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The one-leg stance is frequently used in balance training and rehabilitation programs for various balance disorders. There are some typical one-leg stance postures in Tai Chi (TC) and yoga, which are normally used for improving balance. However, the mechanism is poorly understood. Besides, the differences of one-leg stance postures between TC and yoga in training balance are still unknown. Therefore, the aim of the present study was to investigate cortical activation and rambling and trembling trajectories to elucidate the possible mechanism of improving one-leg stance balance, and compare the postural demands during one-leg stance postures between TC and yoga. Thirty-two healthy young individuals were recruited to perform two TC one-leg stance postures, i.e., right heel kick (RHK) and left lower body and stand on one leg (LSOL), two yoga postures, i.e., one-leg balance and Tree, and normal one-leg standing (OLS). Brain activation in the primary motor cortex, supplementary motor area (SMA), and dorsolateral prefrontal cortex (DLPFC) was measured using functional near-infrared spectroscopy. The center of pressure was simultaneously recorded using a force platform and decomposed into rambling and trembling components. One-way repeated-measures analysis of variance was used for the main effects. The relative concentration changes of oxygenated hemoglobin (ΔHbO) in SMA were significantly higher during RHK, LSOL, and Tree than that during OLS ( p < 0.001). RHK ( p < 0.001), LSOL ( p = 0.003), and Tree ( p = 0.006) all showed significantly larger root mean square rambling (RmRMS) than that during OLS in the medial-lateral direction. The right DLPFC activation was significantly greater during the RHK than that during the Tree ( p = 0.023), OLB ( p < 0.001), and OLS ( p = 0.013) postures. In conclusion, the RHK, LSOL, and Tree could be used as training movements for people with impaired balance. Furthermore, the RHK in TC may provide more cognitive training in postural control than Tree and OLB in yoga. Knowledge from this study could be used and implemented in training one-leg stance balance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Wang, Chang, Wang, Wang, Ni, Niu and Zhang.)

Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Recently, one of the specific BH3-mimetics, Venetoclax has been approved by FDA providing new options for newly diagnosed AML patient especially who are unfitted to receive conventional chemotherapy. Though the clinical success of venetoclax has been achieved in clinical outcomes such as complete remission (CR) and overall survival. Acquired resistance to ABT-199 which is induced by the regulation of apoptosis pathway is still an important clinical problem. To this end, the attempt to combine drugs which can reverse the compensatory regulation is urgent. Methods: In three AML cell lines (KG-1, Kasumi-1 and THP-1), the anti-AML effects of the combination of ABT-199 (Venetoclax) and metformin or the two drugs used alone were compared. CCK8 was used to evaluate the cell viability, and flow cytometry was used to estimate the rate of apoptosis, Western blot method was performed to detect apoptosis-related protein levels. In mice experiments, female BALB/c-nu nude mice were subcutaneously injected with THP-1 cells for subcutaneous tumor formation, and the combined effect of ABT-199 and metformin was tested. The evaluation indicators were tumor size, tumor weight, and Ki67 staining. Mouse body weight and HE staining were detected to evaluate liver damage and adverse drug reactions. Results: Both in vitro and in vivo experiments showed that compared with metformin or ABT-199 alone, the combined use of the two drugs exerts a synergistic effect on promoting apoptosis, thereby producing a strong anti-leukemia effect. Furthermore, after a short incubation time, ABT-199 swiftly increased the expression level of the anti-apoptotic protein Mcl-1, while the combined use of metformin and ABT-199 significantly reduced the level of Mcl-1. Notably, Metformin significantly downregulates the level of Mcl-1 protein by inhibiting its protein production. To less extent, metformin can also downregulate the expression of another anti-apoptotic protein, BCL-xl. Conclusion: Metformin downregulates the expression of anti-apoptotic proteins Mcl-1 and Bcl-xl by inhibiting protein production, and shows a synergistic anti-tumor effect with ABT-199 in acute myeloid leukemia., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Portal hypertension treatment has always been regarded as complex and diverse. With the innovation of concepts and technologies, its treatment model has been transformed from a single-disciplinary diagnosis and treatment model to a multidisciplinary collaborative diagnosis and treatment model. In the multidisciplinary diagnosis and treatment model, the surgical treatment of portal hypertension is not a treatment that is about to disappear soon, but one of the indispensable treatment methods under the multidisciplinary diagnosis and treatment model, and it will play an increasingly important role. Surgeons should formulate individualized, standardized, and minimally invasive treatment methods under the input of new concepts, master the surgical indications and individualized surgical methods for different populations, and maximize the optimization surgical treatment methods for portal hypertension. Therefore, it is necessary to re-examine the role of surgical treatment in the diagnosis and treatment of liver cirrhotic portal hypertension.

