Association between postoperative nadir platelet count and postoperative cardiovascular complications following septal myectomy in patients with hypertrophic cardiomyopathy: a retrospective cohort study.

BACKGROUND: Platelet count is associated with cardiovascular risk and mortality in several cardiovascular diseases, but the association of the nadir platelet counts post-septal myectomy with the cardiovascular complication risk in hypertrophic obstructive cardiomyopathy patients remains unclear. METHODS: This retrospective cohort study reviewed all adult patients who underwent septal myectomy at a single tertiary referral center over a 5-year period. Postoperative nadir platelet count was defined as the lowest platelet count in the first 4 postoperative days or until hospital discharge. The composite outcome included cardiovascular death, myocardial infarction, heart failure, malignant arrhythmia, cardiac tamponade, and major bleeding events within 30 days postoperatively. Univariable and multivariable logistic regression and restricted cubic spline models were used to assess the association between postoperative nadir platelet count and the 30-day postoperative cardiovascular complication risk. RESULTS: Among the 113 enrolled patients, 23 (20.4%) developed cardiovascular events within 30 days postoperatively. The incidence of postoperative cardiovascular complications was significantly higher in patients with a nadir platelet count ≤ 99 × 109/L than in those with a nadir platelet count > 99 × 109/L (33.3% vs. 7.1%, crude risk ratio: 4.67, 95% confidence interval: 1.69-12.85, P < 0.001). Multivariable logistic regression revealed that postoperative nadir platelet count was negatively associated with 30-day postoperative cardiovascular complications (adjusted odds ratio: 0.97; 95% confidence interval: 0.95-0.99; P = 0.005) and the association was linear (Pnonlinearity = 0.058) after full adjustment. The association between nadir platelet count and cardiovascular complications within 30 days post-surgery was consistent in all predefined subgroups (Pinteraction > 0.05). CONCLUSION: The postoperative nadir platelet count was significantly associated with the 30-day post-myectomy risk of cardiovascular complications in hypertrophic obstructive cardiomyopathy patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT04275544).

Transcutaneous electric acupoint stimulation reduced consumption of profopol in patients undergoing laparoscopic surgery: A randomized clinical trial.

BACKGROUND: Propofol is a common regimen for general anesthesia maintenance. But propofol can dose-dependently generate cardiopulmonary depression. Thus, any strategy to reduce propofol dosage during laparoscopic surgery may have underlying beneficial effect for patient prognosis. Previous studies indicated both analgesic and sedative effect of acupoint stimulation. However, its main sedative effect on patients under general anesthesia remains unclear. OBJECTIVE: The aim of this study was to investigate the sedative effect of transcutaneous electrical acupoint stimulation (TEAS) on patients scheduled for laparoscopic surgery under general anesthesia. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: In this randomized clinical trial, patients scheduled for laparoscopic surgery under general anesthesia in Xijing hospital were randomly assigned to 3 groups, receiving electrical stimulation at the Shenmen (HT7)/Ximen (PC4) (TEAS group), stimulation at the shoulder (non-acupoint group) or no stimulation (control group), respectively. MAIN OUTCOME MEASURES: One hundred sixty-two patients completed the study. The primary outcome was the consumption of propofol, and secondary outcomes included features of recovery after surgery, major complications after surgery and by 1 year after surgery. RESULTS: In patients undergoing laparoscopic surgery, the doses of propofol decreased significantly in the TEAS group compared (0.10 ±â€…0.02 mg·kg-1·min-1) with the other 2 groups (both 0.12 ±â€…0.02 mg·kg-1·min-1, P < .001). The mean differences (95% confidence interval) for non-acupoint versus TEAS and control versus TEAS were 0.021 (0.012, 0.030) and 0.024 (0.013, 0.034), respectively. Time to awake and to extubation were not significantly different among the groups. The incidences of major complications after surgery and by 1 year after surgery were not significantly different among the groups. CONCLUSION: TEAS could induce additional sedative effect in patients during laparoscopic surgery and reduce propofol consumption.

