Current drugs for HIV-1: from challenges to potential in HIV/AIDS.

The human immunodeficiency virus (HIV) persists in latently infected CD4+T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome (AIDS) is associated with HIV-1. Possibly, treating HIV/AIDS is an essential but challenging clinical goal. This review provides a detailed account of the types and mechanisms of monotherapy and combination therapy against HIV-1 and describes nanoparticle and hydrogel delivery systems. In particular, the recently developed capsid inhibitor (Lenacapavir) and the Ainuovirine/tenofovir disoproxil fumarate/lamivudine combination (ACC008) are described. It is interestingly to note that the lack of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and the multipass transmembrane proteins serine incorporator 5 (SERINC5) may be one of the reasons for the enhanced infectivity of HIV-1. This discovery of SERINC3 and SERINC5 provides new ideas for HIV-1 medication development. Therefore, we believe that in treating AIDS, antiviral medications should be rationally selected for pre-exposure and post-exposure prophylaxis to avoid the emergence of drug resistance. Attention should be paid to the research and development of new drugs to predict HIV mutations as accurately as possible and to develop immune antibodies to provide multiple guarantees for the cure of AIDS.

Death receptor 5 promotes tumor progression in gastric cancer.

Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor stemness. Unlike death receptor 4 (DR4TRAIL-R1), DR5 was expressed in the cytoplasm and nucleus, and was found to be positively correlated with lymphovascular invasion, lymph node metastasis, and TNM stage. Patients with positive DR5 had worse overall survival (OS) (P = 0.006). The multivariate Cox model showed that DR5 is an independent poor prognostic factor (hazard ratio = 1.693). Furthermore, knockdown of DR5 inhibited aggressive behaviors, including proliferation and metastasis in gastric cancer cells, and inhibited lung metastasis in vivo. In summary, nuclear localization of DR5 expression is a poor prognosis factor in gastric cancer and promotes growth, invasion, and metastasis of tumor cells in vitro and in vivo.

Investigating the mechanism of Echovirus 30 cell invasion.

Viruses invade susceptible cells through a complex mechanism before injecting their genetic material into them. This causes direct damage to the host cell, as well as resulting in disease in the corresponding system. Echovirus type 30 (E30) is a member of the Enterovirus B group and has recently been reported to cause central nervous system (CNS) disorders, leading to viral encephalitis and viral meningitis in children. In this review, we aim to help in improving the understanding of the mechanisms of CNS diseases caused by E30 for the subsequent development of relevant drugs and vaccines.

Biogenic methane in coastal unconsolidated sediment systems: A review.

Marine sediments are the world's largest known reservoir of methane. In many coastal regions, methane is trapped in sediments buried at depths ranging from centimeters to hundreds of meters below the seafloor, in the forms of gas pockets, dispersed gas bubbles and dissolved gas, also known as shallow gas (methane-dominated gas mixture). The existence of shallow gas affects the engineering geological environment and threatens the safety of artificial facilities. The escape of shallow gas from sediments into the atmosphere can even threaten ecosystem security and affect global climate change. However, until now, shallow gas has remained a mystery to the scientific community. For example, how it is generated, how it distributes and migrates in sediments, and what are the factors that influence these processes that are still unclear. In the context of increasingly intense offshore development and global warming, there is a huge gap between existing scientific understanding of shallow gas and the need to develop scientific solutions for related problems. Based on this, this paper systematically collects the information on all aspects of shallow gas mentioned above, comprehensively summarizes the current scientific understanding, and analyzes the existing shortcomings, which will provide systematic references for the research on environmental disaster prevention, engineering technology, climate change, and other fields.

Time to surgery does not affect oncologic outcomes in locally advanced gastric cancer after neoadjuvant chemotherapy: a meta-analysis.

Aim: The authors conducted a meta-analysis to determine the association between time-to-surgery (TTS) after neoadjuvant chemotherapy and patient outcomes in locally advanced gastric cancer. Methods: Electronic databases were searched to identify potential studies, in which the authors compared patient outcomes between those with TTS within 4 (and 6) weeks of completion of neoadjuvant chemotherapy and those after 4 (and 6) weeks. Results: Six studies, including 1238 patients, were eligible for inclusion. Pooled data showed no significant differences in rates of pathological complete response, major pathological response, ypN0, complications, R0 resection and operative time between groups of longer TTS and shorter TTS. Conclusion: There was no statistically advantageous impact of prolonged TTS on pathological and surgical outcomes. Large, population-based studies are warranted.

Piceatannol enhances Beclin-1 activity to suppress tumor progression and its combination therapy strategy with everolimus in gastric cancer.

The effects and regulation of Beclin-1-an autophagy-related protein-have not been fully defined, however, a negative correlation has been reported between Beclin-1 expression and carcinogenesis. Meanwhile, no compound has been shown to directly inhibit its activity. Here, we evaluate piceatannol, a naturally occurring polyphenolic compound, as a potential targeting agonist of Beclin-1, to assess its efficacy as an antitumor agent against gastric cancer. More specifically, we determine the effects of piceatannol treatment on cell viability using a monitoring system and colony forming assay. Piceatannol was found to efficiently inhibit the proliferation of several human gastric cancer cell lines. Autophagic flux is increased by piceatannol treatment, and correlates with inhibition of cell proliferation and colony formation. Additionally, microscale thermophoresis and surface plasmon resonance results show a direct interaction between piceatannol and Beclin-1, which reduces the phosphorylation activity of Beclin-1 at the Ser-295 site. Notably, piceatannol impairs the binding of Beclin-1 to Bcl-2 and enhances the recruitment of binding of UV radiation resistance-associated gene protein, which further triggers Beclin-1-dependent autophagy signaling. An increase in autophagic activity via treatment with the mTOR inhibitor, everolimus, effectively sensitizes piceatannol-induced antitumor effects. Xenograft models confirmed that piceatannol inhibits tumor development and elicits a potent synergistic effect with everolimus in vivo. Taken together, the findings of this study strongly support the application of combinatorial piceatannol and everolimus therapy in future clinical trials for gastric cancer patients.

