MicroRNA-92a-3p Enhances Cisplatin Resistance by Regulating Krüppel-Like Factor 4-Mediated Cell Apoptosis and Epithelial-to-Mesenchymal Transition in Cervical Cancer

Recent studies have confirmed the existence and key roles of microRNA (miRNAs) in cancer drug resistance, including cervical cancer (CC). The present study aims to establish a novel role for miR-92a-3p and its associated gene networks in cisplatin (DDP) resistance of CC. First, the disparities in miRNA expression between CC tissues and adjacent normal tissues were screened based on GSE19611 microarray data that retrieved from Gene Expression Omnibus (GEO), and we identified several miRs that were significantly downregulated or upregulated in CC tissues including miR-92a-3p. Moreover, miR-92a-3p was significantly up-regulated in DDP-resistant cells and was the most differently expressed miRNA. Functionally, knockdown of miR-92a-3p increased the sensitivity of DDP-resistant cells to DDP via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Conversely, overexpression of miR-92a-3p significantly induced DDP resistance in CC parental cells including HeLa and SiHa cells. Moreover, Krüppel-like factor 4 (KLF4) was identified as a direct target of miR-92a-3p, and an obvious inverse correlation was observed between the expression of miR-92a-3p and KLF4 in 40 pairs of cancer tissues. Furthermore, KLF4 knockdown reversed the promoting effect of miR-92a-3p inhibition on DDP sensitivity in DDP-resistant CC cells. Besides, high expression of miR-92a-3p was associated with DDP resistance, as well as a short overall survival in clinic. Taken together, these findings provide important evidence that miR-92a-3p targets KLF4 and is significant in DDP resistance in CC, indicating that miR-92a-3p may be an attractive target to increase DDP sensitivity in clinical CC treatment.

Lipid-Head-Polymer-Tail Chimeric Nanovesicles

Lipid nanovesicles (LNVs) and polymer nanovesicles (PNVs), also known as liposomes and polymersomes, are becoming increasingly vital in global health. One recent example is the widely distributed mRNA Covid-19 vaccines. However, the two major classes of nanovesicles both exhibit their own issues that significantly limit potential applications. Here, by covalently attaching a naturally occurring phosphate “lipid head” and a synthetic polylactide “polymer tail” via facile ring-opening polymerization on a 500-gram scale, a type of “chimeric” nanovesicles (CNVs) can be easily produced. Compared to LNVs, the reported CNVs exhibit reduced permeability for small and large molecules; on the other hand, the CNVs are less hydrophobic and exhibit enhanced tolerance toward proteins in buffer solutions without the need for hydrophilic polymeric corona such as poly(ethylene glycol), in contrast to conventional PNVs. The proof-of-concept in vitro delivery experiments using hydrophilic solutions of fluorescein-PEG, rhodamine-PEG, and anti-cancer drug doxorubicin demonstrate that these CNVs, as a structurally diverse class of nano-materials, are highly promising as alternative carriers for therapeutic molecules in translational nanomedicine.

Combined Analysis of Gut Microbiota and Plasma Metabolites Reveals the Effect of Red-Fleshed Apple Anthocyanin Extract on Dysfunction of Mice Reproductive System Induced by Busulfan

Busulfan is currently an indispensable anti-cancer drug, but the side effects on male reproductive system are so serious. Meanwhile, red-fleshed apples are natural products with high anthocyanin content. In this research, we analyzed the effect of red-fleshed apple anthocyanin extract (RAAE) on busulfan-treated mice. Compared with the busulfan group, main plasma biochemical indicators were significantly improved after RAAE treatment. Compared with BA0 (busulfan without RAAE) group, total antioxidant capacity(T-AOC) and the activity of superoxide dismutase (SOD) and glutathione catalase (GSH-Px) in RAAE treatment groups were obviously increased, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly decreased. Malondialdehyde (MDA) was significantly decreased in the RAAE groups. In addition, we found RAAE alleviated busulfan-disrupted spermatogenesis through improving genes expression which are important for spermatogenesis, such as DDX4, PGK2, and TP1. Furthermore, we found that RAAE increased beneficial bacteria Akkermansia and Lactobacillaceae, and significantly depleted harmful bacteria Erysipelotrichia. The correlation studies indicated that RAAE ameliorated busulfan-induced rise in LysoPC levels through regulating gut microbial community and their associated metabolites. In conclusion, this study extends our understanding of the alleviated effect of RAAE on busulfan-induced male reproductive dysfunction through regulating the relationships between gut microbiota and metabolites.

TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway

Background Worldwide, Breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer that PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. Methods and Result In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulate the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression that p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation, invasion, and promote apoptosis in breast cancer cells. Conclusions In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets

Cancer is now also reflected as a disease of the tumor microenvironment, primarily supposed to be a decontrolled genetic and cellular expression disease. Over the past two decades, significant and rapid progress has been made in recognizing the dynamics of the tumor's microenvironment and its contribution to influencing the response to various anti-cancer therapies and drugs. Modulations in the tumor microenvironment and immune checkpoint blockade are interesting in cancer immunotherapy and drug targets. Simultaneously, the immunotherapeutic strategy can be done by modulating the immune regulatory pathway; however, the tumor microenvironment plays an essential role in suppressing the antitumor's immunity by its substantial heterogeneity. Hypoxia inducible factor (HIF) is a significant contributor to solid tumor heterogeneity and a key stressor in the tumor microenvironment to drive adaptations to prevent immune surveillance. Checkpoint inhibitors here halt the ability of cancer cells to stop the immune system from activating, and in turn, amplify your body's immune system to help destroy cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways and important drugs involved are Ipilimumab and Nivolumab, mainly along with other drugs in this group. Targeting the hypoxic tumor microenvironment may provide a novel immunotherapy strategy, break down traditional cancer therapy resistance, and build the framework for personalized precision medicine and cancer drug targets. We hope that this knowledge can provide insight into the therapeutic potential of targeting Hypoxia and help to develop novel combination approaches of cancer drugs to increase the effectiveness of existing cancer therapies, including immunotherapy.

Impact of the COVID-19 pandemic on new starts to oral oncology medications in the US

Introduction The COVID-19 pandemic has had a significant impact on healthcare delivery. Although others have documented the impact on new cancer diagnoses, trends in new starts for oncology drugs are less clear. We examined changes in new users of oral oncology medications in the US following COVID-19 stay-at-home orders in 2020 compared to prior years. Methods We examined prescription data for members enrolled with a national pharmacy benefits manager in the US from January 1-October 31 of 2018, 2019, and/or 2020. This is a retrospective, observational study comparing new users per 100,000 members per month for all oral oncology drugs, and separately for breast, lung, and prostate cancer, leukemia, and melanoma oral drugs. We performed a difference-in-differences analysis for change in new users from pre-period (prior to pandemic-induced disruption, January-March), to post-period (following pandemic-induced disruption, April-October), between 2020 and 2019, and 2020 and 2018. Results New oral oncology drug users per 100,000 members per month declined by an additional 11.3% in the 2020 post-period compared to 2019 ( p = 0.048). New oral breast cancer drug starts declined by an additional 14.0% in the 2020 post-period compared to 2019 ( p = 0.040). Similar but non-significant trends were found between 2020 and 2018. No significant differences were found between post-period monthly new starts of leukemia, melanoma, lung or prostate cancer disease-specific oral medications. Conclusions Long-term implications of delays in cancer treatment initiation are unclear, although there is concern that patient outcomes may be negatively impacted.

Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery

Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles including pyrazolopyrimidines and imidazopyrimidines is a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which have been discovered as core structure for promising anti-cancer agents used in clinic or clinical evaluations. Pyrimidine-fused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous penta-heterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous penta-heterocycle derivatives as anti-cancer agents.

Effects of Anti-Cancer Drug Sensitivity-Related Genetic Differences on Therapeutic Approaches in Refractory Papillary Thyroid Cancer

Thyroid cancer (TC) includes tumors of follicular cells; it ranges from well differentiated TC (WDTC) with generally favorable prognosis to clinically aggressive poorly differentiated TC (PDTC) and undifferentiated TC (UTC). Papillary thyroid cancer (PTC) is a WDTC and the most common type of thyroid cancer that comprises almost 70–80% of all TC. PTC can present as a solid, cystic, or uneven mass that originates from normal thyroid tissue. Prognosis of PTC is excellent, with an overall 10-year survival rate >90%. However, more than 30% of patients with PTC advance to recurrence or metastasis despite anti-cancer therapy; consequently, systemic therapy is limited, which necessitates expansion of improved clinical approaches. We strived to elucidate genetic distinctions due to patient-derived anti-cancer drug-sensitive or -resistant PTC, which can support in progress novel therapies. Patients with histologically proven PTC were evaluated. PTC cells were gained from drug-sensitive and -resistant patients and were compared using mRNA-Seq. We aimed to assess the in vitro and in vivo synergistic anti-cancer effects of a novel combination therapy in patient-derived refractory PTC. This combination therapy acts synergistically to promote tumor suppression compared with either agent alone. Therefore, genetically altered combination therapy might be a novel therapeutic approach for refractory PTC.