Objective: We aimed to identify potential variables predictive of a resident achieving faculty future entrustment as a way to enhance attending surgeons' planning of teaching in the operating room leading to improved resident operative autonomy in practice., Methods: We reviewed 273 resident performance evaluations from 91 surgical cases that were collected from 11 general surgery chief residents and 16 attending surgeons between April 2018 and June 2019 using a validated evaluation instrument. The primary outcome measure was prospective resident entrustment estimated by the rater for future similar cases. We used descriptive statistics and the boosted tree analysis model to find potential predictors for the outcome measure and examine test-retest reliability by procedure., Results: Step-specific guidance (r = 0.77, p < 0.0001) was the variable most highly associated with prospective resident entrustment in bivariate linear analysis. The boosted tree analysis demonstrated step-specific guidance was the strongest predictor for prospective resident entrustment in the OR, and its predictive importance was much higher than the overall guidance (0.64 > 0.18). Test-retest reliability was from 0.93 to 0.98 across procedures, indicating the likelihood that attending surgeons granted future autonomy complied with their evaluation of prospective resident entrustment was high., Conclusions: By assessing step-specific guidance, attending surgeons can reliably judge residents' future entrustment and potentially better plan for operative teaching/supervision that may lead to granting a surgical resident operative autonomy on similar cases in the future. Our findings provide insight into prospective faculty development of surgical teaching aimed at improving resident readiness for independent practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Humans are social animals, but not everyone will be mindful of others to the same extent. Individual differences have been found, but would social mindfulness also be shaped by one's location in the world? Expecting cross-national differences to exist, we examined if and how social mindfulness differs across countries. At little to no material cost, social mindfulness typically entails small acts of attention or kindness. Even though fairly common, such low-cost cooperation has received little empirical attention. Measuring social mindfulness across 31 samples from industrialized countries and regions ( n = 8,354), we found considerable variation. Among selected country-level variables, greater social mindfulness was most strongly associated with countries' better general performance on environmental protection. Together, our findings contribute to the literature on prosociality by targeting the kind of everyday cooperation that is more focused on communicating benevolence than on providing material benefits., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high mortality rate worldwide. The percentage of HCC patients with vascular invasion is high. However, tumor thrombus in the hepatic vein (HVTT) has a lower incidence than tumor thrombus in the portal vein (PVTT). Conventionally, HCC patients with HVTT are treated the same as HCC patients with PVTT and offered sorafenib or other systemic agents. However, according to recent studies, it is evident that HCC with HVTT shows different outcomes when classified into different subgroups. In this review, we discuss the recent progress and changes in treatment of HCC with HVTT., Competing Interests: Conflict-of-interest statement: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Self-management of ambulatory cancer pain is full of challenges. Motivated by the need for better pain management, we developed a WeChat-supported platform, Medication Housekeeper (MediHK), to enhance communication, optimize outcomes, and promote self-management in the home setting., Objective: We conducted a randomized controlled trial to assess whether the joint physician-pharmacist team through MediHK would provide better self-management of ambulatory patients with cancer pain., Methods: Patients were randomly assigned to either an intervention group or control group. During the 4-week study period, the pharmacist would send 24-hour pain diaries daily, adverse drug reaction (ADR) forms every 3 days, and the Brief Pain Inventory form every 15 days to patients in the intervention group via MediHK. If a patient needed a change in drug/dosage or treatment of an ADR after the comprehensive review, the pharmacist would propose pharmacological interventions to the attending physician, who was then responsible for prescribing or adjusting pain medications. If no adjustments were needed, the pharmacist provided appropriate targeted education based on knowledge deficits. Patients in the control group received conventional care and did not receive reminders to fill out the forms. However, if the control group patients filled out a form via MediHK, the pain management team would review and respond in the same way as for the intervention group. The primary outcomes included pain intensity and pain interference in daily life. Secondary outcomes included patient-reported outcome measures, medication adherence, ADRs, and rehospitalization rates., Results: A total of 100 patients were included, with 51 (51%) in the intervention group and 49 (49%) in the control group. The worst pain scores, least pain scores, and average pain scores in the intervention group and the control group were statistically different, with median values of 4 (IQR 3-7) vs 7 (IQR 6-8; P=.001), 1 (IQR 0-2) vs 2 (IQR 1-3; P=.02), and 2 (IQR 2-4) vs 4 (IQR 3-5; P=.001), respectively, at the end of the study. The pain interference on patients' general activity, mood, relationships with others, and interests was reduced, but the difference was not statistically significant compared with the control group (Ps=.10-.76). The medication adherence rate increased from 43% to 63% in the intervention group, compared with an increase of 33% to 51% in the control group (P<.001). The overall number of ADRs increased at 4 weeks, and more ADRs were monitored in the intervention group (P=.003). Rehospitalization rates were similar between the 2 groups., Conclusions: The joint physician-pharmacist team operating through MediHK improved pain management. This study supports the feasibility of integrating the internet into the self-management of cancer pain., Trial Registration: Chinese Clinical Trial Registry ChiCTR1900023075; https://www.chictr.org.cn/showproj.aspx?proj=36901., (©Lu Zhang, Howard L McLeod, Ke-Ke Liu, Wen-Hui Liu, Hang-Xing Huang, Ya-Min Huang, Shu-Sen Sun, Xiao-Ping Chen, Yao Chen, Fang-Zhou Liu, Xiao Jian. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 16.08.2021.)

Hepatocellular carcinoma (HCC) is usually associated with varying degrees of cirrhosis. Among cirrhotic patients with solitary HCC in the absence of macro-vascular invasion, whether tumor size drives prognosis or not after hepatectomy remains unknown. This study aimed to investigate the prognostic impact of tumor size on long-term outcomes after hepatectomy for solitary HCC patients with cirrhosis and without macrovascular invasion. A total of 813 cirrhotic patients who underwent curative hepatectomy for solitary HCC and without macrovascular invasion between 2001 and 2014 were retrospectively studied. We set 5 cm as the tumor cut-off value. Propensity score matching (PSM) was performed to minimize the influence of potential confounders including cirrhotic severity that was histologically assessed according to the Laennec staging system. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after PSM. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the  ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival. These results were further confirmed in the PSM cohort of 235 pairs of patients. In cirrhotic patients with solitary HCC and without macrovascular invasion, tumor size may significantly affect the prognosis after curative hepatectomy., (© 2021. The Author(s).)