Effect of remimazolam vs propofol on emergence from general anesthesia in patients undergoing cerebral endovascular procedures: A randomized controlled, non-inferiority trial.

STUDY OBJECTIVE: This study aimed to compare the time to emergence from general anesthesia with remimazolam versus propofol in patients undergoing cerebral endovascular procedures. DESIGN: A prospective, double-blind, randomized controlled, non-inferiority trial. SETTING: An academic hospital. PATIENTS: Adult patients scheduled for cerebral endovascular procedures. INTERVENTIONS: Patients were randomized at a 1:1 ratio to undergo surgery under general anesthesia with remimazolam (0.1 mg kg-1 for induction and 0.3-0.7 mg kg-1 h-1 for maintenance) or propofol (1-1.5 mg kg-1 for induction and 4-10 mg kg-1 h-1 for maintenance). MEASUREMENTS: The primary outcome was the time to emergence from anesthesia. The non-inferiority margin was -2.55 min in group difference. Major secondary outcomes included hypotension during induction, incidence of postoperative delirium and Modified Rankin Scale (mRs) at 30 days and 90 days after surgery. MAIN RESULTS: Of the 142 randomized patients, 129 completed the trial. In the modified intention-to-treat analysis, the mean time to emergence from anesthesia was 16.1 [10.4] min in the remimazolam group vs. 19.0 [11.2] min in the propofol group. The group difference was -2.9 min [95% CI -6.5, 0.7] (P = 0.003 for non-inferiority). The remimazolam group had lower rate of hypotension during induction (11.3% vs 25.4%, P = 0.03) and use of vasopressors during surgery (29.6% vs 62.0%, P < 0.001). The two groups did not differ in postoperative delirium and mRs at 30 and 90 days after surgery. CONCLUSIONS: In patients undergoing cerebral endovascular procedures, remimazolam did not increase the time from anesthesia vs propofol.

Association of intraoperative cerebral and somatic tissue oxygen saturation with postoperative acute kidney injury in adult patients undergoing multiple valve surgery.

BACKGROUND: The association between tissue oxygenation with postoperative acute kidney injury (AKI) in adult patients undergoing multiple valve surgery has not been specifically studied. METHODS: In this prospective exploratory cohort study, 99 patients were enrolled. The left forehead, the left forearm, the left upper thigh, and the left renal region tissue oxygen saturation using near-infrared spectroscopy were monitored. The association between each threshold and AKI was assessed. The relative and absolute thresholds were < 70%, < 75%, < 80%, < 85%, < 90%, < 95%, and < 100% baseline, and baseline-standard deviation (SD), -1.5 SD, -2 SD, -2.5 SD, and -3 SD. Multivariate logistic regression analysis was adopted to explore the association. RESULTS: AKI occurred in 53 (54%) patients. The absolute value-based SrrO2 thresholds associated with AKI were baseline-3 SD (odds ratio [OR], 4.629; 95% confidence interval [CI], 1.238-17.314; P = 0.023) and baseline-2.5 SD (OR, 2.842; 95% CI, 1.025-7.881; P = 0.045) after adjusting for the potential confounders, those are renal region tissue oxygen saturation of 55% and 60%, but not statistically significant after correcting for multiple testing (corrected P = 0.114 and 0.179, respectively). CONCLUSION: The SrrO2 desaturation, defined as < baseline - 2.5 SD or < baseline - 3 SD, may be associated with AKI. The thresholds need to be verified in future large-scale studies. TRIAL REGISTRATIONS: The study was registered at ClinicalTrials.gov, first trial registration: 26/10/2017, identifier: NCT03323203.

Low skeletal muscle mass as an early sign in children with fabry disease.

