Human pluripotent stem cell-derived kidney organoids: Current progress and challenges.

Human pluripotent stem cell (hPSC)-derived kidney organoids share similarities with the fetal kidney. However, the current hPSC-derived kidney organoids have some limitations, including the inability to perform nephrogenesis and lack of a corticomedullary definition, uniform vascular system, and coordinated exit pathway for urinary filtrate. Therefore, further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development, regeneration, disease modeling, and drug screening. In this review, we discussed recent advances in the generation of hPSC-derived kidney organoids, how these organoids contribute to the understanding of human kidney development and research in disease modeling. Additionally, the limitations, future research focus, and applications of hPSC-derived kidney organoids were highlighted.

Anti-necroptosis and anti-ferroptosis compounds from the Deep-Sea-Derived fungus Aspergillus sp. MCCC 3A00392.

Eight undescribed (1-8) and 46 known compounds (9-54) were isolated from the deep-sea-derived Aspergillus sp. MCCC 3A00392. Compounds 1-3 were three novel oxoindolo diterpenoids, 4-6 were three bisabolane sesquiterpenoids, while 7 and 8 were two monocyclic cyclopropanes. Their structures were established by exhaustive analyses of the HRESIMS, NMR, and theoretical calculations of the NMR data and ECD spectra. Compounds 10, 33, 38, and 39 were able to inhibit tumor necrosis factor (TNF)-induced necroptosis in murine L929 cell lines. Functional experiments verified that compounds 10 and 39 inhibited necroptosis by downregulating the phosphorylation of RIPK3 and MLKL. Moreover, compound 39 also reduced the phosphorylation of RIPK1. Compounds 10, 33, and 34 displayed potent inhibitory activities against RSL-3 induced ferroptosis with the EC50 value of 3.0 µM, 0.4 µM, and 0.1 µM, respectively. Compound 10 inhibited ferroptosis by the downregulation of HMOX1, while compounds 33 and 34 inhibited ferroptosis through regulation of NRF2/SLC7A11/GCLM axis. However, these compounds only showed weak effect in either the necroptosis or ferroptosis relative mouse disease models. Further studies of pharmacokinetics and pharmacodynamics might improve their in vivo bioactivities.

Safety, tolerability, and immunogenicity of a CpG/Alum adjuvanted SARS-CoV-2 recombinant protein vaccine (ZR202-CoV) in healthy adults: Preliminary report of a phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial.

This was a phase 1 dose-escalation study of ZR202-CoV, a recombinant protein vaccine candidate containing a pre-fusion format of the spike (S)-protein (S-trimer) combined with the dual-adjuvant system of Alum/CpG. A total of 230 participants were screened and 72 healthy adults aged 18-59 years were enrolled and randomized to receive two doses at a 28-day interval of three different ZR202-CoV formulations or normal saline. We assessed the safety for 28 days after each vaccination and collected blood samples for immunogenicity evaluation. All formulations of ZR202-CoV were well-tolerated, with no observed solicited adverse events ≥ Grade 3 within 7 days after vaccination. No unsolicited adverse events ≥ Grade 3, or serious adverse events related to vaccination occurred as determined by the investigator. After the first dose, detectable immune responses were observed in all subjects. All subjects that received ZR202-CoV seroconverted at 14 days after the second dose by S-binding IgG antibody, pseudovirus and live-virus based neutralizing antibody assays. S-binding response (GMCs: 2708.7 ~ 4050.0 BAU/mL) and neutralizing activity by pseudovirus (GMCs: 363.1 ~ 627.0 IU/mL) and live virus SARS-CoV-2 (GMT: 101.7 ~ 175.0) peaked at 14 days after the second dose of ZR202-CoV. The magnitudes of immune responses compared favorably with COVID-19 vaccines with reported protective efficacy.

Sex Differences in the Association of Weight-Adjusted-Waist Index with Sarcopenic Obesity: A Cross-Sectional Study of Hemodialysis Patients.

