Chemokines driven ovarian cancer progression, metastasis and chemoresistance: Potential pharmacological targets for cancer therapy.

Ovarian cancer is a leading cause of death among women globally often characterized by poor prognosis and aggressive tumor growth. The therapeutic outcomes of ovarian cancer patients are majorly limited by the development of acquired chemo/radioresistance and the lack of targeted therapies. The tumor microenvironment (TME) comprises a diverse population of cells including adipocytes, fibroblasts, tumor cells, and immune cells which play an imperative role in promoting tumor growth, invasion, and malignant phenotypes of cancer cells. The cells present in TME secrete various inflammatory mediators including chemokines and cytokines, which regulate the tumor progression and metastasis. This review article highlights new insights about the general mechanisms associated with chemokines-mediated cell proliferation, inflammation, tumor initiation, progression, metastasis, chemoresistance, and immune evasion in ovarian cancer. We also discuss the microRNAs (miRNAs) regulating the oncogenic potential of chemokines. Overall, this is a comparatively less explored area that could provide important insights into ovarian cancer development and a promising avenue for targeted therapy of ovarian cancer.

Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.

The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.

Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions.

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

MicroRNAs: As Critical Regulators of Tumor- Associated Macrophages.

Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.

MiRNA-3163 limits ovarian cancer stem-like cells via targeting SOX-2 transcription factor.

Cancer stem cells (CSCs) are pivotal in both cancer progression and the acquisition of drug resistance. MicroRNAs (miRNAs) play a crucial role in modulating CSC properties and are being explored as potential targets for therapeutic interventions. MiR-3163 is primarily known for its tumor suppressive properties in various human malignancies, with lower expression reported across different cancer types. However, its role in regulating the ovarian CSC phenotype and the underlying mechanism remain largely unknown. Here, we report a remarkable downregulation of miR-3163 in ovarian cancer stem-like cells (CSLCs). Enforced expression of miR-3163 in ovarian adherent and CSLCs, significantly disrupts the stemness phenotype. Moreover, downregulation of miR-3163 expression in ovarian cancer cells (OV2008 and OVCAR-3) inhibits the stem-like cells characterized by CD44+CD117+ expression. Sphere formation assay results reveal that overexpression of miR-3163 in ovarian cancer cells significantly inhibits spheroid formation ability, confirming the regulatory properties of miR-3163 on ovarian CSLCs. Mechanistic investigation reveals that miR-3163 depletes ovarian CSLCs via targeting SOX-2. Furthermore, we establish SOX-2 as a direct target of miR-3163 through dual-luciferase assay. Taken together, our study demonstrates that overexpression of miR-3163 could be a promising strategy for efficiently eradicating the CSC population to prevent chemoresistance and tumor relapse in ovarian cancer patients.

On-device synaptic memory consolidation using Fowler-Nordheim quantum-tunneling.

Introduction: For artificial synapses whose strengths are assumed to be bounded and can only be updated with finite precision, achieving optimal memory consolidation using primitives from classical physics leads to synaptic models that are too complex to be scaled in-silico. Here we report that a relatively simple differential device that operates using the physics of Fowler-Nordheim (FN) quantum-mechanical tunneling can achieve tunable memory consolidation characteristics with different plasticity-stability trade-offs. Methods: A prototype FN-synapse array was fabricated in a standard silicon process and was used to verify the optimal memory consolidation characteristics and used for estimating the parameters of an FN-synapse analytical model. The analytical model was then used for large-scale memory consolidation and continual learning experiments. Results: We show that compared to other physical implementations of synapses for memory consolidation, the operation of the FN-synapse is near-optimal in terms of the synaptic lifetime and the consolidation properties. We also demonstrate that a network comprising FN-synapses outperforms a comparable elastic weight consolidation (EWC) network for some benchmark continual learning tasks. Discussions: With an energy footprint of femtojoules per synaptic update, we believe that the proposed FN-synapse provides an ultra-energy-efficient approach for implementing both synaptic memory consolidation and continual learning on a physical device.