Is it possible to treat melanoma by intercepting the CXCR4/CXCL12 pathway?

Melanoma is a particularly aggressive type of skin cancer that can spread to distant organs, resulting in poor patient outcomes. C-X-C motif chemokine ligand 12 (CXCL12) interacts to the C-X-C chemokine receptor type 4 (CXCR4). This connection between CXCR4 and its companion ligand CXCL12 is important in melanoma metastasis and progression, encouraging cell proliferation, invasion, and survival via downstream signaling pathways. Furthermore, CXCR4 is implicated in the interaction between melanoma cells and the tumor microenvironment, which promotes malignant cell migration and immune evasion. Given the importance of the CXCR4/CXCL12 axis in melanoma, addressing this axis has the potential to prevent metastasis and improve patient outcomes. We present an overview of the CXCR4/CXCL12 axis in cancer progression and explain its role in the melanoma microenvironment in this paper. Furthermore, we investigate CXCR4's predictive usefulness as a possible biomarker for monitoring melanoma progression. Finally, we discuss the most recent research and clinical trials on CXCR4 inhibitors, emphasizing their efficacy and limits. We hope to improve the quality of life for melanoma patients by better understanding the role of CXCR4 and investigating novel therapeutic options.

Unravelling the mechanism of polarization transfer from spin-1/2 to spin-1 system in solids.

An analytic theory based on the concept of "effective-fields" is proposed to explain the mechanism of polarization transfer from spin I = 1/2 to spin S = 1 in non-rotating (static) solids. Employing an isolated two-spin model system, the matching conditions responsible for polarization transfer in cross-polarization (CP) experiments are identified and described in terms of the single-transition operators. In contrast to other existing treatments, the polarization transfer among spins is quantified through analytic expressions highlighting the individual contributions emerging from all plausible CP matching conditions. The interplay between the CP matching conditions observed in experiments is outlined in both isotropic and anisotropic systems and verified through comparison between simulations based on analytic and exact numerical methods. The predictions emerging from the analytic theory are verified over a wide range of experimentally relevant parameters and could be beneficial in the optimization of the CP experiments.

Tumor hypoxia and role of hypoxia-inducible factor in oral cancer.

BACKGROUND: Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor hypoxia can help us predict response to treatment and survival. METHODS: A review of the literature on the present evidence and potential clinical importance of tumor hypoxia in head and neck cancer was carried out. The data obtained from the literature search is presented as a narrative review. RESULTS: The literature shows possible associations between prognosis and low tumor oxygenation. Intermediate hypoxia biomarkers like HIF-1, GLUT-1, miRNA, and lactate, can help in predicting the response to therapy and survival as their altered expression is related to prognosis. CONCLUSIONS: Hypoxia is common in HNC and can be detected by use of biomarkers. The tumors that show expression of hypoxia biomarkers have poor prognosis except for patients with human papilloma virus-associated or VHL-associated cancers. Therapeutic targeting of hypoxia is emerging; however, it is still in its nascent stage, with increasing clinical trials hypoxia is set to emerge as an attractive therapeutic target in HNC.

Is cross-species horizontal gene transfer responsible for gallbladder carcinogenesis.

BACKGROUND: Cross-species horizontal gene transfer (HGT) involves the transfer of genetic material between different species of organisms. In recent years, mounting evidence has emerged that cross-species HGT does take place and may play a role in the development and progression of diseases. METHODS: Transcriptomic data obtained from patients with gallbladder cancer (GBC) was assessed for the differential expression of antisense RNAs (asRNAs). The Basic Local Alignment Search Tool (BLAST) was used for cross-species analysis with viral, bacterial, fungal, and ancient human genomes to elucidate the evolutionary cross species origins of these differential asRNAs. Functional enrichment analysis and text mining were conducted and a network of asRNAs targeting mRNAs was constructed to understand the function of differential asRNAs better. RESULTS: A total of 17 differentially expressed antisense RNAs (asRNAs) were identified in gallbladder cancer tissue compared to that of normal gallbladder. BLAST analysis of 15 of these asRNAs (AFAP1-AS1, HMGA2-AS1, MNX1-AS1, SLC2A1-AS1, BBOX1-AS1, ELFN1-AS1, TRPM2-AS, DNAH17-AS1, DCST1-AS1, VPS9D1-AS1, MIR1-1HG-AS1, HAND2-AS1, PGM5P4-AS1, PGM5P3-AS1, and MAGI2-AS) showed varying degree of similarities with bacterial and viral genomes, except for UNC5B-AS1 and SOX21-AS1, which were conserved during evolution. Two of these 15 asRNAs, (VPS9D1-AS1 and SLC2A1-AS1) exhibited a high degree of similarity with viral genomes (Chikungunya virus, Human immunodeficiency virus 1, Stealth virus 1, and Zika virus) and bacterial genomes including (Staphylococcus sp., Bradyrhizobium sp., Pasteurella multocida sp., and, Klebsiella pneumoniae sp.), indicating potential HGT during evolution. CONCLUSION: The results provide novel evidence supporting the hypothesis that differentially expressed asRNAs in GBC exhibit varying sequence similarity with bacterial, viral, and ancient human genomes, indicating a potential shared evolutionary origin. These non-coding genes are enriched with methylation and were found to be associated with cancer-related pathways, including the P53 and PI3K-AKT signaling pathways, suggesting their possible involvement in tumor development.