Objective: To explore the association between weight-adjusted-waist index (WWI) and sarcopenic obesity (SO) in patients with maintenance hemodialysis (MHD). Methods: A multicenter, cross-sectional study that included 3311 adult MHD patients was conducted in 20 hemodialysis (HD) centers from June 1, 2021, to August 30, 2021. Body composition was evaluated by body composition monitor based on bioimpedance spectroscopy. Hand grip strength was measured by CAMRY® dynamometer. WWI was calculated as waist circumference (cm) divided by the square root of body weight (kg). Multiple logistic regression models, spearman correlation analysis, and receiver-operating characteristic (ROC) analyses were conducted. Results: The median age of the study was 55 years, and 39.4% of patients were female. The prevalence of SO was 22.7% in the total population, and patients with SO had higher WWI. Higher WWI quartiles were independently associated with a higher risk of SO in men after adjusting for potential confounders, including age, dialysis vintage, body mass index, biochemical indicators, and various medical histories; the odds ratio (OR) of SO was highest in the fourth quartile of the WWI (OR: 4.08, 95% confidence interval: 2.65-6.27, P for trend <0.001). Age-adjusted WWI provided a better diagnostic power than WWI only for SO in men (area under the ROC curve: 0.72 vs. 0.68, P < 0.001). WWI was not associated with SO in female HD patients. Conclusion: WWI is independently associated with SO in male but not female MHD patients. This anthropometric index is simple to calculate, making it applicable in clinical practice.

Abnormalities of serum lipid metabolism in patients with acute paraquat poisoning caused by ferroptosis.

As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ poisoning continues to present a medical challenge. In this study, the objective was to investigate the early metabolic changes in serum metabolism and identify the key metabolic pathways involved in patients with PQ poisoning. Quantitative analysis was conducted to determine the relevant metabolites. Additionally, experiments were carried out in both plasma and cell to elucidate the mechanisms underlying metabolic disorder and cell death in PQ poisoning. The study found that polyunsaturated fatty acids (PUFAs) and their metabolites, such as arachidonic acid (AA) and hydroxy eicosatetraenoic acids (HETEs), were significantly increased by non-enzymatic oxidative reaction. Reactive oxygen species (ROS) production increased rapidly at 2 h after PQ poisoning, followed by an increase in PUFAs at 12 h, and intracellular glutathione, cysteine (Cys), and Fe2+ at 24 h. However, at 36 h later, intracellular glutathione and Cys decreased, HETEs increased, and the expression of SLC7A11 and glutathione peroxidase 4 (GPX4) decreased. Ultrastructural examination revealed the absence of mitochondrial cristae. Deferoxamine was found to alleviate lipid oxidation, and increase the viability of PQ toxic cells in the low dose. In conclusion, unsaturated fatty acids metabolism was the key metabolic pathways in PQ poisoning. PQ caused cell death through the induction of ferroptosis. Inhibition of ferroptosis could be a novel strategy for the treatment of PQ poisoning.

Low Lean Tissue Index and Muscle Strength Combined with High Fat Tissue Index Are Associated with Cardiovascular Disease-Related Hospitalisation in Patients on Haemodialysis.

INTRODUCTION: The combined clinical impact of muscle mass, muscle function, and adipose mass on hospitalisation events, especially those that have exact causes, such as cardiovascular diseases (CVDs), had been rarely studied in patients on haemodialysis (HD). This study aimed to determine the influence of lean tissue index (LTI), fat tissue index (FTI), and hand grip strength (HGS) on the risk of CVD-related hospitalisation in patients undergoing chronic HD. METHODS: This multi-centre observational study enrolled a total of 2,041 clinically stable patients aged >18 years and who had undergone HD for at least 3 months at 17 HD units in 2019. The follow-up period was up to 2 years. LTI and FTI were assessed using a body composition monitoring machine, and HGS was measured by a CAMRY® dynamometer. Cox regression models were fit to estimate the associations of body composition and HGS with CVD-related hospitalisation risk. RESULTS: During a mean follow-up of 22.6 months, CVD-related hospitalisation occurred in 492 patients. Compared with the non-CVD group, patients with CVD-related hospitalisation were older; had lower diastolic blood pressure; were more likely to have a history of diabetes; had worse activity status scores and lower levels of LTI, HGS, serum uric acid, and serum creatinine; and had higher FTI levels, body mass index, and extracellular water/intracellular water ratio. In the Cox regression models, low LTI and high FTI were independently associated with CVD-related hospitalisation in both men and women. In men, low HGS was an independent risk factor for CVD-related hospitalisation. When patients were further stratified into four distinct groups according to the sex-specific median values of LTI and FTI, the combination of low LTI and high FTI was an independent risk factor for CVD-related hospitalization (hazard ratio [HR] = 1.79 in men, 95% confidence interval 1.26-2.55; HR = 2.48 in women, 95% confidence interval 1.66-3.71; reference: high LTI/low FTI group). CONCLUSIONS: Among patients on chronic HD, low LTI, and high FTI were associated with CVD-related hospitalisation in men and women, whereas HGS was an independent risk factor for CVD-related hospitalisation in men but not in women. Combining low LTI and high FTI increased the association with hospitalisation risk and was an independent predictor of CVD-related hospitalisation.