BACKGROUND & AIMS: Fabry disease (FD) is a rare X-linked metabolic storage disorder due to the deficiency of lysosomal α-galactosidase A which causes the accumulation of glycosphingolipids throughout the body. Underweight and low BMI have been occasionally reported in FD patients previously. Whether underweight is common in the early stage of FD and body composition analysis to determine the cause have not been reported. METHODS: Children who were diagnosed with FD in the Children's Hospital of Zhejiang University School of Medicine from July 2014 to December 2022 were enrolled. Clinical data were obtained from medical records. Whole body dual energy X-ray absorptiometry scans (DXA) were used to assess body composition (fat mass, FM; fat free mass, FFM and bone mass) according to the International Society of Clinical Densitometry's standard operating method. Whole body muscle mass was calculated as fat-free mass minus bone mass. Appendicular skeletal muscle mass (ASM) was calculated as the sum of the arm and the leg muscle mass. The FM, FFM, ULSM and LLSM indices were calculated by dividing the total FM, FFM, and upper and lower limb skeletal muscle mass (ULSM and LLSM) by the height squared. RESULTS: A total of eighteen children (14 boys and 4 girls) were enrolled. Thirteen boys had the classical phenotype, and five children (1 boy with the N215S mutation and 4 girls) had the late-onset phenotype. Seven children with the classical phenotype (53.8%) and two of the five children (40%) with the late-onset phenotype had abnormal BMIs. Sixteen of the eighteen children (88.9%) had a height in the normal range, suggesting that low BMI was mainly due to underweight. By DXA body composition analysis, the FMI was abnormal in 3 children (2 boys and 1 girl), and the FFMI was abnormal in 12 children (9 boys and 3 girls). For the classical phenotype, 2 of the 13 children (15.4%) had abnormal FMI values, while 10 (76.9%) had abnormal FFMI values. Eight patients (61.5%) with the classical phenotype had a significant reduction in muscle mass index, ASM index and LLSM index values compared with age- and sex- matched Chinese controls. Late-onset patients also had mild low skeletal muscle mass compared to controls. The results suggested that low skeletal muscle mass is common in early FD. CONCLUSIONS: This is the first study to examine body composition and muscle mass in early Fabry disease patients. Low skeletal muscle mass is a common early symptom in children with Fabry disease, suggesting that skeletal muscle is significantly affected in the early stages of FD.

Early onset of nephrogenic diabetes insipidus due to fabry disease in a child with GLA N215S mutation: Case report and literature review.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder. Renal involvement in FD is characterized by proteinuria and progressive renal decline. Reports on FD with nephrogenic diabetes insipidus as the initial manifestation are rare. In this paper, we report a pediatric case with an N215S variant. Results: A boy with an onset of polydipsia and polyuria at approximately 4 years of age was diagnosed with nephrogenic diabetes insipidus. Whole-exome sequencing showed a GLA N215S variation with no secondary cause of diabetes insipidus. No family history of polydipsia or polyuria was reported; however, the patient's maternal grandmother and her two younger brothers had hypertrophic cardiomyopathy. Both brothers required surgery due to severe cardiac involvement, and the youngest brother died of heart disease at the age of 50 years. The patient's polydipsia and polyuria worsened over the next 7 years. Serum sodium was normal, but the patient required high-dose potassium chloride to maintain normal serum potassium levels. His physical and intellectual development was normal, with no common complications of nephrogenic diabetes insipidus, such as anemia, malnutrition, vomiting, high fever, or convulsions. Dried blood spot testing showed α-galactosidase A (α-gal A) activity of 0.6 µmol/L/h and a Lyso-GL-3 level of 7.01 ng/ml. The patient developed mild proteinuria and mild myocardial hypertrophy. Renal biopsy showed myeloid bodies and zebra bodies. After more than 1 year of ERT, his urine specific gravity increased to 1.005-1.008, which was a new sign reflecting the efficacy of ERT, although urine output was maintained at 3-5 ml/kg/hour. We will continue to monitor the patient's renal tubular function and urine output. Conclusions: Nephrogenic diabetes insipidus may be the initial manifestation in children with FD and/or N215S variation. In FD, the same mutation in a family may present a completely different phenotype.

