[Risk prediction of metabolic syndrome and coronary artery disease in overweight and obese populations based on serum metabolomics].

Objective: By identifying different metabolites in the serum and clarifying the potential metabolic disorder pathways in metabolic syndrome (MS) and stable coronary artery disease patients, to evaluate the predictive value of specific metabolites based on serum metabolomics for the occurrence of MS and coronary heart disease in overweight or obese populations. Methods: This is a retrospective cross-sectional study. Patients with Metabolic Syndrome (MS group), patients with stable coronary heart disease (coronary heart disease group), and overweight or obese individuals (control group) recruited from the Central District of the First Affiliated Hospital of Zhengzhou University from 2017 to 2019 were assigned to the training set, meanwhile, the corresponding three groups of people recruited from the East District of the hospital during the same period were assigned to the validation test. The serum metabolomics profiles were determined by ultra-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). Clinical characteristics (age, gender, body mass index (BMI), blood pressure, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate transaminase (AST), total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glomerular filtration rate (eGFR), creatinine (CR)) were also collected. Based on the orthogonal partial least-squares discrimination analysis (OPLS-DA) model, the significantly changed metabolites for MS and coronary artery disease patients were screened according to variable important in projection (VIP), and the receiver operating characteristic (ROC) analysis was evaluated for the risk prediction values of changed metabolites. Results: A total of 488 subjects were recruited in this study, the training set included 40 MS, 249 coronary artery disease patients and 148 controls, the validation set included 16 MS, 18 coronary artery disease patients and 17 controls. We made comparisons of the serum metabolites of coronary artery disease vs. controls, MS vs. controls, and coronary artery disease vs. MS, and a total of 22 different metabolites were identified. The disturbed metabolic pathways involved were phospholipid metabolism, amino acid metabolism, purine metabolism and other pathways. Through cross-comparisons, we identified 2 specific metabolites for MS (phosphatidylcholine (18∶1(9Z)e/20) and pipecolic acid), 4 specific metabolites for coronary artery disease (lysophosphatidylcholine (17∶0), PC(16∶0/16∶0), hypoxanthine and histidine), and 4 common metabolites both for MS and coronary artery disease (isoleucine, phenylalanine, glutathione and LysoPC(14∶0)). Based on the cut-off values from ROC curve, the predictive value of the above metabolites for the occurrence of MS in overweight or obese populations is 100%, the predictive value for the occurrence of coronary heart disease is 87.5%, and the risk predictive value for coronary heart disease in MS patients is 82.1%. Conclusions: The altered serum metabolites suggest that MS and coronary heart disease may involve multiple metabolic pathway disorders. Specific metabolites based on serum metabolomics have good predictive value for the occurrence of MS and coronary heart disease in overweight or obese populations.

[Research advances on improving the therapeutic efficacy of mesenchymal stem cell-derived exosomes in wound repair].

How to promote high-quality wound healing is a common problem for plastic surgery and burn physicians. In recent years, numerous animal studies have demonstrated that mesenchymal stem cell-derived exosomes promote wound repair through multiple mechanisms and are promising cell-free therapeutic agents with broad prospect of application. How to enhance the therapeutic efficacy of exosomes, optimize their drug delivery strategy, and improve their biological properties are the challenges to be overcome in order to move from basic research to clinical application of exosome therapy for wound repair. This article focuses on methods to improve the wound repair potential of mesenchymal stem cell-derived exosomes, and reviews the recent research advances on improving the therapeutic efficacy of mesenchymal stem cell-derived exosomes in wound repair from three aspects, including pretreatment of parental mesenchymal stem cells, hydrogel bio-scaffold loaded with exosomes, and engineered exosomes, to provide a reference for further clinical studies.

[Clinical effects of free transplanted pre-expanded scapular flap in reconstructing scar contracture deformity of neck].