Physiological and Metabolic Adaptation to Heat Stress at Different Altitudes in Yaks.

Yaks have strong adaptability to extremely cold and hypoxic conditions but are susceptible to high ambient temperature when yaks are raised in low-altitude areas during the high-temperature season. Twenty-four adult male yaks with similar weights and ages were randomly divided into TN (Thermoneutral, altitude = 3464 m), LHS (Light heat stress, altitude = 1960 m), and MHS (Medium heat stress, altitude = 906 m) groups to evaluate adaptation strategies to HS. Non-targeted and targeted metabolomics were applied to investigate the effects of different extents of HS on yaks. LHS- and MHS-yaks showed higher rectal temperatures and respiratory rates than TN-yaks. MHS-yaks had higher levels of red blood cells (RBCs), hemoglobin (Hb), whole blood relative index of middle shear at a shear rate of 5 S-1 (WMS), whole blood relative index of high shear at a shear rate of 200 S-1 (WHS), Casson viscosity (CV), middle shear flow resistance at a shear rate of 5 S-1 (MSFR), and high shear flow resistance at a shear rate of 200 S-1 (HSFR) as compared to TN- and LHS-yaks. Differential metabolites and metabolic pathways, including fatty acid metabolism, lipid metabolism, glucose metabolism, and amino acid metabolism, were altered by HS. Metabolites in the glucose metabolism pathway in LHS- and MHS-yaks were lower than those in TN-yaks. However, LHS-yaks showed higher levels of metabolites in the HIF-1 signaling pathway compared to TN- and MHS-yaks. Most of the tricarboxylic acid cycle (TCA) intermediates and fatty acids were significantly decreased in MHS-yaks compared to the other two groups. As a whole, yaks raised at a low altitude (25.6 °C) suffered from severe HS, but they adapted to HS with vasodilatation for dissipating heat and the increased antioxidants and metabolite levels of energy substrates.

Physiological and Proteomic Responses of Dairy Buffalo to Heat Stress Induced by Different Altitudes.

Buffalo are mainly distributed in low-altitude (LA), medium-altitude (MA), and high-altitude (HA) regions characterised by different thermal and oxygen environments in Yunnan province, China. Due to black skin, sparse hair, and the low density of skin sweat glands, buffalo are more sensitive to heat stress. Here, we used data-independent acquisition (DIA) proteomics to reveal a broad spectrum of proteins that play roles in adaptation to the heat stress of buffalo raised at low altitude or hypoxia at high altitude. LA buffalo showed higher body temperatures than MA- and HA buffalo, and HA buffalo had higher levels of GSH and SOD and lower levels of ROS compared to LA and MA buffalo. In 33 samples, 8476 peptides corresponding to 666 high-confidence proteins were detected. The levels of circulating complement proteins in the immune pathways were lower in LA and MA buffalo than in HA buffalo. There were higher levels of alpha-1 acid glycoprotein in LA buffalo than in MA and HA buffalo. Relative to MA buffalo, levels of blood oxygen delivery proteins were higher in LA and HA buffalo. A higher abundance of apolipoproteins was detected in LA and MA buffalo than in HA buffalo. In summary, buffalo adopted similar adaptation strategies to oxidative stress induced by heat stress or hypoxia, including immunological enhancement, high efficiency of blood oxygen delivery, and the inhibition of lipid oxidation.

Correlation between TCM Constitutional Types and Lung Carcinoma in Various Geographical Areas: A Systematic Review and Meta-Analysis.