Acupuncture-related techniques for postoperative cognitive complications: a systemic review and meta-analysis.

BACKGROUND: Postoperative cognitive complications are major challenges for postoperative recovery. Acupuncture-related techniques have been used for treating neurocognitive dysfunctions. However, whether they help to prevent postoperative cognitive complicationss remains unclear. We intend to evaluate the effect of acupuncture-related techniques on the incidence of postoperative cognitive complications (PCC) in patients undergoing surgery under general anesthesia. METHODS: Based on PRISMA guidelines, a search of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov was performed to identify eligible trials published from inception to June 6, 2021. The search was performed in June 2021. The inclusion criteria were prospective, randomized, controlled clinical trials that compared acupuncture-related techniques with other techniques or non-acupuncture treatment in patients undergoing surgery under general anesthesia. Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using fixed and random effects statistical models. RESULTS: The analysis included 12 studies with 1058 patients. Compared with patients not receiving acupuncture, patients treated with acupuncture-related techniques had a lower incidence of PCCs (OR, 0.44; 95% CI, 0.33 to 0.59; P < 0.001; n = 968) and lower levels of biomarkers, including IL-6, TNF-α, and S100ß. Acupuncture with needles and without needles showed similar effects on the prevention of PCCs. The effects of acupuncture-related techniques on PCCs were observed in both English and non-English articles. Subgroup analyses showed that both agitation and/or delirium (OR, 0.51; 95% CI, 0.34 to 0.76; P < 0.001; n = 490) and delayed cognitive recovery (OR, 0.33; 95% CI, 0.21 to 0.51; P < 0.001; n = 478) were reduced after treatment with acupuncture-related techniques. In adult studies evaluating MMSE scores, the scores were not different between groups (SMD, - 0.71; 95% CI, - 1.72 to 0.3; P = 0.17; n = 441). CONCLUSIONS: Acupuncture-related techniques, including needle techniques and electrical techniques, are associated with fewer postoperative cognitive complications, suggesting that acupuncture could be considered a potential option in the perioperative setting. Additional research is needed to develop higher-quality evidence and optimal regimens. TRIAL REGISTRATION: PROSPERO (CRD42021258378).

Integration of ATAC-Seq and RNA-Seq identifies key genes and pathways involved in the neuroprotection of S-adenosylmethionine against perioperative neurocognitive disorder.

The gene-regulatory landscape is highly dynamic in healthy and diseased brains. DNA methylation is a well-known epigenetic modification that regulates gene expression, and our previous study demonstrated that S-adenosylmethionine (SAM), a methylome modulator, was a neuroprotectant against perioperative neurocognitive disorder (PND). However, the underlying mechanism remains to be elucidated. Here, we integrated an assay for transposase-accessible chromatin by sequencing (ATAC-seq) and RNA sequencing (RNA-seq) to identify the key genes and pathways involved in the neuroprotection of SAM against PND. Our RNA-seq data demonstrated that genes involved in biological processes such as Wnt signaling, inflammatory response, transcription and long-term potentiation likely mediate the neuroprotection of SAM. Our ATAC-seq data provided comprehensive maps of chromatin accessibility changes induced by laparotomy and laparotomy + SAM treatment, and functional annotation of the regions with high variations in chromatin accessibility highlighted the role of the Wnt signaling pathway in PND pathogenesis and SAM treatment. Further motif analysis identified key transcription factors (e.g., CTCF, TFDP1, TCFL5, KLF15, ZBTB14, TFAP2E) that may participate in the neuroprotection of SAM. In conclusion, the current study provides an epigenomic perspective to understand the pathogenesis of PND and its treatment by SAM.

A severe complication of J-tip guide wire during catheterization: A case report and discussion.

