of receptor tyrosine kinases (RTKs) is usually involved in tumor initiation, progression, and metastasis. However, developing specific and efficient molecular tools to regulate RTK phosphorylation remains a considerable challenge. In this study, we reported novel aptamer-based chimeras to inhibit the phosphorylation of RTKs, such as c-Met and EGFR, by enforced recruitment of a protein tyrosine phosphatase receptor type F (PTPRF). Our studies revealed that aptamer-based chimeras displayed a generic and potent inhibitory effect on RTK phosphorylation induced by growth factor or auto-dimerization in different cell lines and modulated cell biological behaviors by recruiting PTPRF. Furthermore, based on angstrom accuracy of the DNA duplex, the maximum catalytic radius of PTPRF was determined as ∼25.84 nm, providing a basis for the development of phosphatase-recruiting strategies. Taken together, our study provides a generic methodology not only for selectively mediating RTK phosphorylation and cellular biological processes but also for developing novel therapeutic drugs.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Breast cancer (BC) has emerged as the most common malignancy among females. The genomic profile of BC is diverse in nature and complex due to heterogeneity among various geographically different ethnic groups. The primary objective of this study was to carry out a comprehensive mutational analysis of Indian BC cases by performing whole exome sequencing. The cohort included patients with a median age of 48 years. TTN, TP53, MUC16, SYNE1, and OBSCN were the frequently altered genes found in our cohort. The PIK3CA and KLC3 genes are driver genes implicated in various cellular functions and cargo transportation through microtubules, respectively. Except for CCDC168 and PIK3CA, several gene pairings were found to be significantly linked with co-occurrence. Irrespective of their hormonal receptor status, RTK/RAS was observed with frequently altered signaling pathways. Further analysis of the mutational signature revealed that SBS13, SBS6, and SBS29 were mainly observed in our cohort. This study supplements the discovery of diagnostic biomarkers and provides new therapeutic options for the improved management of BC.

Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy.

This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy.

While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 μM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 μM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.

Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways in which interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with the formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acid, and lipid metabolism. 5'-Phosphoribosyl-N-formylglycinamide, a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase, which catalyzes 5'-phosphoribosyl-N-formylglycinamide synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTP depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTP reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis.

Maintenance of genome stability prevents disease and affiliates with growth factor receptor tyrosine kinases. We identified de novo purine synthesis as a pathway in which key enzymatic players are regulated through MET receptor and whose depletion via MET targeting explains MET inhibition-associated formation of DNA double-strand breaks. The mechanistic importance of MET inhibition-dependent E2F1 downregulation for interference with DNA integrity has translational implications for MET-targeting-based treatment of malignancies.

Breast cancer (BC) is the most common cancer among women and a major cause of death from cancer. The role of estrogen and progestins, including synthetic hormones like R5020, in the development of BC has been highlighted in numerous studies. In our study, we employed machine learning and advanced bioinformatics to identify genes that could serve as diagnostic markers for BC. We thoroughly analyzed the transcriptomic data of two BC cell lines, T47D and UDC4, and performed differential gene expression analysis. We also conducted functional enrichment analysis to understand the biological functions influenced by these genes. Our study identified several diagnostic genes strongly associated with BC, including MIR6728, ENO1-IT1, ENO1-AS1, RNU6-304P, HMGN2P17, RP3-477M7.5, RP3-477M7.6, and CA6. The genes MIR6728, ENO1-IT1, ENO1-AS1, and HMGN2P17 are involved in cancer control, glycolysis, and DNA-related processes, while CA6 is associated with apoptosis and cancer development. These genes could potentially serve as predictors for BC, paving the way for more precise diagnostic methods and personalized treatment plans. This research enhances our understanding of BC and offers promising avenues for improving patient care in the future.

Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.

Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor 2 (VEGFR2) are known as valid targets for cancer therapy. Overexpression of EGFR induces uncontrolled cell proliferation and VEGF expression triggering angiogenesis via VEGFR2 signaling. On the other hand, VEGF expression independent of EGFR signaling is already known as one of the mechanisms of resistance to anti-EGFR therapy. Therefore, drugs that act as dual inhibitors of EGFR and VEGFR2 can be a solution to the problem of drug resistance and increase the effectiveness of therapy. In this review, we summarize the relationship between EGFR and VEGFR2 signal transduction in promoting cancer growth and how their kinase domain structures can affect the selectivity of an inhibitor as the basis for designing dual inhibitors. In addition, several recent studies on the development of dual EGFR and VEGFR2 inhibitors involving docking simulations were highlighted in this paper to provide some references such as pharmacophore features of inhibitors and key residues for further research, especially in computer-aided drug design.

The fibroblast growth factor receptor 2 (FGFR2) gene is one of the most extensively studied genes with many known mutations implicated in several human disorders, including oncogenic ones. Most FGFR2 disease-associated gene mutations are missense mutations that result in constitutive activation of the FGFR2 protein and downstream molecular pathways. Many tertiary structures of the FGFR2 kinase domain are publicly available in the wildtype and mutated forms and in the inactive and activated state of the receptor. The current literature suggests a molecular brake inhibiting the ATP-binding A loop from adopting the activated state. Mutations relieve this brake, triggering allosteric changes between active and inactive states. However, the existing analysis relies on static structures and fails to account for the intrinsic structural dynamics. In this study, we utilize experimentally resolved structures of the FGFR2 tyrosine kinase domain and machine learning to capture the intrinsic structural dynamics, correlate it with functional regions and disease types, and enrich it with predicted structures of variants with currently no experimentally resolved structures. Our findings demonstrate the value of machine learning-enabled characterizations of structure dynamics in revealing the impact of mutations on (dys)function and disorder in FGFR2.

Aberrant epigenetic modifications are fundamental contributors to the pathogenesis of various cancers. Consequently, targeting these aberrations with small molecules, such as histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors, presents a viable strategy for cancer therapy. The objective of this study is to assess the anti-cancer efficacy of trichostatin C (TSC), an analogue of trichostatin A sourced from the fermentation of Streptomyces sp. CPCC 203909. Our investigations reveal that TSC demonstrates potent activity against both human lung cancer and urothelial bladder cancer cell lines, with IC50 values in the low micromolar range. Moreover, TSC induces apoptosis mediated by caspase 3/7 and arrests the cell cycle at the G2/M phase. When combined with the DNMT inhibitor decitabine, TSC exhibits a synergistic anti-cancer effect. Additionally, protein analysis elucidates a significant reduction in the expression of the tyrosine kinase receptor Axl. Notably, elevated concentrations of TSC correlate with the up-regulation of the transcription factor forkhead box class O1 (FoxO1) and increased levels of the proapoptotic proteins Bim and p21. In conclusion, our findings suggest TSC as a promising anti-cancer agent with HDAC inhibitory activity. Furthermore, our results highlight the potential utility of TSC in combination with DNMT inhibitors for cancer treatment.

Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of "wet-lab" experiments. In this review, we explore the applications of computational approaches in membrane protein oncological characterization, particularly focusing on three prominent membrane protein families: receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and solute carrier proteins (SLCs). We chose these families due to their varying levels of understanding and research data availability, which leads to distinct challenges and opportunities for computational analysis. We discuss the utilization of multi-omics data, machine learning, and structure-based methods to investigate aberrant protein functionalities associated with cancer progression within each family. Moreover, we highlight the importance of considering the broader cellular context and, in particular, cross-talk between proteins. Despite existing challenges, computational tools hold promise in dissecting membrane protein dysregulation in cancer. With advancing computational capabilities and data resources, these tools are poised to play a pivotal role in identifying and prioritizing membrane proteins as personalized anticancer targets.

Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.