Chiral 3-substituted benzoxaboroles were designed as carbapenemase inhibitors and efficiently synthesised via asymmetric Morita-Baylis-Hillman reaction. Some of the benzoxaboroles were potent inhibitors of clinically relevant carbapenemases and restored the activity of meropenem in bacteria harbouring these enzymes. Crystallographic analyses validate the proposed mechanism of binding to carbapenemases, i.e. in a manner relating to their antibiotic substrates. The results illustrate how combining a structure-based design approach with asymmetric catalysis can efficiently lead to potent β-lactamase inhibitors and provide a starting point to develop drugs combatting carbapenemases.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: This study aimed to analyze a Chinese institution's experience with managing cervical necrotizing fasciitis (CNF) and observe the effects of a new therapeutic approach for postoperative drainage system., Methods: A retrospective study was established including a total of 46 CNF patients who underwent surgical debridement between April 2006 and April 2018. Analyses of demographic data, etiology, comorbidity, microbiology, complications, treatment methods, duration of treatment, and treatment outcomes were obtained., Results: There were 16 kinds of microbes cultured in 29 patients. Diabetic patients were more commonly infected by microbes (P < 0.05). There was a significant reduction in the number of operative time (P < 0.05) and length of hospitalization (P < 0.01) with postoperative therapy of double-cannula irrigation-drainage (DCID) system., Conclusion: CNF management includes controlling for comorbidities especially glycemic control and reasonable utilization of antibiotics and aggressive postoperative therapy. DCID system can effectively reduce operative frequency and duration of hospitalization.

In recent years, immunotherapy has achieved remarkable effectiveness for liver cancer and has attracted much attention, especially the combination therapy based on immune checkpoint blockers. Multidisciplinary experts have written the "Chinese multidisciplinary expert consensus on combined immunotherapy based on immune checkpoint inhibitors for hepatocellular carcinoma (2021 version)", which provides reference guidance for clinically relevant professionals to grasp indications, strengthen monitoring, timely and effective treatment of adverse reactions, and formulate reasonable combined treatment plan.

Essential Hypertension (EH) results in the burden of cardiovascular disease (CVD) such as Heart Failure (HF) and Ischemic Stroke (IS). A rapidly emerging field involving the role of Wnt/β-catenin signaling pathway in cardiovascular development and dysfunction has recently drawn extensive attention. In the present study, we conducted a genetic association between genomic variants in Wnt/β-catenin signaling pathway and EH, HF, IS. A total of 95 SNPs in 12 Wnt signaling genes ( WNT3A, WNT3, WNT4, DKK1, DKK2, LRP5, LRP6, CTNNB1, APC, FZD1, FRZB, SFRP1 ) were genotyped in 1,860 participants (440 patients with EH, 535 patients with HF, 421 patients with IS and 464 normal control subjects) using Sequenom MassArray technology. WNT3A rs752107(C > T) was strongly associated with an increased risk of EH, HF and IS. Compared with WNT3A rs752107 CC genotype, the CT genotype carriers had a 48% increased risk of EH (OR = 1.48, 95% CI = 1.12-1.96, P = 0.006), the TT genotype conferred a 139% increased risk of EH (OR = 2.39, 95% CI = 1.32-4.34, P = 0.003). Regarding HF and IS, the risk of HF in the T allele carriers (CT + TT) was nearly increased by 58% (OR = 1.58, 95% CI = 1.22-2.04, P = 4.40 × 10 -4 ) and the risk of IS was increased by 37% (OR = 1.37, 95% CI = 1.04-1.79, P = 0.025). Expression quantitative trait loci (eQTL) analysis indicated that rs752107 C allele corresponded to a significant reduction of WNT3A expression. We described a genetic variant of WNT3A rs752107 in Wnt/β-catenin signaling strongly associated with the risk of EH, HF and IS for the first time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ren, Luo, Ouyang, Cheng, Chen, Zhou, Huang and Zhang.)

The clinical data of 22 patients with giant renal hamartoma in Zhejiang Provincial People's Hospital who underwent robot-assisted laparoscopic nephron-sparing surgery from October 2014 to January 2020 were retrospectively analyzed. All the patients successfully completed the operation. The operation time and renal artery occlusion time was (179±34) min and (19.8±2.5) min, respectively. The intraoperative blood loss was (117±62) ml, and the postoperative hospital stay was (9.0±1.5) d. All cases were confirmed as renal angiomyolipoma by postoperative pathology. No urine leakage, postoperative bleeding and other complications occurred. Postoperative telephone follow-up was performed for 6 to 52 months, and no tumor recurrence on the surgical side was reported.

