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Hydroarylation of alkynes with unactivated C(sp 2 )−H bonds via chelated C−H metalation mainly occurs at γ -position to the coordinating atom of directing groups via stable 5-membered metallacycles, while β -C(sp 2 )−H bond-involved hydroarylation has been a formidable challenge. Herein, we used a phosphine oxide-ligated Ni−Al bimetallic catalyst to enable β -C−H bond-involved hydroarylations of alkynes via a rare 7-membered nickelacycle. Directed activation of C–H bonds usually occurs through 5-membered metallacycles, which poses limitations of regiochemistry. Herein, the authors use a phosphine oxide-ligated Ni−Al bimetallic catalyst to enable β-C−H bond-involved hydroarylations of alkynes via a rare 7-membered nickelacycle.

MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1.

Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.

Urge urinary incontinence (UUI) poses diagnostic challenges due to subjective assessments and limited biomarkers. This study aims to enhance accuracy by integrating skin sympathetic nerve activity (SKNA) with urine biomarkers. A prospective analysis included 36 UUI and 36 non-UUI participants. All participants underwent measurements of SKNA and evaluations of nine urine biomarkers, both with and without urinary creatinine correction. Logistic regression and support vector machine with L1 penalty were applied to SKNA and urine biomarker measurements. Six-fold stratified cross-validation ensuring equitable distribution of UUI positive and negative samples was adopted. Nonzero model weights were extracted to identify most relevant biomarkers. Elevated SKNA and calibrated urine biomarkers were observed in UUI participants. Calibrated urinary biomarkers alone achieves better accuracy than using raw biomarkers. Integration of SKNA and calibrated biomarkers demonstrated superior diagnostic performance for UUI (AUC = 0.80 ± 0.07; sensitivity = 0.72, specificity = 0.83) compared to using SKNA alone, raw or calibrated urine biomarkers alone, and alternative combinations. Baseline SKNA, calibrated MCP-1, MIP-1β, and IP-10 emerged as promising biomarkers. In conclusion, combining SKNA and urinary creatinine-normalized biomarkers yielded the highest diagnostic accuracy for UUI. This study proposes an innovative diagnostic algorithm, advancing UUI diagnostics by integrating autonomic function parameters and urine biomarker analysis.

Background It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers. Methods A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored. Results Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81–0.98), breast cancer (RR = 0.87, 95% CI: 0.82–0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61–0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90–0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54–0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23–3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32–2.33). Conclusion Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers.

Epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) are currently the most effective treatment for non-small cell lung cancer (NSCLC) patients, who carry primary EGFR mutations. However, the patients eventually develop drug resistance to EGFR-TKIs after approximately one year. In addition to the acquisition of the EGFR T790M mutation, the activation of alternative receptor-mediated signaling pathways is a common mechanism for conferring the insensitivity of EGFR-TKI in NSCLC. Upregulation of the Mer receptor tyrosine kinase (MERTK), which is a member of the Tyro3-Axl-MERTK (TAM) family, is associated with a poor prognosis of many cancers. The binding of specific ligands, such as Gas6 and PROS1, to MERTK activates phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) cascades, which are the signaling pathways shared by EGFR. Therefore, the inhibition of MERTK can be considered a new therapeutic strategy for overcoming the resistance of NSCLC to EGFR-targeted agents. Although several small molecules and monoclonal antibodies targeting the TAM family are being developed and have been described to enhance the chemosensitivity and converse the resistance of EGFR-TKI, few have specifically been developed as MERTK inhibitors. The further development and investigation of biomarkers which can accurately predict MERTK activity and the response to MERTK inhibitors and MERTK-specific drugs are vitally important for obtaining appropriate patient stratification and increased benefits in clinical applications.

Background Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients. Methods Data from National Health and Nutrition Examination Survey (NHANES) 1999–2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5–9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves. Results TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p  < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15–2.63, p  = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results ( p  = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death ( p  < 0.05). Conclusion TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.