Background: Lung carcinoma is a serious disorder that negatively influences the quality of life of sufferers. Despite the growing number of investigations into the management and prognosis of lung carcinoma, few research studies have been conducted to demonstrate the association between TCM constitution and lung carcinoma. Methods: We searched PubMed, EMBASE, Science Net, Cochrane Library, China National Knowledge Infrastructure, VIP database, Wanfang database, and China Biomedical Literature Database for Chinese and English versions until January 31, 2021. We also manually searched for Chinese lung cancer, Chinese physical medicine, Chinese medical trial registries, and unpublished surveys or references. The literature was screened against inclusive and exclusive criteria, and two investigators' results were independently summarized. The primary outcome was a ratio of body type. Single-group rates were meta-analyzed using Stata 14.0 statistical software, bias was estimated by funnel plotting, and sources of heterogeneity were evaluated by subgroup and sensitivity examinations. Results: 18 randomized controlled trials were totally included to compare the single-group ratio and 95% confidence interval of nine constitution types of lung cancer, namely, mild constitution (ES = 0.12, 95% CI (0.08, 0.15), P < 0.0001), Qi deficiency constitution (ES = 0.20, 95% CI (0.15, 0.26), P < 0.0001), Qi depression constitution (ES = 0.09, 95% CI (0.07, 0.12), P < 0.0001), damp-heat constitution (ES = 0.05, 95% CI (0.03, -0.06), P < 0.0001), phlegm dampness constitution (ES = 0.05, 95% CI (0.03, -0.06), P < 0.0001), special constitution (ES = 0.01, 95% CI (0.01, 0.02), P=0.993), blood stasis constitution (ES = 0.05, 95% CI (0.04, 0.07), P < 0.0001), Yang deficiency constitution (ES = 0.16, 95% CI (0.12, 0.19), P < 0.0001), and Yin deficiency constitution (MD = 0.15, 95% CI (0.11, 0.18), P < 0.0001). Conclusion: This study showed that Qi deficiency, Yang deficiency, and Yin vacuity were the predominant types of physical conditions of lung cancer cases.

Efficacy and Safety of Jinshuibao Capsule in Diabetic Nephropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: This systematic review was able to evaluate the clinical evidence of JSBC in the randomized controlled trial (RCT) of diabetic nephropathy. Methods: The Chinese and English literatures published in PubMed, Cochrane Library, VIP, Wanfang Data, CNKI, and CBM before July 30, 2019, were retrieved. This study includes only randomized controlled trials of treatments related to diabetic nephropathy. We assessed the methodological quality of the subjects involved according to the assessment criteria in 5.3.3 of the Cochrane Assessment Manual. RevMan 3.5.5 software was used to analyze the relevant data, meta-analysis, and inverted funnel analysis chart. Results: This study included 26 RCTs, including 4676 patients in total (2342 cases in the experimental group and 2334 cases in the control group). The results of 8 randomized controlled trials showed that urinary microprotein excretion rate (UAER) significantly decreased (P < 0.0001) before and after treatment of diabetic nephropathy. Conclusion: The available clinical evidence has suggested that JSBC combined with western drugs is differentially effective in the treatment of diabetic nephropathy. The combination of JSBC with western medicine is more effective. However, due to the small amount and low quality of the included literatures, the current evidence is not certain to be fully clinically applicable.

Aging exacerbates the morphological and mechanical response of mineralized collagen fibrils in murine cortical bone to disuse.

Mineralized collagen fibrils (MCFs) are the fundamental building blocks of bone tissue and contribute significantly to the mechanical behavior of bone. However, it is still largely unknown how the collagen network in bone responds to aging and the disuse normally accompanying it. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, age-related alterations in the microstructure and mechanical properties of murine cortical tibia at multiple scales were investigated in this study. The potential difference in the responses of bone to disuse at different ages was studied. The results indicated that the age- and disuse-related alterations in bone initiate from MCFs in the bone matrix. The D-periodic spacing, radial elastic modulus of a single MCF and the mineral-to-matrix ratio on the cortical bone surface were larger in aged mice than in adult mice. Disuse, on the other hand, mainly has a major influence on aged mice, particularly on the morphology and mechanical properties of MCFs, but it only has modest effects on adult bone. These findings revealed insights into the morphological and mechanical adaptation of mineralized collagen fibrils in murine cortical bone to aging and disuse. STATEMENT OF SIGNIFICANCE: Bone is a complex structured composite material consisting of an interwoven framework of collagen fibrils reinforced by mineral particles and embedded in an extrafibrillar mineralized matrix. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, this study suggests that the effects of aging, as well as the accompanying disuse, on the morphology and mechanical properties of bone initiate from the mineralized collagen fibril level. More interestingly, the MCF in the bone of aged mice seems to be more sensitive to disuse than that in adult mice. These findings significantly further the current understanding of the adaptation process of bone to aging at the mineralized collagen fibril level and provide direct insights into the physiological response of bone to aging and the abnormal mechanical environment.