High-resolution heteronuclear correlations between spin-1/2 and half-integer quadrupolar nuclei under fast MAS solid-state NMR.

High isotropic resolution is essential for the structural elucidation of samples with multiple sites. In this study, utilizing the benefits of TRAPDOR-based heteronuclear multiple quantum coherence (T-HMQC) and a pair of one rotor period long cosine amplitude modulated low-power (cos-lp) pulse-based symmetric-split-t1 multiple-quantum magic angle spinning (MQMAS) methods, we have developed a proton-detected 2D 35Cl/1H T-HMQC-MQMAS pulse sequence under fast MAS (70 kHz) to achieve high-resolution in the indirect dimension of the spin-3/2 (35Cl) nuclei connected via protons. As T-HMQC polarizes not only single-quantum central transition (SQCT) but also triple-quantum (TQ) coherences, the proposed 2D pulse sequence is implemented via selection of two coherence pathways (SQCT→TQ →SQCT and TQ → SQCT→TQ) resulting in the 35Cl isotropic dimension and is superior to the existing double-quantum satellite-transition (DQST) T-HMQC in terms of resolution.

Computational Approach to Elucidating Insulin-Protamine Binding Interactions and Dynamics in Insulin NPH Formulations.

Insulin NPH is an intermediate-acting insulin. Its protracted action profile is due to the formation of microcrystalline suspensions when insulin is complexed with a basic peptide protamine, zinc ion, and phenolic ligands. Despite advancements in analytical techniques, the binding epitope and binding mode of the protamine in the insulin-protamine complex are still unknown. In this study, we used bioinformatics tools such as molecular docking and molecular dynamics (MD) simulations to compute the binding sites and energetics of the insulin-protamine complex. We have taken four naturally occurring protamine peptides that are independently docked with the insulin R6 hexamer and subjected them to 200 ns MD simulations to observe the dynamics of the complexes and estimate the binding energies. The arginine-rich protamine peptides were found to bind on the surface of the insulin hexamer through hydrogen bonding, hydrophobic, and electrostatic interactions well supported by the calculated negative binding energies. The overall structure of the insulin hexamer was retained upon binding, highlighting its dynamic stability in the complex. Furthermore, the residues at the termini of the protamine peptides in the complex were seen to be highly dynamic, which stabilize toward the end of the simulation.

Aspirin and Cancer Survival: An Analysis of Molecular Mechanisms.

The benefit of aspirin on cancer survival is debated. Data from randomized clinical trials and cohort studies are discordant, although a meta-analysis shows a clear survival advantage when aspirin is added to the standard of care. However, the mechanism by which aspirin improves cancer survival is not clear. A PubMed search was carried out to identify articles reporting genes and pathways that are associated with aspirin and cancer survival. Gene ontology and pathway enrichment analysis was carried out using web-based tools. Gene-gene and protein-protein interactions were evaluated. Crosstalk between pathways was identified and plotted. Forty-one genes were identified and classified into primary genes (PTGS2 and PTGES2), genes regulating cellular proliferation, interleukin and cytokine genes, and DNA repair genes. The network analysis showed a rich gene-gene and protein-protein interaction between these genes and proteins. Pathway enrichment showed the interleukin and cellular transduction pathways as the main pathways involved in aspirin-related survival, in addition to DNA repair, autophagy, extracellular matrix, and apoptosis pathways. Crosstalk of PTGS2 with EGFR, JAK/AKT, TP53, interleukin/TNFα/NFκB, GSK3B/BRCA/PARP, CXCR/MUC1, and WNT/CTNNB pathways was identified. The results of the present study demonstrate that aspirin improves cancer survival by the interplay of 41 genes through a complex mechanism. PTGS2 is the primary target of aspirin and impacts cancer survival through six primary pathways: the interleukin pathway, extracellular matrix pathway, signal transduction pathway, apoptosis pathway, autophagy pathway, and DNA repair pathway.

A Scoping Review: Is Yoga an Effective Intervention for Erectile Dysfunction and Premature Ejaculation?