J-tip guide wire entrapment within the heart is a serious and dangerous complication that is rarely mentioned. We present a case in which the J-tip guide wire was entrapped in the right atrium during tunneled cuffed venous catheterization. We were unable to remove the guide wire using previously reported methods and concluded with surgery. Owing to the special structure of the guide wire itself, a safe removal process needs to be discussed. Patient consent for publication was obtained prior to the submission of the manuscript.

Acupoint Stimulation for Enhanced Recovery After Colon Surgery: A Prospective Multicenter Randomized Controlled Trial.

Purpose: The aim of this study was to evaluate the efficacy of transcutaneous electrical acupoint stimulation (TEAS) in improving bowel function and thus shortening hospital stay after laparoscopic colon surgery within the ERAS pathway. Patients and Methods: From November 2016 to March 2018, 100 patients who underwent elective colon surgery were enrolled and 94 finished study (n = 47 for each) in three university hospitals. Patients in the TEAS group received TEAS 30 min before surgery and once a day for 3 days after surgery, while those in the Control Group received no stimulation. Primary outcome was the time to discharge. Results: Compared with standardized postoperative care, TEAS resulted in a shorter time to first flatus (P=0.03) and time to first defecation (P=0.03), as well as a reduction in the length of hospital stay (P=0.02). Median patient-controlled analgesia (PCA) deliveries and PCA attempts at 24h, 48h and 72h after surgery were less in the TEAS group (P<0.01). No evidence of significant advantages in postoperative pain intensity, nausea, vomiting, sleeping quality and expenses was found in the TEAS group. Conclusion: Perioperative TEAS further shortens the time to meet discharge criteria after laparoscopic colon surgery in patients under ERAS strategy.

Screening for Potential Therapeutic Agents for Non-Small Cell Lung Cancer by Targeting Ferroptosis.

Ferroptosis is a form of non-apoptotic and iron-dependent cell death originally identified in cancer cells. Recently, emerging evidence showed that ferroptosis-targeting therapy could be a novel promising anti-tumour treatment. However, systematic analyses of ferroptosis-related genes for the prognosis of non-small cell lung cancer (NSCLC) and the development of antitumor drugs exploiting the ferroptosis process remain rare. This study aimed to identify genes related to ferroptosis and NSCLC and to initially screen lead compounds that induce ferroptosis in tumor cells. We downloaded mRNA expression profiles and NSCLC clinical data from The Cancer Genome Atlas database to explore the prognostic role of ferroptosis-related genes. Four prognosis-associated ferroptosis-related genes were screened using univariate Cox regression analysis and the lasso Cox regression analysis, which could divide patients with NSCLC into high- and low-risk groups. Then, based on differentially expressed risk- and ferroptosis-related genes, the negatively correlated lead compound flufenamic acid (FFA) was screened through the Connective Map database. This project confirmed that FFA induced ferroptosis in A549 cells and inhibited growth and migration in a dose-dependent manner through CCK-8, scratch, and immunofluorescence assays. In conclusion, targeting ferroptosis might be a therapeutic alternative for NSCLC.

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity. Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients. Design, Setting, and Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle. Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion. Main Outcomes and Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12. Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] µg/dL vs 6.1 [3.4] µg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population. Conclusions and Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression. Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.

Glomerular IgA Deposition and Serum Antineutrophil Cytoplasmic Antibody Positivity in a Child With Dystrophic Epidermolysis Bullosa: Case Report and Literature Review.

Patients with epidermolysis bullosa (EB) could develop significant urological complications, such as hydroureteronephrosis, renal amyloidosis and IgA nephropathy (IgAN). Here, we presented a 12-year-old boy carrying pathogenic COL7A1 mutation with diagnosis of dystrophic epidermolysis bullosa (DEB). The patient had concomitant gross hematuria and proteinuria. Pathological examinations and immunostaining of renal biopsy showed glomeruli with mesangial hypercellularity and deposition of IgA, which were indicative of IgAN. Interestingly, serological evaluation showed antineutrophil cytoplasmic antibody (ANCA) directed against myeloperoxidase and proteinase 3. Treatment with glucocorticoid, immunosuppressants, angiotensin-converting enzyme inhibitor and antibiotics efficiently improved hemato-proteinuria, and ANCAs became negative as well. This case of DEB presented a unique collection of clinical manifestations and pathological alterations. IgAN and serum positive ANCA were possibly associated with sustained infection secondary to DEB, and can be managed by empirical treatment for primary IgAN.