Comparing the efficacy of different intra-articular injections for knee osteoarthritis: A network analysis.

BACKGROUND: The findings on the effectiveness of platelet-rich plasma, ozone, and hyaluronic acid in the treatment of osteoarthritis of the knee are controversial, and the existing original studies and meta-analyses are mostly comparisons of a single joint cavity injection method, lacking direct and indirect comparisons of different drugs in the joint cavity. The lack of direct and indirect comparisons of different drugs in the joint cavity makes it difficult to have a clearer and more comprehensive understanding of joint cavity injection methods. In this study, the efficacy of platelet-rich, ozone, sodium hyaluronate, and combined knee cavity injections were compared directly or indirectly using a reticulated meta-analysis in this field, and the efficacy of treatment measures was ranked to provide more comprehensive and reliable evidence-based clinical evidence for the selection of knee cavity injections in osteoarthritis of the knee. OBJECTIVE: To compare the effects of platelet-rich plasma, ozone, and sodium glassate injection interventions on the efficacy of osteoarthritis of the knee through reticulated Meta-analysis, and to comprehensively compare the clinical effectiveness of platelet-rich plasma, ozone, and sodium glassate injection joint cavity injection for the treatment of osteoarthritis of the knee. METHODS: The PubMed, CBM, CNKI, VIP, and Wan-Fang databases were searched for information on the effectiveness of platelet-rich plasma, ozone, and sodium vitrate injection for the comparative treatment of osteoarthritis of the knee, with a search time frame of each database from the date of creation to July 20, 2021. Two investigators independently screened the literature, extracted data according to inclusion and exclusion criteria, and evaluated the quality of the literature in parallel. Statistical analysis was performed using Stata 16.0 software to compare the differences in the efficacy of each treatment measure using the ratio and 95% confidence interval as effect indicators and to rank the efficacy. RESULTS: Thirty-three RCTs with 7003 patients with osteoarthritis of the knee were included, involving 5 therapeutic measures. Meta-analysis showed that the efficacy of platelet-rich plasma injection was superior to both ozone and hyaluronic acid therapies. Hyaluronic acid+ozone and platelet-rich plasma+hyaluronic acid were both superior to ozone and hyaluronic acid monotherapy. The differences in efficacy between hyaluronic acid and ozone compared with platelet-rich plasma were statistically significant, and the differences in efficacy between the 2 combination therapies (platelet-rich plasma+hyaluronic acid, hyaluronic acid+ozone) and the 3 monotherapies (platelet-rich plasma, ozone, hyaluronic acid) were statistically significant. Platelet-rich plasma+hyaluronic acid, hyaluronic acid+ozone compared with 3 monotherapies (platelet-rich plasma, ozone, hyaluronic acid) were statistically significant, except for the difference in efficacy with platelet-rich plasma, which was not statistically significant, indicating that this platelet-rich plasma+hyaluronic acid and Hyaluronic acid+ozone combination therapy was superior to monotherapy. Also, the efficacy of platelet-rich plasma was better than hyaluronic acid and ozone and the difference was statistically significant, indicating that platelet-rich plasma was more effective than ozone and sodium glass in the treatment of osteoarthritis of the knee in monotherapy. CONCLUSION: It is believed that in the course of clinical practice, hyaluronic acid+ozone or platelet-rich plasma+hyaluronic acid combination therapy or platelet-rich plasma therapy can be preferred for patients with osteoarthritis of the knee.

Exploring the clinical efficacy of different nonsurgical rehabilitation interventions for humeral lateral epicondylitis: A protocol for network meta-analysis.

