In order to explore novel colorimetric biosensors with high sensibility and selectivity, two new Keggin polyoxometalates (POMs)-based Cu-trz (1,2,4-triazole) metal–organic frameworks (MOFs) with suitable specific surface areas and multiple active sites were favorably fabricated; then single-walled carbon nanotubes (SWNTs) were merged with new POMOFs to construct POMOF/SWNT nanocomposites. Herein, POMOF/SWNT nanocomposites as peroxidase mimics were explored for the first time, and the peroxidase-mimicking activity of the prepared POMOF/SWNT nanocomposites is heavily dependent on the mass ratio of POMOFs and SWNTs, in which the maximum activity is achieved at the mass ratio of 2.5:1 (named PMNT-2). More importantly, PMNT-2 exhibits the lowest limit of detection (0.103 μM) among all reported materials to date and the assumable selectivity toward l-cysteine (l-Cys) detection. With these findings, a convenient, sensitive, and effective “on–off switch” colorimetric platform for l-Cys detection has been successfully developed, providing a promising prospect in the biosensors and clinical diagnosis fields.

Malignant tumors typically undergo an atavistic regression characterized by the overexpression of embryonic genes and proto-oncogenes, including a variety of cancer/testis antigens (CTAs) that are testis-derived and are not expressed or expressed in trace amounts in somatic tissues. Based on this theory, we established a new method to identify unknown CTAs, the spermatogenic cells-specific monoclonal antibody-defined cancer/testis antigen (SADA) method. Using the SADA method, we identified BAP31 as a novel CTA and confirmed that BAP31 expression is associated with progression and metastasis of several cancers, particularly in cervical cancer. We found that BAP31 was significantly upregulated in stage I, II, and III cervical cancer patients and highly correlated with poor clinic outcomes. We further demonstrated that BAP31 regulates cervical cancer cell proliferation by arresting the cell cycle at the G0/G1 stage and that depletion of BAP31 inhibits hyper-proliferation. Moreover, depletion of BAP31 inhibits cervical cancer cell invasion and migration by regulating the expression and subcellular localization of Drebrin, M-RIP, SPECC1L, and Nexilin, and then affect the cytoskeleton assemblage. Finally, the depletion of BAP31 prevents cervical cancer progression and metastasis in vivo. These findings provide a new method for identifying novel CTAs as well as mechanistic insights into how BAP31 regulates cervical cancer hyper-proliferation and metastasis.

Prostate cancer is a common malignancy in men worldwide. Lysophosphatidic acid receptor 1 (LPAR1) is a critical gene and it mediates diverse biologic functions in tumor. However, the correlation between LPAR1 and prognosis in prostate cancer, as well as the potential mechanism, remains unclear. In the present study, LPAR1 expression analysis was based on The Cancer Genome Atlas (TCGA) and the Oncomine database. The correlation of LPAR1 on prognosis was also analyzed based on R studio. The association between LPAR1 and tumor-infiltrating immune cells were evaluated in the Tumor Immune Estimation Resource site, ssGSEA, and MCPcounter packages in R studio. Gene Set Enrichment Analysis and Gene Ontology analysis were used to analyze the function of LPAR1. TCGA datasets and the Oncomine database revealed that LPAR1 was significantly downregulated in prostate cancer. High LPAR1 expression was correlated with favorable overall survival. LPAR1 was involved in the activation, proliferation, differentiation, and migration of immune cells, and its expression was positively correlated with immune infiltrates, including CD4+ T cells, B cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, and natural killer cells. Moreover, LPAR1 expression was positively correlated with those chemokine/chemokine receptors, indicating that LPAR1 may regulate the migration of immune cells. In summary, LPAR1 is a potential prognostic biomarker and plays an important part in immune infiltrates in prostate cancer.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have been proved to be T cell-mediated autoimmune diseases. Recent researches indicate that humoral immunity is also involved in the pathogenesis of these disorders. T follicular helper (Tfh) cells are critical for B cell differentiation and antibody production. However, the role of Tfh cells in MS and EAE remains unclear. Here, we found elevated frequencies of CD4+CXCR5+PD-1+ Tfh-like cells in both MS patients and EAE. In EAE mice, Tfh-like cells, together with B cells, were found in the ectopic lymphoid structures in spinal cords. Moreover, Tfh-like cells promoted the antibody production via IL-21/IL-21R and CD40 ligand/CD40 interaction and the synergy effect of STAT3 and non-canonical NF-κB signaling pathway inside B cells. Moreover, adoptive transfer of Tfh-like cells could increase the severity and delay the remission of EAE. In conclusion, our data indicate that Tfh-like cells contribute to the pathogenesis of EAE.

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Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed in vitro and in vivo. Human CC tissue microarrays were used to analyze IGF2BP2 expression in CC. The knockdown of E6/E7 and IGF2BP2 attenuated the aerobic glycolytic capacity and growth of CC cells, while IGF2BP2 overexpression rescued this effect in vitro and in vivo. IGF2BP2 expression was higher in CC tissues than in adjacent tissues and was positively correlated with tumor stage. Mechanistically, E6/E7 proteins promoted aerobic glycolysis, proliferation, and metastasis in CC cells by regulating MYC mRNA m 6 A modifications through IGF2BP2. We found that E6/E7 promote CC by regulating MYC methylation sites via activating IGF2BP2 and established a link between E6/E7 and the promotion of aerobic glycolysis and CC progression. Blocking the HPV E6/E7-related metabolic pathway represents a potential strategy for the treatment of CC.

Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence.

INTRODUCTION: This multicenter, randomized, noninferiority trial compared electroacupuncture with prucalopride for the treatment of severe chronic constipation (SCC). METHODS: Participants with SCC (≤ 2 mean weekly complete spontaneous bowel movements [CSBMs]) were randomly assigned to receive either 28-session electroacupuncture over 8 weeks with follow-up without treatment over 24 weeks or prucalopride (2 mg/d before breakfast) over 32 weeks. The primary outcome was the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8, based on the modified intention-to-treat population, with −10% as the noninferior margin. RESULTS: Five hundred sixty participants were randomized, 280 in each group. Electroacupuncture was noninferior to prucalopride for the primary outcome (36.2% vs 37.8%, with a difference of −1.6% [95% confidence interval, −8% to 4.7%], P < 0.001 for noninferiority); almost the same results were found in the per-protocol population. The proportions of overall CSBM responders through weeks 1–8 were similar in the electroacupuncture and prucalopride groups (24.91% vs 25.54%, with a difference of −0.63% [95% confidence interval, −7.86% to 6.60%, P = 0.864]). Except during the first 2-week treatment, no between-group differences were found in outcomes of excessive straining, stool consistency, and quality of life. Adverse events occurred in 49 (17.69%) participants in the electroacupuncture group and 123 (44.24%) in the prucalopride group. One non-treatment-related serious adverse event was recorded in the electroacupuncture group. DISCUSSION: Electroacupuncture was noninferior to prucalopride in relieving SCC with a good safety profile. The effects of 8-week electroacupuncture could sustain for 24 weeks after treatment. Electroacupuncture is a promising noninferior alternative for SCC (see Visual Abstract, http://links.lww.com/AJG/B776).