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

Introduction: We evaluated the effect of an operative coaching (OC) model on general surgery chief residents' operative efficiency (OE) measured by operative times. We hypothesized that higher levels of entrustment surgeons intend to offer resident in future similar cases are associated with improved OE., Materials and Methods: From July 2018 to June 2019, we used a validated instrument to score prospective resident entrustment in 228 evaluations of 6 chief residents during 12 OC sessions each (3 lap colectomy, 3 lap cholecystectomy, 3 ventral hernia, 3 inguinal hernia). Operative times of matched case CPT codes performed by coached chiefs (N = 500) were matched via CPT code to the cases of uncoached chiefs in the academic year 2016-2017 (N = 478). Statistical analysis was performed using Pearson correlation and one-way ANOVA., Results: Prospective entrustment scores from coached chief residents were associated with significantly shorter operative times in matched complex cases (CC) (r = -0.58, p = 0.0047). A similar trend was observed in noncomplex cases (NCC) (r = -0.29, p = 0.18). Compared to the historical cohort, coached chief residents showed a decrease in mean operative time during complex cases (p = 0.0008, d = 0.44), but an increase in mean operative times for noncomplex cases (p < 0.0001, d = 0.33)., Conclusions: An OC model improves chief residents' prospective entrustment leading to increased OE in cases with greater levels of operative complexity, showing a decrease in mean operative time compared to uncoached residents in certain procedures. This is the first report showing formal coaching may be a method to enhance chief resident OE., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Grazing is the dominant land use way for natural grasslands. Different grazing intensities could affect soil stoichiometry in grasslands by influencing the selective feeding by livestock, litter input, and microbial community structure. In this study, a grazing experiment was carried out in a grassland of agro-pastoral ecotone in Northern China for three years (2017-2019). The concentrations of total carbon (TC), total nitrogen (TN), dissolved organic carbon (DOC), dissolved nitrogen (DN), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) in soils were measured. We analyzed the stoichiometric characteristics of those parameters. The results showed that different grazing intensities (1, 2, 4 sheep·0.2 hm -2 ) had no significant effect on soil TC after three years. The moderate grazing intensity significantly reduced soil TN in 10-20 cm layer in 2019. The light, moderate, and heavy grazing intensities significantly increased soil C/N at 10-20 cm layer, while grazing intensities did not affect soil DOC, DN and DOC/DN. The soil DOC and DN content showed a decreasing trend with the increase of grazing intensity in 2019. It indicated that continuous high intensity grazing might reduce soil dissolved nutrients. The light grazing inten-sity increased soil MBC, while heavy grazing intensity reduced soil MBC significantly, with the increase of grazing year. Different grazing intensities did not affect soil MBN and MBC/MBN.

Objective: Individual differences in glycemic response to metformin in antidiabetic treatment exist widely. Although some associated genetic variations have been discovered, they still cannot accurately predict metformin response. In the current study, we set out to investigate novel genetic variants affecting metformin response in Chinese type 2 diabetes (T2D) patients., Methods: A two-stage study enrolled 500 T2D patients who received metformin, glibenclamide or a combination of both were recruited from 2009 to 2012 in China. Change of HbA 1c , adjusted by clinical covariates, was used to evaluate glycemic response to metformin. Selected single nucleotide polymorphisms (SNPs) were genotyped using the Infinium iSelect and/or Illumina GoldenGate genotyping platform. A linear regression model was used to evaluate the association between SNPs and response., Results: A total of 3739 SNPs were screened in Stage 1, of which 50 were associated with drug response. Except for one genetic variant preferred to affect glibenclamide, the remaining SNPs were subsequently verified in Stage 2, and two SNPs were successfully validated. These were PRKAG2 rs2727528 (discovery group: β=-0.212, P =0.046; validation group: β=-0.269, P =0.028) and PRKAG2 rs1105842 (discovery group: β=0.205, P =0.048; validation group: β=0.273, P =0.025). C allele carriers of rs2727528 and C allele carriers of rs1105842 would have a larger difference of HbA 1c level when using metformin., Conclusion: Two variants rs2727528 and rs1105842 in PRKAG2 , encoding γ2 subunit of AMP-activated protein kinase (AMPK), were found to be associated with metformin response in Chinese T2D patients. These findings may provide some novel information for personalized pharmacotherapy of metformin in China., Competing Interests: The authors declared no competing interests for this work., (© 2021 Xiao et al.)

Objective: To summarize and analyze the clinical characteristics of primary hyperpara-thyroidism (PHPT) with normocalcemic parathormone elevation (NPE) after surgical treatment, so as to improve the therapeutic ability and standardized post-operative follow-up of PHPT patients., Methods: Nine patients who were diagnosed with PHPT in the Department of Endocrinology of China-Japan Friendship Hospital from August 2017 to November 2019 were selected as the subjects. They all developed NPE within 6 months after surgical treatment. The clinical features and outcomes were collected and analyzed retrospectively, in addition, the related literature was reviewed., Results: Clinical features: among the 9 patients, 6 were middle-aged and elderly females and 3 were male. The main clinical manifestations were bone pain, kidney stones, nausea and fatigue except for one case of asymptomatic PHPT. Pre-operative examination showed high serum calcium [(3.33±0.48) mmol/L], low serum phosphorus [0.76 (0.74, 0.78) mmol/L], high 24-hour urinary calcium [8.1(7.8, 12.0) mmol/24 h], obviously elevated intact PTH [(546.1±257.7) ng/L], vitamin D deficiency [25-hydroxyvitamin D 3 (21.0±5.7) nmol/L]. Serum levels of bone alkaline phosphatase [7 patients 41.3(38.6, 68.4) μg/L, 2 patients >90 μg/L] and N-terminal midcourse osteocalcin (>71.4 μg/L) were significantly elevated. The estimated glomerular filtration rate decreased in 2 patients. Imaging examination: 7 patients had osteoporosis. Renal calculi were found in 3 patients by renal ultrasound. Imaging examination of parathyroid glands found definite lesions in all the patients, including 2 cases of multiple lesions and 7 cases of single lesions., Treatment and Outcome: two patients underwent parathyroidectomy, while other patients were treated with microwave thermal ablation. PTH increased 1 month after therapy [(255.0±101.4) ng/L], and no recurrent lesions were found by parathyroid ultrasound. After combined treatment with cal-cium and vitamin D for six months, PTH decreased significantly and the level of serum calcium remained normal at anytime during the follow-up period., Conclusion: The occurrence of postoperative NPE may be related to the higher pre-operative PTH, vitamin D deficiency and lower creatinine clearance. However, NPE may not predict recurrent hyperthyroidism or incomplete parathyroidectomy. Adequate calcium and vitamin D supplementation after surgery seems to be beneficial for patients with NPE. Post-operative follow-up of PHPT patients should be standardized to prevent and treat post-operative NPE.