BACKGROUND: Lateral epicondylitis is a common musculoskeletal disorder characterized by the decreased grip and upper limb strength and pain in the lateral aspect of the elbow joint. At present, shock wave, corticosteroid injection, platelet-rich plasma injection, and Dextrose prolotherapy therapy nonsurgical rehabilitation treatment methods are commonly used in clinical. However, the conclusions of studies comparing treatment efficacy between them are controversial, with most studies focusing on limited comparisons and a lack of direct and indirect comparisons between them, making it difficult to have a clearer and more comprehensive understanding of the efficacy between them. PURPOSE: To comprehensively compare the effectiveness of shockwave, corticosteroid injection, platelet-rich plasma injection, and Dextrose prolotherapy therapy for the treatment of external humeral lateral epicondylitis using a reticulo-meta-analysis. METHODS: Randomized controlled trials on the effectiveness of shock wave, corticosteroid injection, platelet-rich plasma injection, and Dextrose prolotherapy therapy for the treatment of external humeral lateral epicondylitis were searched in PubMed, The Cochrane Library, CNKI, and Wan-Fang databases for the period January 1, 2016 to January 1, 2021 for each database. Two investigators independently screened the literature, extracted data according to inclusion and exclusion criteria, and evaluated the quality of the literature in parallel. Statistical analyses were performed using Stata 14.0 software to compare differences in efficacy between treatment measures using ratio and 95% confidence interval as effect indicators and to rank efficacy. RESULTS: Nine randomized controlled trials with a total of 289 patients with external humeral lateral epicondylitis were included, involving 4 nonsurgical rehabilitation measures and 6 intervention options. Quadrilateral ring to test the inconsistency of each closed-loop study finding, and the results show that the inconsistency factor was bounded at 1.65, with lower 95% confidence interval of 0.47 and 2.84 for both, which in summary indicates that the formation between the treatment measures in this study indicates that each closed-loop inconsistency was good. The SUCRA curve showed that platelet-rich plasma injection + shockwave was the first treatment with an area under the curve of 86.9%. Six treatment measures were ranked as follows: platelet-rich plasma injection + shockwave > platelet-rich plasma injection > shockwave > corticosteroid > corticosteroid + shockwave > prolotherapy. CONCLUSIONS: It is believed that in the course of clinical practice, platelet-rich plasma injection combined with shockwave therapy can be preferred for patients with humeral epicondylitis.

MgIG exerts therapeutic effects on crizotinib-induced hepatotoxicity by limiting ROS-mediated autophagy and pyroptosis.

Crizotinib (CRIZO) has been widely employed to treat non-small-cell lung cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO-induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit-8 assay and flow cytometry to detect CRIZO-induced cytotoxicity on human hepatocytes (HL-7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose-dependent manner. Furthermore, the reactive oxygen species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon-like bubbles and autophagosomes in HL-7702 cells. Subsequently, Western blotting, quantitative real-time PCR and ELISA assays revealed that ROS-mediated pyroptosis and autophagy contributed to CRIZO-induced hepatic injury. Based on the role of ROS in CRIZO-induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO-1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF-κB activity, thereby reducing CRIZO-induced hepatotoxicity. In conclusion, CRIZO promoted autophagy activation and pyroptosis via the accumulation of ROS in HL-7702 cells. MgIG exerts therapeutic effects on CRIZO-induced hepatotoxicity by decreasing the level of ROS.

Tuberindine A, a Truffle Alkaloid with an Unprecedented Skeleton Exhibiting Anti-hyperuricemic Bioactivity.

Tuberindines A and B (1 and 2), truffle alkaloids with intriguing structures, were isolated from Tuber indicum and detected in other truffle species. They appear to arise biosynthetically from amino acid and isosaccharinic units. Compound 1 upregulated the expression of organic anion transporters OAT1 and ABCG2 and significantly exhibited antihyperuricemic bioactivity in vitro and in vivo, which might support the value of truffles as a dietary supplement.

Association Between Serum Aminotransferases and Risk of New-Onset Cardiometabolic Disease in a Healthy Chinese Population: A Cohort Study.