Transcutaneous Electrical Acupoint Stimulation Combined With Auricular Acupressure Reduces Postoperative Delirium Among Elderly Patients Following Major Abdominal Surgery: A Randomized Clinical Trial.

Background: Postoperative delirium is common in elderly patients following major surgery. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation combined with auricular acupressure on the incidence of postoperative delirium among older patients undergoing major abdominal surgery. Methods: In this single-center, randomized controlled clinical trial, 210 patients aged 65 years or older undergoing major abdominal surgery were randomized to receive either intervention treatment (transcutaneous electrical acupoint stimulation started at 30 min before anesthesia until the end of the surgery, followed by intermittent auricular acupressure in the first three postoperative days; n = 105) or standard care (n = 105). The primary outcome was the incidence of delirium at the first seven postoperative days or until hospitalization depended on which came first. Secondary outcomes included delirium severity, opioid consumption, postoperative pain score, sleep quality, length of postoperative hospital stay, and postoperative 30-day complications. Enrollment was from April 2019 to March 2020, with follow-up ending in April 2020. Results: All of the 210 randomized patients [median age, 69.5 years, 142 (67.6%) male] completed the trial. The incidence of postoperative delirium was significantly reduced in patients received intervention treatment (19/105 (18.1%) vs. 8/105 (7.6%), difference, -10.5% [95% CI, -1.5% to -19.4%]; hazard ratio, 0.41 [95% CI, 0.18 to 0.95]; P= 0.023). Patients in the control group had a higher postoperative Memorial Delirium Assessment Scale (4 vs. 3; difference, -1; 95% CI, -1 to 0; P = 0.014) and a greater increase in Pittsburgh Sleep Quality Index score from baseline to postoperative day three (2.5 vs. 2.0; difference, -1; 95% CI, -2 to -1; P < 0.001) than patients in the intervention group. No significant difference was observed as of other secondary outcomes. Conclusion: In elderly patients undergoing major abdominal surgery, transcutaneous electrical acupoint stimulation combined with auricular acupressure reduced the incidence of postoperative in-hospital delirium compared with standard care. A multicenter, randomized clinical trial with a larger sample size is necessary to verify these findings. Clinical Trial Registration: [https://clinicaltrials.gov], identifier [NCT03726073].

Heteroplasmic and homoplasmic m.616T>C in mitochondria tRNAPhe promote isolated chronic kidney disease and hyperuricemia.

Inherited kidney diseases are the fifth most common cause of end-stage renal disease (ESRD). Mitochondrial dysfunction plays a vital role in the progression of inherited kidney diseases, while mitochondrial-transfer RNA (mt-tRNA) variants and their pathogenic contributions to kidney disease remain largely unclear. In this study, we identified the pathogenic mt-tRNAPhe 616T>C mutation in 3 families and documented that m.616T>C showed a high pathogenic threshold, with both heteroplasmy and homoplasmy leading to isolated chronic kidney disease and hyperuricemia without hematuria, proteinuria, or renal cyst formation. Moreover, 1 proband with homoplamic m.616T>C presented ESRD as a child. No symptoms of nervous system evolvement were observed in these families. Lymphoblast cells bearing m.616T>C exhibited swollen mitochondria, underwent active mitophagy, and showed respiratory deficiency, leading to reduced mitochondrial ATP production, diminished membrane potential, and overproduction of mitochondrial ROS. Pathogenic m.616T>C abolished a highly conserved base pair (A31-U39) in the anticodon stem-loop which altered the structure of mt-tRNAPhe, as confirmed by a decreased melting temperature and slower electrophoretic mobility of the mutant tRNA. Furthermore, the unstable structure of mt-tRNAPhe contributed to a shortage of steady-state mt-tRNAPhe and enhanced aminoacylation efficiency, which resulted in impaired mitochondrial RNA translation and a significant decrease in mtDNA-encoded polypeptides. Collectively, these findings provide potentially new insights into the pathogenesis underlying inherited kidney disease caused by mitochondrial variants.