Objective: To investigate the clinical effects of free transplanted pre-expanded scapular flap in reconstructing scar contracture deformity of neck. Methods: A retrospective observational study was conducted. From February 2010 to August 2020, 17 cervical scar deformity patients (9 males and 8 females, aged 8-42 years) who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University. The patients underwent skin and soft tissue expander (hereinafter referred to as expander) implantation in scapular region in stage Ⅰ procedures, and the free transplanted pre-expanded flaps were used to resurface the wounds followed by neck scar resection in the stage Ⅱ procedures. The wound size after neck scar release was 12.0 cm×6.0 cm-30.0 cm×24.0 cm, and the size of the flap ranged from 13.0 cm×7.5 cm to 31.5 cm×25.0 cm. The wounds in donor site of 15 patients were sutured directly, and the wounds in donor site of 2 patients were covered with full-thickness skin graft from abdominal area. The survival of flaps was observed after the operation of stage Ⅱ. Six months after stage Ⅱ surgery, Z plasty was performed to treat the incision scar contracture in 2 patients. For the 5 patients of overweight or bloating appearance in the 1/3 proximal flap underwent debulking procedures in 6-9 months after stage Ⅱsurgery. Before the stage Ⅰ surgery and six months after the last procedure (stage Ⅱ or stage Ⅲ), mental cervical angle (MCA) and cervical mandibular angle (CMA) were measured and the improvement of neck scar was evaluated by the angle values. The cervical motor function, skin color and texture in recipient areas, and scar in the donor sites assessed by Vancouver scar scale (VSS) were observed during follow-up. Data were statistically analyzed with paired sample t test. Results: After stage Ⅱ surgery, 15 patients' flaps survived well; venous crisis occurred in 2 flaps within 24 h after operation, and the flaps survived well after emergency exploration and thrombus removal+vascular re-anastomosis. Compared with the angle values of MCA of (126±12)° and CMA of (148±13)° of patients before the stage Ⅰ surgery, the angle values of MCA of (107±12)° and CMA of (123±11)° of patients in six months after the last procedure were significantly decreased (with t values of 10.68 and 6.54, respectively, P<0.05). After 2 years of follow-up, the patient's neck dorsiflexion, lateral bending, or other motor functions were not restricted; the color and texture of the flap in recipient site were close to those of the normal neck skin; the patient cases with VSS scores of scarring of 3, 4, 5, 6, and 7 were 1, 3, 7, 5, and 1 case, respectively. Conclusions: The free transplantation of the pre-expanded scapular flaps can provide sufficient tissue for wound coverage after the release of cervical scar contracture deformity; the expanded skin tissue is featured by thin soft tissue and good pliability, which is conducive to restore the neck appearance; the donor sites are relatively covert with less tension, therefore, the treatment is an effective method for correcting the contracture in the neck.

Comparison of clinical outcomes between posterolateral approach and modified Hardinge approach in salvage total hip arthroplasty after medial buttress plate failure for femoral neck fractures.

OBJECTIVE: The purpose of this study was to investigate the clinical outcomes of salvage total hip arthroplasty (THA) after medial buttress plate surgery for femoral neck fractures via the modified Hardinge approach (MHA) and posterolateral approach (PLA) through a retrospective analysis. PATIENTS AND METHODS: From October 2016 to October 2020, a total of 41 patients with failed femoral neck fractures treated with cannulated screws and medial buttress plates underwent unilateral salvage THA, and a retrospective study was conducted. According to the surgical approach, patients were divided into PLA group and MHA group. Clinical and radiological data were evaluated. The primary outcome indicators were the Pain Visual Analog Scale (VAS) and Hip Harris Score (HHS). Secondary outcome indicators include hemoglobin (HGB), hematocrit (HCT), creatine kinase (CK), creatine kinase-MB (CK-MB), etc. The occurrence of postoperative complications was also recorded. RESULTS: There were no differences in demographic or clinical characteristics before surgery. There were no differences in postoperative HGB, HCT, CK-MB and radiological parameters. The surgical approach had no effect on the hospitalization period. The PLA group had earlier ambulation time, and the serum level of CK was also low. Analysis of the HHS and VAS showed that on postoperative day 3, the PLA group had superior scores. The incidence of complications did not significantly differ between groups. CONCLUSIONS: The posterolateral approach for salvage THA provides better functional recovery with less muscle damage in the early postoperative period.

Metabolic Reprogramming by Ribitol Expands the Therapeutic Window of BETi JQ1 against Breast Cancer.

Many cancer patients still lack effective treatments, and pre-existing or acquired resistance limits the clinical benefit of even the most advanced medicines. Recently, much attention has been given to the role of metabolism in cancer, expanding from the Warburg effect to highlight unique patterns that, in turn, may improve diagnostic and therapeutic approaches. Our recent metabolomics study revealed that ribitol can alter glycolysis in breast cancer cells. In the current study, we investigate the combinatorial effects of ribitol with several other anticancer drugs (chrysin, lonidamine, GSK2837808A, CB-839, JQ1, and shikonin) in various breast cancer cells (MDA-MB-231, MCF-7, and T-47D). The combination of ribitol with JQ1 synergistically inhibited the proliferation and migration of breast cancer cells cell-type dependently, only observed in the triple-negative MDA-MB-231 breast cancer cells. This synergy is associated with the differential effects of the 2 compounds on expression of the genes involved in cell survival and death, specifically downregulation in c-Myc and other anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), but upregulation in p53 and cytochrome C levels. Glycolysis is differentially altered, with significant downregulation of glucose-6-phosphate and lactate by ribitol and JQ1, respectively. The overall effect of the combined treatment on metabolism and apoptosis-related genes results in significant synergy in the inhibition of cell growth and induction of apoptosis. Given the fact that ribitol is a metabolite with limited side effects, a combined therapy is highly desirable with relative ease to apply in the clinic for treating an appropriate cancer population. Our results also emphasize that, similar to traditional drug development, the therapeutic potential of targeting metabolism for cancer treatment may only be achieved in combination with other drugs and requires the identification of a specific cancer population. The desire to apply metabolomic intervention to a large scope of cancer types may be one of the reasons identification of this class of drugs in a clinical trial setting has been delayed.

