Extracellular Vesicles in Triple-Negative Breast Cancer: Immune Regulation, Biomarkers, and Immunotherapeutic Potential.

Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for ~10-20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile and limited targeted therapies, TNBC treatment poses significant challenges. Unlike other BC subtypes, TNBC lacks specific molecular targets, rendering endocrine therapies and HER2-targeted treatments ineffective. The chemotherapeutic regimen is the predominant systemic treatment modality for TNBC in current clinical practice. However, the efficacy of chemotherapy in TNBC is variable, with response rates varying between a wide range of patients, and the emerging resistance further adds to the difficulties. Furthermore, TNBC exhibits a higher mutational burden and is acknowledged as the most immunogenic of all BC subtypes. Consequently, the application of immune checkpoint inhibition has been investigated in TNBC, yielding promising outcomes. Recent evidence identified extracellular vesicles (EVs) as an important contributor in the context of TNBC immunotherapy. In view of the extraordinary ability of EVs to transfer bioactive molecules, such as proteins, lipids, DNA, mRNAs, and small miRNAs, between the cells, EVs are considered a promising diagnostic biomarker and novel drug delivery system among the prospects for immunotherapy. The present review provides an in-depth understanding of how EVs influence TNBC progression, its immune regulation, and their contribution as a predictive biomarker for TNBC. The final part of the review focuses on the recent key advances in immunotherapeutic strategies for better understanding the complex interplay between EVs and the immune system in TNBC and further developing EV-based targeted immunotherapies.

In silico CD4 + T-cell multiepitope prediction and HLA distribution analysis for Marburg Virus-A strategy for vaccine designing.

Marburg, a RNA virus (MRV), is responsible for causing hemorrhagic fever that affects humans and non-human primates. World Health Organization (WHO), National Institutes of Health (NIH) and Centre of Disease Control and Prevention (CDC) considered this as an extremely dangerous virus, thus categorised as risk group 4, category A priority pathogen and category "A" bioterrorism agent, respectively. Despite of all these alarming concerns, no prophylaxis arrangements are available against this virus till date. In fact, the construction of immunogenic vaccine candidates by traditional molecular immunology methods is time consuming and very expensive. Considering these concerns, herein, we have designed CD4 + T Cell multiepitopes against MRV using in silico approach. The pin-point criteria of the screening and selection of potential epitopes are, non-mutagenic, antigenic, large HLAs coverage, non-toxic and high world population coverage. This kind of methodology and investigations can precisely reduce the expenditure and valuable time for experimental planning in development of vaccines in laboratories. In current scenario, researchers are frequently using in silico approaches to speed up their vaccine-based lab studies. The computational studies are highly valuable for the screening of large epitope dataset into smaller one prior to in vitro and in vivo confirmatory analyses.

Topological and system-level protein interaction network (PIN) analyses to deduce molecular mechanism of curcumin.

Curcumin is an important bioactive component of turmeric and also one of the important natural products, which has been investigated extensively. The precise mode of action of curcumin and its impact on system level protein networks are still not well studied. To identify the curcumin governed regulatory action on protein interaction network (PIN), an interectome was created based on 788 key proteins, extracted from PubMed literatures, and constructed by using STRING and Cytoscape programs. The PIN rewired by curcumin was a scale-free, extremely linked biological system. MCODE plug-in was used for sub-modulization analysis, wherein we identified 25 modules; ClueGo plug-in was used for the pathway's enrichment analysis, wherein 37 enriched signalling pathways were obtained. Most of them were associated with human diseases groups, particularly carcinogenesis, inflammation, and infectious diseases. Finally, the analysis of topological characteristic like bottleneck, degree, GO term/pathways analysis, bio-kinetics simulation, molecular docking, and dynamics studies were performed for the selection of key regulatory proteins of curcumin-rewired PIN. The current findings deduce a precise molecular mechanism that curcumin might exert in the system. This comprehensive in-silico study will help to understand how curcumin induces its anti-cancerous, anti-inflammatory, and anti-microbial effects in the human body.

Tannic acid inhibits lipid metabolism and induce ROS in prostate cancer cells.

Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipogenic signaling and suppression of lipid metabolic pathways. The expression of proteins responsible for lipogenesis was down regulated. The membrane permeability and functionality of PCa were severely affected and caused nuclear disorganization during drug exposure. Finally, these consolidated events shifted the cell's survival balance towards apoptosis. These results suggest that TA distinctly interferes with the lipid signaling and metabolism of PCa cells.

Cucurbitacin D Reprograms Glucose Metabolic Network in Prostate Cancer.

Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of PrCa metastasis. Herein, we report that cucurbitacin D (Cuc D) effectively inhibits glucose uptake and lactate production in metastatic PrCa cells via modulating glucose metabolism. This metabolic shift by Cuc D was correlated with decreased expression of GLUT1 by its direct binding as suggested by its proficient molecular docking (binding energy -8.5 kcal/mol). Cuc D treatment also altered the expression of key oncogenic proteins and miR-132 that are known to be involved in glucose metabolism. Cuc D (0.1 to 1 µM) treatment inhibited tumorigenic and metastatic potential of human PrCa cells via inducing apoptosis and cell cycle arrest in G2/M phase. Cuc D treatment also showed inhibition of tumor growth in PrCa xenograft mouse model with concomitant decrease in the expression of GLUT1, PCNA and restoration of miR-132. These results suggest that Cuc D is a novel modulator of glucose metabolism and could be a promising therapeutic modality for the attenuation of PrCa metastasis.

Cross-Linked Polyphenol-Based Drug Nano-Self-Assemblies Engineered to Blockade Prostate Cancer Senescence.

Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid-docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced in vitro therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFßR1/FOXO1/p21 signaling. Decrease in ß-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, in vivo and ex vivo imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing PC-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown in vivo by inhibiting TGFßR1 proteins and regressing tumor growth through apoptotic induction in the PC-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy.

Disparity in rates of HPV infection and cervical cancer in underserved US populations.

There is a higher rate of HPV infection and cervical cancer incidence and mortality in underserved US population who reside in Appalachian mountain region compared to Northern Plains. Social and behavioral factors such as smoking and alcohol consumption are for such a high incidence. However, by and large, the reasons for these discrepancies lie in the reluctance of the underserved population to adopt preventive measures such as prophylactic Human papilloma virus (HPV) vaccines and Pap smear screening that have significantly reduced the incidence and mortality rate of cervical cancer in Caucasian women. Thus, it is clear that drastic change in social behavior and implementation of preventive measures is required to effectively reduce the incidence and mortality from cervical cancer in this underserved population.