Coptidis Rhizoma, as a bulk medicinal material, is in great demand in clinical practice. Its quality is uneven in the market due to the mixture of genuine, counterfeit and adulterants. Therefore, it is particularly important to establish a quality control system for Coptidis Rhizoma. Based on the concept of Chinese medicine quality marker(Q-marker), the potential quality markers of Coptidis Rhizoma were analyzed and predicted from the perspective of chemistry and pharmacology. The sources of the Q-markers of Coptidis Rhizoma were identified by literature retrieval. The potential Q-markers were then screened through the visualization of the &quot;components-targets-pathways&quot; network. High performance liquid chromatography(HPLC) was used to establish a multi-indicator qualitative and quantitative control method featuring fingerprints for 10 batches of Coptidis Rhizoma. A supervised mode of orthogonality partial least squares method-discriminant analysis(OPLS-DA) was used to screen the main marker components that caused differences between groups. The literature review results showed that the alkaloids were the main source of Coptidis Rhizoma Q-markers.The fingerprints of 13 common peaks were successfully established, and berberine, palmatine, berberine and epiberberine were selected as Q-markers of Coptidis Rhizoma, and their contents were determined.Based on the concept of the Q-marker of traditional Chinese medicine, the four components can be selected as the Q-marker of Coptidis Rhizoma after comprehensive consideration. The results of this study are not only conducive to the quality evaluation of Coptidis Rhizoma on the market, but also provide a reference for the overall quality control of Coptidis Rhizoma and lay foundation for the future exploration of the mechanism of Coptidis Rhizoma.

Background & Aims: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues., Methods: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching., Results: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes., Conclusions: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19., Lay Summary: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes., Competing Interests: Conflict of interests All authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Palladium-catalyzed aerobic oxidative cyclizations of substituted 2-(1H-pyrrol-1-yl)phenols with isocyanides via an O-H/C-H insertion cascade have been developed. This strategy provides facile access to pyrrolo[2,1-c][1,4]benzoxazine derivatives in good to excellent yields under an O2 atmosphere. The notable features of this protocol include its mild reaction conditions, atom-economy, and broad functional group tolerance.

Background: Chinese herbal medicine (CHM) has been nationally and globally used in treating gout for over a millennium. The potential relationship between the incidence of chronic kidney disease (CKD) in gout patients and CHM therapy is unclear. Thus, this study aimed to provide some evidence regarding the relationship between CHM therapy and the occurrence of CKD in gout patients. Methods : We used data from the National Health Insurance Research database (NHIRD) in Taiwan. In this population-based nested case-control study, all participants were identified by International Classification of Diseases, Ninth Revision (ICD-9). Conditional logistic regression was used to calculate the odds ratio (OR) of the risk of CKD in gout patients treated with CHM therapy. Results : Data on 1718 gout patients with CKD and 1:1 matched 1718 gout patients without CKD were collected for analysis. The results showed that CHM therapy in gout patients did not increase the risk of developing CKD (adjusted OR = 1.01; 95% confidence interval [CI]: 0.86-1.18; p > 0.05). Moreover, CHM therapy in gout patients for >365 days did not increase the incidence of CKD (adjusted OR = 1.30; 95% CI: 0.90-1.88; p = 0.162). Conclusion : Traditional CHM therapy does not increase the incidence of CKD in gout patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xiao, Ye, Liang, Chen, Wang, Xu and Wei.)

Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

Background: Prospective resident entrustment (i.e., trust an attending surgeon intends to give to a resident in the near future) in the operating room (OR) closely associates with granted future autonomy. However, the process of determining resident entrustment takes time and effort. Thus, this study aimed to assess the efficiency of granting incremental resident entrustment for upcoming surgical cases., Methods: We analyzed prospective resident entrustment of 6 chief residents in 76 cases of laparoscopic cholecystectomy, laparoscopic colectomy, ventral hernia, and inguinal hernia scored by attending surgeon, resident, and a surgeon observer. Matched direct costs and operative time were extracted from hospital billing. We assessed the efficiency of granting incremental prospective resident entrustment with direct cost per minute incurred in the evaluated case. Effect size was computed to assess the differences between groups., Results: Sixty-three cases (82.9%) were matched; 47.6% (30/63) of matched cases received prospective resident entrustment score ≥ 4. The direct cost per minute increased in three procedures (laparoscopic cholecystectomy, laparoscopic colectomy, and ventral hernia) with increased intention of granting incremental resident entrustment. Inguinal hernia was the only procedure in which chiefs were entrusted with future independence while the direct cost per minute decreased., Conclusions: Our findings demonstrate more time and effort are required (except for inguinal hernia) for residents to be entrusted with increased independence in the future. Faculty and resident development programs are recommended to improve the efficiency of the process of granting incremental operative entrustment to optimize resident training quality and cost of care delivery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Liver resection (LR) is the primary treatment method for patients with hepatocellular carcinoma (HCC). Improving surgical safety and reducing surgical morbidity and mortality is important for patients receiving LR. Various devices have been developed to facilitate vascular transection to reduce intraoperative blood loss, which is considered to be a predictor of poor surgical outcomes in patients undergoing LR. Vascular staplers have been widely applied for the division of major vascular and biliary structures in the process of LR; however, when and how to use these tools remains controversial. This review aims to report the rationality and necessity of using vascular staplers in vessel transection during liver surgery. Due to the risk of intraoperative and postoperative hemorrhage and biliary fistula, the process of transection of the portal pedicle and hepatic vein is a crucial step during LR. Stapling represents a vascular dissection technique that is widely used in laparoscopic LR and has then been popularized in open LR. Advocates argue that stapler transection methods provide several advantages, including diminished blood loss, fewer transfusion requirements and shorter operative times. However, other studies have failed to demonstrate those benefits when using these tools compared with the simple clamp-crushing technique. Using the stapler vascular transection method resulted in smaller surgical margins and similar surgical outcomes compared with those of the clamp-crushing vascular transection method. However, the intraoperative use of vascular staplers may significantly increase the financial burden of liver resection for patients with HCC, while not improving short- and long-term outcomes. Therefore, it has been suggested that vascular staplers should not be routinely used in LR. The current review discussed the above points and recommended that the stapling transection of the portal pedicle and hepatic vein should be applied during laparoscopic LR in a rational manner. However, the suturing ligation method should be routinely used in open LR., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Zhang et al.)

The TGF-β receptor kinase inhibitors (TRKI) have been reported to inhibit tumorigenicity in colon cancer. However, there is no direct evidence showing that these inhibitors function through inhibiting the TGF-β- mediated tumor-promoting effects in vivo. We established a TGF-β inducible reporter system by inserting a luciferase reporter gene to the vector downstream of TGF-β-inducible promoter elements, and transfected it into colon cancer cell lines. TRKIs SB431542 and LY2109761 were used to treat TGF-β inducible cells in vitro and in vivo. The luciferase activity was induced 5.24-fold by TGF-β in CT26 inducible cells, while it was marginally changed in MC38 inducible cells lacking Smad4 expression. Temporary treatment of mice with SB431542 inhibited the TGF-β pathway and TGF-β induced bioluminescence activity in vivo. Long-term treatment with LY2109761 inhibited tumorigenicity and liver metastasis in vivo in concomitant with reduced luciferase activity in the tumor. In this study, we established a model to monitor the TGF-β pathway in vivo and to compare the antitumor effects of TRKIs. Based on this novel experimental tool, we provided direct evidences that LY2109761 inhibits tumorigenicity and liver metastasis by blocking the pro-oncogenic functions of TGF-β in vivo., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Coronavirus Disease 2019 (COVID-19) emerges as a global pandemic and there is a lack of evidence about the clinical course and outcome of patients on maintenance hemodialysis (MHD). Here we conducted a retrospective longitudinal study aimed to analyze the clinical features and outcome of MHD patients hospitalized with COVID-19. Of 3126 inpatients with COVID-19 at 3 Branches of Wuhan Tongji Hospital from Jan 18th to Mar 9th, 2020, 19 patients were undergoing maintenance hemodialysis. Among the 19 MHD patients with COVID-19, 6 patients (31.6%) died, and 13 patients (68.4%) were able to be discharged. Baseline characteristics, clinical courses, laboratory findings, and dynamic trajectories of major laboratory markers were compared between survivors and nonsurvivors. According to our findings, MHD patients with COVID-19 who experienced non-surviving outcome had more elevated CRP, IL6 and procalcitonin as well as fibrinogen levels at various points compared to survivors. Thus the dysregulation of immune response as well as coagulation abnormalities might be highly involved in the pathological process of COVID-19, contributing to the poor prognosis in MHD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Nutrient resorption is an important strategy of nutrient conservation, which reflecting the ability of plants to conserve and utilize nutrients and adapt to environment. To explore the relationship between nutrient content and nutrient resorption of broadleaved woody species of different life forms ( i.e ., evergreen vs. deciduous), we sampled 30 broadleaved woody species in subtropical region of China located in Yangjifeng National Nature Reserve, Jiangxi Province. The nitrogen (N) and phosphorus (P) concentrations in green and senescent leaves of each species were measured to calculate nutrient resorption efficiency. Furthermore, we analyzed the relationship of leaf nutrient concentration and resorption efficiency for the different life forms. The results showed that N and P concentrations in green leaves were significantly higher in deciduous trees than those in evergreen trees. The P concentrations of senescent leaves in deciduous woody species was significantly higher than that in evergreen woody species. There was no significant difference of N concentration in senescent leaves between evergreen and deciduous species. Nitrogen resorption efficiency (NRE) and phosphorus resorption efficiency (PRE) of the 30 broadleaved woody species were 49.6% and 50.9%, respectively. There were no significant differences between the NRE and PRE of evergreen and deciduous species. NRE and PRE negatively correlated with N and P concentrations in senescent leaves, respectively. Additionally, evergreen and deciduous species showed similar relationships between nutrient resorption efficiency and nutrient concentration in senescent leaves. The sca-ling exponent of allometric relationship between NRE and PRE was 1.18 across all the species. The nutrient resorption efficiency of all the species were affected by the nutrient status of the senesced leaves. Plants examined in this study generally re-absorbed P from senescing leaves than N.