There is increasing concern among both healthcare professionals and the general public about the long-term effectiveness and possible adverse effects of medicines used to treat premature ejaculation (PE) and erectile dysfunction (ED). There is also a growing recognition of the advantages of incorporating alternative or traditional approaches into healthcare systems. Yoga is gaining popularity globally and has emerged as a viable adjunct and alternative to add value to patient care and prevention of illnesses, which requires further investigation. This scoping review aimed to explore the effects of yoga as an independent or adjunct intervention in treating ED and PE. In this review study, researchers conducted a systematic literature review from 2000 to 2023 as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases of Scopus, Google Scholar, Web of Science, and PubMed were used for literature searches. Studies published in the English language on male individuals with ED and PE and those with comorbid stress, anxiety, and depression were also included. Studies on these sexual dysfunctions, comorbid with HIV/AIDS, and severe psychiatric conditions, i.e., schizophrenia, bipolar affective disorders, and substance dependence, except alcohol, were excluded. Ten studies out of the 2016 selected articles met the inclusion criteria and were included in the final analysis. The findings of this scoping review revealed that yoga interventions are more effective in managing PE and ED, with a greater emphasis on the former. Yoga is an effective, safe, and affordable approach recommended for managing erectile functions and PE. Men can improve their quality of life and regain confidence in sexual functioning by incorporating yoga into their routines. The study shows the potential benefits of yoga for both conditions, indicating the need for further robust studies in this area. Researchers advocate practising yoga under professional supervision for optimal safety and guidance.

Is Training Working Memory in Children with Learning Disabilities a Viable Solution? A Systematic Review.

Background: Working memory (WM) is one of the most influential cognitive functions in encoding, registering, and retrieving information. It influences the learning process in children. Its role becomes essential, especially in a child with a learning disability (LD). Researchers worldwide are giving much prominence to WM, especially in devising cognitive retraining strategies for better cognitive functioning and academic attainment in these children. This current study aims to explore globally used instruments to measure this construct and review effective WM training models in the cognitive rehabilitation of children with LD. This study used a systematic review, availing the elaborate "Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA)" guidelines. Summary: The databases of Google Scholar, PubMed, and Web of Science were searched thoroughly, and those studies, which met the inclusion criteria, were considered for this review. Out of 770 studies found with keywords, only six met the inclusion criteria and were selected for a detailed analysis. The outcome of the current review provides trustworthy evidence of poor performance, especially in tasks involving verbal and executive WM in children with all types of learning disabilities (LD) and difficulties. The studies reviewed support the hypothesis that WM can improve with training and significantly improve children's academic attainment. Key Message: Further this review recommends that research and efforts must go into devising these cognitive training techniques. Children have high cerebral plasticity; hence, using cognitive training (emphasizing WM training and other cognitive functions) with them would enhance their cognitive functioning and capacity, improving their academic performance.

Discovering Potential in Non-Cancer Medications: A Promising Breakthrough for Multiple Myeloma Patients.

MM is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse; therefore, advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which are typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM.

Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells.

Multiple Myeloma (MM) is a malignant expansion of plasma cells in the bone marrow (BM), resulting in a disease characterized by symptoms of end organ damage from light chain secretion, crowding of the BM, and bone lesions. Although the past two decades have been characterized by numerous novel therapies emerging, the disease remains incurable due to intrinsic or acquired drug resistance. A major player in MM's drug resistance arises from its intimate relationship with the BM microenvironment (BMME). Through stress-inducing conditions, soluble messengers, and physical adhesion to BM elements, the BMME activates numerous pathways in the myeloma cell. This not only propagates myeloma progression through survival and growth signals, but also specific mechanisms to circumvent therapeutic actions. In this review, we provide an overview of the BMME, the role of individual components in MM survival, and various therapy-specific resistance mechanisms reported in the literature.

Amyloidogenic Propensity of Metabolites in the Uric Acid Pathway and Urea Cycle Critically Impacts the Etiology of Metabolic Disorders.

Novel insights into the etiology of metabolic disorders have recently been uncovered through the study of metabolite amyloids. In particular, inborn errors of metabolism (IEMs), including gout, Lesch-Nyhan syndrome (LNS), xanthinuria, citrullinemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, are attributed to the dysfunction of the urea cycle and uric acid pathway. In this study, we endeavored to understand and mechanistically characterize the aggregative property exhibited by the principal metabolites of the urea cycle and uric acid pathway, specifically hypoxanthine, xanthine, citrulline, and ornithine. Employing scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), we studied the aggregation profiles of the metabolites. Insights obtained through molecular dynamics (MD) simulation underscore the vital roles of π-π stacking and hydrogen bonding interactions in the self-assembly process, and thioflavin T (ThT) assays further corroborate the amyloid nature of these metabolites. The in vitro MTT assay revealed the cytotoxic trait of these assemblies, a finding that was substantiated by in vivo assays employing the Caenorhabditis elegans (C. elegans) model, which revealed that the toxic effects were more pronounced and dose-specific in the case of metabolites that had aged via longer preincubation. We hence report a compelling phenomenon wherein these metabolites not only aggregate but transform into a soft, ordered assembly over time, eventually crystallizing upon extended incubation, leading to pathological implications. Our study suggests that the amyloidogenic nature of the involved metabolites could be a common etiological link in IEMs, potentially providing a unified perspective to study their pathophysiology, thus offering exciting insights into the development of targeted interventions for these metabolic disorders.