Optimized tools and timing of response reassessment after neoadjuvant chemoradiation in rectal cancer.

PURPOSE: Reassessment tools of response to long-course neoadjuvant chemoradiation treatment (nCRT) in patients with locally advanced rectal cancer (LARC) are important in predicting complete response (CR) and thus deciding whether a wait-and-watch strategy can be implemented in these patients. Choosing which routine reassessment tools are optimal and when to use them is still unclear and will be researched in the study. METHODS: Altogether, 250 patients with LARC who received nCRT from 2013 to 2021 and were followed up were retrospectively reviewed. Common reassessment tools of response included digital rectal examination (DRE), clinical examination and symptoms, endoscopy, biopsy, magnetic resonance imaging (MRI), and blood biomarkers. RESULTS: Overall, 27.20% (68/250) patients had a complete response and 72.80% (182/250) did not. The combination of MRI, endoscopy, and biopsy showed the best performance in terms of accuracy of 74% and area under the curve (AUC, 0.714, 95% CI 0.546-0.882). Reassessing through DRE and presence of symptoms failed to improve the efficacy of response reassessment. After 100 days, biopsy as an assessment tool would obtain a substantial rise in accuracy from 51.28 to 100% (p = 0.003). CONCLUSION: The combination of MRI, endoscopy, and biopsy is suitable as the reassessment tool of response for applying a wait-and-watch strategy after long-course nCRT in patients with LARC. The accuracy of biopsy as reassessment tools would be improved if they were used over 100 days after nCRT in patients with rectal cancer.

Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer.

Background: Adenoid cystic carcinoma (ACC) is a rare type of triple-negative breast cancer that has an indolent clinical behavior. Given the substantial overlapping morphological, immunohistochemical, and molecular features with other basal-like triple-negative breast cancer (BL-TNBC), accurate diagnosis of ACC is crucial for effective clinical treatment. The integrative analysis of the proteome and clinicopathological characteristics may help to distinguish these two neoplasms and provide a deep understanding on biological behaviors and potential target therapy of ACC. Methods: We applied mass spectrometry-based quantitative proteomics to analyze the protein expression in paired tumor and adjacent normal breast tissue of five ACC and five BL-TNBC. Bioinformatic analyses and the clinicopathological characteristics, including histological features, immunohistochemistry, and FISH results, were also collected to get comprehensive information. Results: A total of 307 differentially expressed proteins (DEPs) were identified between ACC and BL-TNBC. Clustering analysis of DEPs clearly separated ACC from BL-TNBC. GSEA found downregulation of the immune response of ACC compared with BL-TNBC, which is consistent with the negative PD-L1 expression of ACC. Vesicle-mediated transport was also inhibited, while ECM organization was enriched in ACC. The top upregulated proteins in DEPs were ITGB4, VCAN, and DPT. Moreover, in comparison with normal breast tissue, ACC showed elevated ribosome biogenesis and RNA splicing activity. Conclusion: This study provides evidence that ACC presents a substantially different proteomic profile compared with BL-TNBC and promotes our understanding on the molecular mechanisms and biological processes of ACC, which might be useful for differential diagnosis and anticancer strategy.

The significance of time interval between perioperative SOX/XELOX chemotherapy and clinical decision model in gastric cancer.

Introduction: To investigate the influences of time interval between multimodality therapies on survival for locally advanced gastric cancer (LAGC) patients, 627 patients were included in a retrospective study, and 350 who received neoadjuvant chemotherapy (NACT) based on SOX (S-1 plus Oxaliplatin)/XELOX (Capecitabine plus Oxaliplatin) treatment, radical surgery, and adjuvant chemotherapy (AC) from 2005.01 to 2018.06 were eligible for analyses. Methods: Three factors were used to assess influences, including time interval from NACT accomplishment to AC initiation (PECTI), time to surgery after NACT accomplishment (TTS), and time to adjuvant chemotherapy after surgery (TAC). Results: Concerning PECTIs, 99 (28.29%) experienced it within 9 weeks, 188 (53.71%) within 9-13 weeks, 63 (18.00%) over 13 weeks. Patients' 5-year overall survival (OS) significantly decreased as trichotomous PECTI increased (78.6% vs 66.7% vs 55.7%, P = .02). Analogously, there was a significant decrease for dichotomous TTS (within vs over 5 weeks) in OS (P = .03) and progression free survival (PFS) (P = .01) but not for dichotomous TAC (within vs over 6 weeks) in OS and PFS (P = .40). Through multivariate Cox analyses, patients with PECTI over 13 weeks had significantly worse OS (P = .03) and PFS (P = .02). Furthermore, extended TTS had significantly worse OS and PFS but insignificantly worse OS and PFS than extended TAC. Therefore, gastric patients receiving perioperative SOX/XELOX chemotherapy and surgery with extended PECTI over 9 weeks or TTS over 5 weeks would have a negative correlation with PFS and OS, and worse when PECTI over 13 weeks. Nomograms (including PECTI, ypT, ypN, Area Under Curve (AUC) = 0.81) could predict patient survival probability and guide intervention with net benefit. Discussion: In control of PECTI, TTS could be extended appropriately, and shortened TAC might make a remedy, and delayed TAC might be allowed when TTS was shortened.