Purpose: This study aimed to investigate the association between serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and incident metabolic disease in a cohort of community-based older Chinese people. Patients and Methods: Five thousand healthy Gaohang residents who attended community health checks at the Shanghai East Hospital in 2013 were recruited. Biological, biochemical, and lifestyle variables were collected. The cohort was followed for new-onset metabolic disease in 2014 and 2017, with a final study population of 3,123 (63%) after follow-up. The study outcome included type-2 diabetes mellitus and metabolic syndrome. Results: Baseline AST and ALT were associated with incident type-2 diabetes mellitus (HR 1.019, 95% CI 1.006-1.032, p = 0.003 and HR 1.016, 95% CI 1.008-1.025, p < 0.001 respectively). These associations persisted after adjusting for traditional risk factors including age, sex, income, waist circumference, systolic blood pressure, diastolic blood pressure, HbA1c, triglyceride, cholesterol, HDL and eGFR. Baseline AST and ALT were associated with incident metabolic syndrome in the crude analysis (HR 0.980, 95% CI 0.965-0.996, p = 0.012 and HR 0.992, 95% CI 0.988-0.997, p = 0.001, respectively). However, the association between AST and ALT with metabolic syndrome was non-significant after adjusting for biochemical parameters such as the lipid profile. Conclusion: This study demonstrated that serum AST and ALT are associated with new-onset type-2 diabetes mellitus, independent of traditional risk factors, in a cohort of older Chinese people. These findings may contribute to disease risk stratification and management in type-2 diabetes.

Nomogram for prognosis of patients with esophageal squamous cell cancer after minimally invasive esophagectomy established based on non-textbook outcome.

BACKGROUND: Non-textbook outcome (non-TO) represents a new prognostic evaluation index for surgical oncology. The present study aimed to develop new nomograms based on non-TO to predict the mortality and recurrence rate in patients with esophageal squamous cell cancer (ESCC) after minimally invasive esophagectomy (MIE). METHODS: The study involved a retrospective analysis of 613 ESCC patients, from the prospectively maintained database from January 2011 to December 2018. All the included ESCC patients underwent MIE, and they were randomly (1:1) assigned to the training cohort (307 patients) and the validation cohort (306 patients). Kaplan-Meier survival analysis was used to analyze the differences recorded between overall survival (OS) and disease-free survival (DFS). In the case of the training cohort, the nomograms based on non-TO were developed using Cox regression, and the performance of these nomograms was calibrated and evaluated in the validation cohort. RESULTS: Significant differences were recorded for 5-year OS and DFS between non-TO and TO groups (p < 0.05). Multivariate cox analysis revealed that non-TO, intraoperative bleeding, T stage, and N stage acted as independent risk factors that affected OS and DFS (p < 0.05). The results for multivariate regression were used to build non-TO-based nomograms to predict OS and DFS of patients with ESCC, the t-AUC curve analysis showed that the nomograms predicting OS and DFS were more accurate as compared to TNM staging, during the follow-up period in the training cohort and validation cohort. Further, the nomogram score was used to divide ESCC patients into low-, middle-, and high-risk groups and significant differences were recorded for OS and DFS between these three groups (p < 0.001). CONCLUSIONS: Non-TO was identified as an independent prognostic factor for ESCC patients. The nomograms based on non-TO could availably predict OS and DFS in ESCC patients after MIE.

Development of Artificial Intelligence for Parathyroid Recognition During Endoscopic Thyroid Surgery.

OBJECTIVE: We aimed to establish an artificial intelligence (AI) model to identify parathyroid glands during endoscopic approaches and compare it with senior and junior surgeons' visual estimation. METHODS: A total of 1,700 images of parathyroid glands from 166 endoscopic thyroidectomy videos were labeled. Data from 20 additional full-length videos were used as an independent external cohort. The YOLO V3, Faster R-CNN, and Cascade algorithms were used for deep learning, and the optimal algorithm was selected for independent external cohort analysis. Finally, the identification rate, initial recognition time, and tracking periods of PTAIR (Artificial Intelligence model for Parathyroid gland Recognition), junior surgeons, and senior surgeons were compared. RESULTS: The Faster R-CNN algorithm showed the best balance after optimizing the hyperparameters of each algorithm and was updated as PTAIR. The precision, recall rate, and F1 score of the PTAIR were 88.7%, 92.3%, and 90.5%, respectively. In the independent external cohort, the parathyroid identification rates of PTAIR, senior surgeons, and junior surgeons were 96.9%, 87.5%, and 71.9%, respectively. In addition, PTAIR recognized parathyroid glands 3.83 s ahead of the senior surgeons (p = 0.008), with a tracking period 62.82 s longer than the senior surgeons (p = 0.006). CONCLUSIONS: PTAIR can achieve earlier identification and full-time tracing under a particular training strategy. The identification rate of PTAIR is higher than that of junior surgeons and similar to that of senior surgeons. Such systems may have utility in improving surgical outcomes and also in accelerating the education of junior surgeons. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2516-2523, 2022.