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score ⩾ 3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60-26.32; P < 0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21-83.93; P < 0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34-7.75; P < 0.001), and recent adjuvant therapy (< 1 month) (adjusted HR 3.16; 95% CI 1.75-5.70; P < 0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score ⩾ 3, advanced tumor stage, and recent adjuvant therapy (< 1 month) may have high risk of mortality.

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Liu, Liao and Chen.)

Uveal melanoma is the ocular malignancy and mainly driven by oncogenic mutations of Gαq/11 proteins. Previous targeted therapy for melanoma treatment was limited to specific downstream signaling pathway, and inhibiting the "molecular switches" G proteins for melanoma treatment therapy was rarely described. We herein report the discovery of imidazopiperazine derivatives as Gαq/11 protein inhibitors. The most promising compound GQ127 showed good efficacy and safety in inositol monophosphate (IP 1 ) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor activities in uveal melanoma cells viability, migration, and invasion. The effects of GQ127 on Gαq/11 signaling pathway were confirmed by analyzing the downstream effectors yes-associated protein (YAP) and extracellular signal-regulated kinase (ERK). More importantly, GQ127 significantly suppressed UM xenograft growth in mouse model without severe toxicity at the testing dose. These findings provide a lead compound that directly targets the Gαq/11 proteins for uveal melanoma treatment.

Acute myeloid leukemia (AML) is a hematopoietic disease with poor survival. Chemotherapy resistance is one of the determinant factors influencing AML prognosis. To identify genes possibly affecting the drug responses in AML, the Illumina Infinium MethylationEPIC (850K) was used to screen for differential DNA methylation loci between patients achieved complete remission (CR) or not (non-CR) after induction therapy in 37 AML patients. Then, 32 differentially methylated sites (DMS) were selected for replication in another 86 AML patients by next-generation sequencing. Nine sites including cg03988660, cg16804603, cg18166936, cg11308319, cg09095403, cg18493214, cg01443536, cg16030878 and cg10143426 were replicated. Analysis of the Gene Expression Omnibus (GEO) database showed that mRNA expression of TBC1D16 and HDAC4 was associated with AML prognosis. Methylation level of the cg16030878 in TBC1D16 3'-UTR correlated positively with TBC1D16 mRNA expression in samples both in the TCGA database and clinically collected in the study. Both higher cg16030878 methylation and higher TBC1D16 mRNA expression were associated with increased risk of non-CR and worse overall survival (OS) in AML patients. In AML cells, knockdown of TBC1D16 decreased cell proliferation and ERK phosphorylation levels, as well as increased sensitivity to mitoxantrone and decitabine indicated by IC 50 . In patients with combined use of decitabine, those patients with CR showed significantly lower TBC1D16 mRNA expression. On the contrary, knockdown of TBC1D16 resulted in decreased sensitivity to cytarabine in U937 cells. Our findings implicated that TBC1D16 is a potential predictor for chemosensitivity and prognosis in adult AML patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response., Methods: Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300 mg loading dose (LD) clopidogrel for 12-24 h or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C19*2, and CYP2C19*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p < 0.001). In addition, FMO3 rs1736557 AA homozygotes showed significantly lower PRI as compared with carriers of the major rs1736557 G allele in the entire cohort and in the MD cohort (p = 0.011, p = 0.008, respectively). The risk of HTPR was decreased significantly in carriers of the rs1736557 A allele (AA vs GG: OR = 0.316, 95% CI: 0.137-0.726, p = 0.005; AA vs GA: OR = 0.249, 95% CI: 0.104-0.597, p = 0.001; AA vs GG+GA: OR = 0.294, 95% CI: 0.129-0.669, p = 0.002), and the association was observed mainly in patients carrying the CYP2C19 LOF allele and in those administered with MD., Conclusion: The FMO3 rs1736557 AA genotype was related to an increased the antiplatelet potency of clopidogrel in Chinese CAD patients. Additional studies are required to verify this finding.

Osimertinib (AZD9291) has been widely used for the treatment of EGFR mutant non-small cell lung cancer. However, resistance to osimertinib is inevitable. In this study we elucidated the molecular mechanisms of resistance in osimertinib-resistant NCI-H1975/OSIR cells. We showed that NCI-H1975/OSIR cells underwent epithelial-mesenchymal transition (EMT), which conferred sensitivity to the GPX4 inhibitor 1S, 3R-RSL3 to induce ferroptotic cell death. The EMT occurrence resulted from osimertinib-induced upregulation of TGFβ2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-κB pathway for survival, since treatment with the NF-κB pathway inhibitor BAY 11-7082 or genetic silence of p65 caused much greater cell death as compared with the parental NCI-H1975 cells. In NCI-H1975 cells, osimertinib activated NF-κB pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGFβ2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-κB pathway. In addition, coexistence of EMT and activation of NF-κB pathway was observed in several NCI-H1975/OSIR clones. These findings shed new light on distinct roles of TGFβ2 in osimertinib-resistant cells and provide new strategies for treatment of this resistant status.

Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015., Competing Interests: None

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Background: Pancreatic resections are complex and technically challenging surgical procedures. They often come with potential limitations to high-volume centers. Distal pancreatectomy is a relatively simple procedure in most cases. It facilitates the development of up-to-date minimally invasive surgical procedures in pancreatic surgery including laparoscopic distal pancreatectomy and robot-assisted distal pancreatectomy., Main Body: To obtain a desirable long-term prognosis, R0 resection and adequate lymphadenectomy are crucial to the surgical management of pancreatic cancer, and they demand standard procedure and multi-visceral resection if necessary. With respect to combined organ resection, progress has been made in evaluating and determining when and how to preserve the spleen. The postoperative pancreatic fistula, however, remains the most significant complication of distal pancreatectomy, with a rather high incidence. In addition, a safe closure of the pancreatic remnant persists as an area of concern. Therefore, much efforts that focus on the management of the pancreatic stump have been made to mitigate morbidity., Conclusion: This review summarized the historical development of the techniques for pancreatic resections in recent years and describes the progress. The review eventually looked into the controversies regarding distal pancreatectomy for tumors in the body and tail of the pancreas.

We report the direct asymmetric synthesis of pyrimido[2,1- b ]benzothiazoles using a commercially available chiral amine catalyst. A variety of 2-benzothiazolimines and aldehydes were well tolerated under the reaction conditions and generated the corresponding products in 81-99% yields with excellent diastereoselectivities and enantioselectivities (up to >20:1 dr, 99% ee). Furthermore, the products could be easily converted to other useful chiral building blocks.

Objective: To evalutate the safety and efficacy of infrahepatic inferior vena cava clamping robot-assisted laparoscopic liver resection. Methods: All data about 24 patients with robotic liver resection at Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology between February 2015 and December 2017 were collected and analyzed. These patients were divided into two groups based on different methods to decrease central venous pressure. Eight patients(6 males and 2 females,aged 49 years(range:50 to 56 years)) were applied with infrahepatic inferior vena cava clamping,and the other 16 matched cases (15 males and 1 female,aged 53 years(range:38 to 69 years)) were categorized into lowering central venous pressure group. Intraoperative blood loss,blood transfusion,intraoperative hemodynamic parameters,postoperative complications,and renal function were compared by t -test,non-parametric test,χ 2 test,or Fisher exact test. Results: There was significantly difference in the intraoperative blood loss between the infrahepatic vena cava clamping group and the lowering central venous group(200(220) ml (range:100 to 400 ml) vs. 750(800) ml (range:100 to 2 000 ml), Z =‒2.169, P =0.030). The clamping time of portal triad and infrahepatic inferior vena cava were 24 (18) minutes and 29 (20) minutes in the infrahepatic inferior vena cava clamping group, and portal triad clamping time was 23 (23) minutes in the low central venous group. There was no significant difference between the two groups ( Z =‒0.323, P =0.747). There was no intraoperative blood transfusion in the infrahepatic inferior vena cava clamping group, and 5 cases in the low central venous group, with a transfusion volume of 1.5(1.5)U. The difference between the two groups was statistically significant ( Z =‒3.353, P =0.001). However, the mean arterial pressure in the infrahepatic vena cava clamping group decreased from (88.6±4.9) mmHg to (67.4±3.8) mmHg(1 mmHg=0.133 kPa), which was lower than that of lowering central venous group (72.4±3.3) mmHg ( t =2.315, P =0.003). And there were no significant differences related to postoperative complications rate or hepatic and renal function in both groups. Conclusion: The infrahepatic inferior vena cava technology is safe and feasible to decrease central venous pressure during robotic liver resections,which will not affect the recovery of hepatic and renal functions.

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

During the past decades, drugs targeting transforming growth factor-β (TGFβ) signaling have received tremendous attention for late-stage cancer treatment since TGFβ signaling has been recognized as a prime driver for tumor progression and metastasis. Nonetheless, in healthy and pre-malignant tissues, TGFβ functions as a potent tumor suppressor. Furthermore, TGFβ signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation. Therefore, targeting TGFβ signaling for cancer therapy is challenging. Recently, we and others showed that blocking TGFβ signaling increased chemotherapy efficacy, particularly for nanomedicines. In this review, we briefly introduce the TGFβ signaling pathway, and the multifaceted functions of TGFβ signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells. We also summarize TGFβ targeting agents. Then, we highlight TGFβ inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy. Finally, the current challenges and future opportunities in targeting TGFβ signaling for cancer therapy are discussed., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Nine new limonoids, meliazedarines A-I ( 1 - 9 ), seven known analogues ( 10 - 16 ), and five known triterpenoids ( 17 - 21 ) were isolated from the fruits of Melia azedarach . Their structures were determined by analysis of 1D and 2D NMR, HRESIMS, X-ray diffraction, and electronic circular dichroism (ECD) data. Compound 7 showed significant cytotoxicity against the HCT116 cell line with IC 50 values of 0.3 ± 0.1 μM.