PP2A protects podocytes against Adriamycin-induced injury and epithelial-to-mesenchymal transition via suppressing JIP4/p38-MAPK pathway.

Protein phosphatase 2A (PP2A) is one of the major protein serine/threonine phosphatases (PPPs) with regulatory effects on several cellular processes, but its role and function in Adriamycin (ADR)-treated podocytes injury needs to be further explored. Mice podocytes were treated with ADR and PP2A inhibitor (okadaic acid, OA). After transfection, cell apoptosis was detected by flow cytometry. Expressions of podocytes injury-, apoptosis- and epithelial-to-mesenchymal transition (EMT)- and JNK-interacting protein 4/p38-Mitogen-Activated Protein Kinase (JIP4/p38-MAPK) pathway-related factors were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. Interaction between PP2A and JIP4/MAPK pathway was confirmed using co-immunoprecipitation (Co-Ip) assay. In podocytes, ADR inhibited PP2A, Nephrin and Wilms' tumor (WT) 1 expressions yet upregulated apoptosis and Desmin expression, and suppressing PP2A expressionenhanced the effects. PP2A overexpression reversed the effects of ADR on PP2A and podocyte injury-related factors expressions and apoptosis of podocytes. JIP4 was the candidate gene interacting with both PP2A and p38-MAPK pathway, and PP2A overexpression alleviated the effects of ADR on p38-MAPK pathway-related factors expressions. Additionally, in ADR-treated podocytes, PP2A suppression enhanced the effects of ADR, yet silencing of JIP4 reversed the effects of PP2A suppression on regulating p38-MAPK pathway-, apoptosis- and EMT-related factors expressions and apoptosis, with upregulations of B-cell lymphoma-2 (Bcl-2) and E-cadherin and down-regulations of Bcl-2 associated protein X (Bax), cleaved (C)-casapse-3, N-cadherin, Vimentin and Snail. PP2A protects ADR-treated podocytes against injury and EMT by suppressing JIP4/p38-MAPK pathway, showing their interaction in podocytes.

Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment.

BACKGROUND: Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. METHODS: In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. RESULTS: BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. CONCLUSIONS: These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects.

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet ß cells, promotion of islet ß cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in ß Cells.

Recent studies suggest that Sphingosine 1-phosphate (S1P) plays an important role in regulating glucose metabolism in type 2 diabetes. However, its effects and mechanisms of promoting insulin secretion remain largely unknown. Here, we found that S1P treatment decreased blood glucose level and increased insulin secretion in C57BL/6 mice. Our results further showed that S1P promoted insulin secretion in a glucose-dependent manner. This stimulatory effect of S1P appeared to be irrelevant to cyclic adenosine monophosphate signaling. Voltage-clamp recordings showed that S1P did not influence voltage-dependent Ca2+ channels, but significantly blocked voltage-dependent potassium (Kv) channels, which could be reversed by inhibition of phospholipase C (PLC) and protein kinase C (PKC). Calcium imaging revealed that S1P increased intracellular Ca2+ levels, mainly by promoting Ca2+ influx, rather than mobilizing intracellular Ca2+ stores. In addition, inhibition of PLC and PKC suppressed S1P-induced insulin secretion. Collectively, these results suggest that the effects of S1P on glucose-stimulated insulin secretion (GSIS) depend on the inhibition of Kv channels via the PLC/PKC signaling pathway in pancreatic ß cells. Further, S1P improved ß cell survival; this effect was also associated with Kv channel inhibition. This work thus provides new insights into the mechanisms whereby S1P regulates ß cell function in diabetes.