Sex-Specific Associations Between Serum Phosphate Concentration and Cardiometabolic Disease: A Cohort Study on the Community-Based Older Chinese Population.

Purpose: This study aimed to investigate the association between sex-specific baseline serum phosphate and the incidence of new-onset cardiometabolic disease in a cohort of Shanghai-based older Chinese individuals. Patients and Methods: A community cohort of 5000 disease-free Chinese men and women was recruited in 2013 and followed until 2017 for the development of cardiometabolic disease. Participants underwent index and follow-up health screens at the Tongji Medical School affiliated Shanghai East Hospital, including blood biochemistry analysis, anthropometric measurements, interview on health-related behaviors, and clinical evaluation. Results: Higher baseline serum phosphate (>1.25 mmol/L) was significantly associated with new-onset type-2 diabetes mellitus (HR 1.730, 95% CI 1.127-2.655) and metabolic syndrome (HR 0.640, 95% CI 1.085-2.155) in women. Baseline serum phosphate was associated with age, BMI, waist circumference, SBP, total calcium, bicarbonate, and total cholesterol in women. The estimated risk of developing diabetes mellitus in women with inorganic phosphate >1.25 mmol/L was 14.54%. Inorganic phosphate accounted for 9.2% of the variance explained in a total estimated 14.52% of variance attributed to BMI, total cholesterol, total calcium, waist circumference, and inorganic phosphate. Conclusion: Serum phosphate concentration showed sex-specific associations with diabetes and metabolic syndrome. Higher inorganic phosphate was associated with increased risk of developing diabetes mellitus in women. These findings may be important in the assessment of individualized metabolic risk.

Textbook outcome after minimally invasive esophagectomy is an important prognostic indicator for predicting long-term oncological outcomes with locally advanced esophageal squamous cell carcinoma.

Background: The textbook outcome (TO) emerges as a novel prognostic factor in surgical oncology. The present study aimed to evaluate the effect of TO on the risk of death and recurrence in patients with esophageal squamous cell carcinoma (ESCC) after minimally invasive esophagectomy (MIE). Methods: The study involved retrospective analysis of 528 patients with ESCC who were subjected to MIE from January 2011 to December 2017. TO included 8 parameters: complete resection; microscopically tumor-negative resection margins (R0); ≥15 lymph nodes removed and examined; no serious postoperative complications; no postoperative intervention; no re-admission to the intensive care unit (ICU); hospital stay ≤21 days; and no readmission ≤30 days. The Cox and logistic regression model were used to analyze the prognostic factors of survival and risk factors for TO. Results: Among the 528 patients with ESCC who were subjected to MIE, 53.2% reached TO. In the case of patients with locally advanced ESCC, 5-year overall survival (OS) was 51.1% (41.2-61.2%) for the TO group but 33.7% (23.7-43.7%) for the non-TO group (HR =0.644, 95% CI: 0.449-0.924, P=0.015). Similarly, 5-year disease-free survival (DFS) was 47.6% (38.0-57.2%) for the TO group but 29.1% (20.1-38.1%) for the non-TO group (HR =0.671, 95% CI: 0.479-0.940, P=0.018). In addition, 5-year recurrence-free survival (RFS) was 62.9% (53.7-72.1%) for the TO group but 39.8% (29.4-50.2%) for the non-TO group (HR =0.606, 95% CI: 0.407-0.902, P=0.012). Multivariate logistic regression analysis further showed that age, American Society of Anesthesiology (ASA) score, intraoperative blood loss, and smoking status acted as independent risk factors for TO. The results of the multivariate analysis assisted in the establishment of a nomogram for the prediction of TO occurrence. This nomogram exhibited satisfactory consistency and prediction ability [area under the receiving operator characteristic (AUROC) =0.717]. Conclusions: The present study showed that achieving of TO after MIE improves survival rate and reduce the recurrence rate in patients with locally advanced ESCC. The study further determined the independent factors associated with TO achievement and established a prediction model.