Background Peripheral artery disease (PAD) is associated with various morbidities. This study aims to investigate the correlation between different lower extremity compositions and development of morbidities in PAD patients. Methods Between January 2018 and December 2020, 108 subjects diagnosed of PAD were enrolled (mean age of 64.1 ± 13.5 years) and utilized dual-energy computed tomography (DECT) with material decomposition to measure the vessel volume, muscle volume, fat volume, and cortical-bone volume in lower extremity respectively. The association between each leg composition and developing complications or morbidities in PAD patients was analyzed over a two-year follow-up. Results Fontaine stage 3 and 4 had lower muscle mass compared to stages 1 and 2. More severe vascular stenosis was associated with lower muscle, fat, and cortical-bone volume. Patients with severe Fontaine stages (3 and 4) and lower-leg vascular stenosis had a higher risk of developing infection or inflammation (OR 45.5, 95% CI: 13.5–166.7, and OR 11.7, 95% CI: 2.8–50, P  < 0.05) and amputation (OR 18.2, 95% CI: 2.2–142.8, and OR 10.7, 95% CI: 1.11–100, P  < 0.05). Lower thigh cortical-bone volume was associated with an increased risk of falls resulting in fractures (OR: 1.39, 95% CI: 1.13–2.19, P  < 0.01). Thigh cortical-bone volume below 64.5 cm 3 was identified as the cut-off value to predict fall-related fractures, with a sensitivity of 100% and specificity of 92%. Conclusions This study demonstrates the potential of DECT with material decomposition to assess lower extremity composition and its relevance in predicting complications and morbidities in PAD patients. Severe vascular stenosis may contribute to muscle wasting and subsequent complications, while lower thigh cortical-bone mass may serve as a predictor of fall-related fractures.

Ethnopharmacological relevance Aconitum tanguticum (Maxim.) Stapf (ATS) is a rare Tibetan medicinal plant that belongs to the Ranunculaceae family. This herb is mainly distributed in the high-altitude areas of Qinghai, Gansu provinces, and Tibetan Autonomous Region in China. In Tibetan medicine, ATS is mainly used to treat lung inflammation, hepatitis, gastrointestinal diseases, influenza, fever caused by infectious diseases, food poisoning, snake and scorpion bites, and yellow water disease. ATS has anti-inflammatory, antiviral, and other pharmacological effects, according to recent research. It is welltolerated by individuals from diverse ethnic groups and has a long history of use in Tibetan medicine. Aim of the study This study investigated the preventive effects of ATS alcoholic extract on acute lung injury (ALI) in mice and aimed to elucidate its possible mechanism of action. Materials and methods Alveolar epithelial cells A549 and specific pathogen-free C57BL/6 mice were induced with lipopolysaccharide (LPS) to establish ALI models both in vivo and in vitro and to explore the pharmacological effects and therapeutic mechanisms of ATS. Results ATS down-regulated the mRNA levels of inflammatory factors NF-κB p65, TNF-α, IL-1β, and IL-8, inhibited the release of reactive oxygen species, inhibited epithelial-mesenchymal transition caused by sustained cell injury, promoted the Keap1/Nrf2/HO-1 signalling pathway, reduced the degree of oxidative stress in vivo, and inhibited the production of proteins associated with LPS-induced ferroptosis. Conclusion The Tibetan medicine ATS reduced pulmonary haemorrhage and oedema in ALI mice, alleviated the degree of lung tissue lesions, inhibited the expression of inflammatory factors and apoptosis, and plays a preventive role against acute lung injury in mice. Graphical Abstract

This study aims to investigate the role of parvovirus B19 infection in the pathogenesis of rheumatoid arthritis (RA). B19-NS1 DNA was cloned into the LentiORF pLEX-MCS vector, then co-transfected with the pLEX-MCS-NS1 vector and packaging system to produce LEX-NS1 lentiviral stock. LEX was also prepared as the control. Transduction of LEX-NS1 or LEX lentivirus into the SW982 cell line then proceeded, and total RNA was extracted for RNA-seq. Pathway analysis and comparison of pathway status between this study and GEO datasets were performed, demonstrating that acute phase response signaling, NRF2-mediated oxidative stress response, and mTOR signaling pathways were activated after the transduction of LEX-NS1 into the SW982 cell line, although the interferon signaling pathway was inhibited. The comparison of all pathways using hierarchical clustering showed that the pathway status after transduction of B19-NS1 was closer to RA than that in osteoarthritis. Similar findings can also be found in cellular immune, humoral immune, cytokine, apoptosis, cellular growth, cellular stress, growth factor, and intracellular pathways. In conclusion, parvovirus B19-NS1 can induce inflammation of the synovium mimicking synovitis in RA; therefore, parvovirus B19 infection might be one of the trigger factors in the pathogenesis of RA.