Recovery of Third, Fourth, and Sixth Cranial Nerve Palsies in Pituitary Adenoma and Meningioma Patients.

BACKGROUND: This retrospective, observational cohort study aimed to determine recovery rate and recovery time of ocular motor nerve palsies (OMP) of third (CN III), fourth (CN IV), or sixth cranial nerves (CN VI)-and associated prognostic factors-in meningioma and pituitary adenoma (PA) patients. METHODS: A total of 25 meningioma (28 eyes) and 33 PA patients (36 eyes), treated at the Leiden University Medical Center in the Netherlands from January 1, 1978 to January 31, 2021, were included. OMPs were evaluated according to a newly created recovery scale using on-clinical and orthoptic examinations, which were performed every 3-4 months until palsy recovery, or at 18 months follow-up. RESULTS: Recovery rates of CN III (meningioma 23.5% vs PA 92.3%), CN IV (meningioma 20% vs PA 100%), and CN VI (meningioma 60% vs PA 100%) palsies were observed at 18 months follow-up, with differences between the 2 tumor types being observed in the treated patients only. Median recovery time of all OMPs combined was significantly longer in meningioma patients (37.9 ± 14.3 months vs 3.3 ± 0.1 months; P < 0.001). No significant protective or risk factors for recovery rate or time were identified. CONCLUSIONS: OMP recovery rates in treated patients were more favorable in patients with PA compared with patients with meningiomas, independent of OMP cause. With these new insights in OMP recovery, more accurate prognoses and appropriate follow-up strategies can be determined for meningioma and PA patients with OMPs.

[Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population].

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.

[Neoadjuvant immunotherapy for colorectal cancer].

Immunotherapy has been one of the hot topics in the field of colorectal cancer research in recent years. Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) are the main beneficiaries of immunotherapy. The response rate of patients with dMMR/MSI-H colorectal cancer receiving neoadjuvant immunotherapy is nearly 100%, of which the pathological complete response rate approximately accounts for 60%-67%. The prospect of neoadjuvant immunotherapy in dMMR or MSI-H colorectal cancer patients, especially in the rectal cancer patients, lies in achieving sustainable clinical complete response so as to achieve organ preservation and avoid adverse effects on reproductive, sexual, bowel and bladder function after surgery and radiotherapy. Studies have shown that part of the colorectal cancer patients of microsatellite stability (MSS) or mismatch repair proficient (pMMR) can respond to neoadjuvant immunotherapy in combination with other treatment methods such as radiotherapy and chemotherapy. In pMMR or MSS colorectal cancer, optimizing neoadjuvant immunotherapy regimens and finding effective efficacy prediction biomarkers are important research directions. In neoadjuvant immunotherapy, overcoming primary and secondary resistance and identifying the pseudoprogression and hyperprogression of neoadjuvant immunotherapy are clinical challenges that require attention. This paper comprehensively reviews the research progress, controversies,challenges and future research directions of neoadjuvant immunotherapy (mainly immune checkpoint inhibitors) in colorectal cancer.

[Construction of a diagnostic model for fatty liver using human body composition analysis].

Objective: To construct a diagnostic model for fatty liver using body composition analysis and further evaluate the diagnostic effect of the model on fatty liver. Methods: 726 cases with chronic liver disease who visited Tianjin Second People's Hospital from April 2019 to June 2022 and had body composition analysis tests were retrospectively enrolled and were divided into a fatty liver group (551 cases with fatty liver) and a control group (175 cases without fatty liver) according to the measured values of abdominal ultrasound and controlled attenuation parameter. An independent sample t-test and a non-parametric rank sum test were used for statistical processing. Logistic regression was used to construct a diagnostic model. Hosmer-Lemeshow was used to validate the fit of model. Receiver operating characteristic curve was used to confirm the diagnostic efficiency of the model. In addition, 341 cases of chronic liver disease who visited Tianjin Second People's Hospital were included to further verify the application effect of the model between July 2022 and February 2023. Results: Compared with the control group, the differences in various indicators of body composition analysis in the fatty liver group were statistically significant (P < 0.05). Basal metabolic rate (X1), visceral fat area (X2), and body fat (X3) were eventually included in the diagnostic model for BCA-FL (body composition analysis-fatty liver)= -7.771+0.002X1-0.035X2+0.456X3 with the Hosmer-Lemeshow test (P=0.059). The measured area under the receiver operating characteristic curve, the sensitivity, and the specificity were 0.888, 0.889, and 0.726, respectively, when the diagnostic threshold value was 0.615 with the Youden index and the receiver operating characteristic curve. In the validated model group, the area under the receiver operating characteristic curve, Youden index, sensitivity, and specificity were 0.875, 0.624, 0.799, and 0.825, respectively. Conclusion: The diagnostic model BCA-FL for fatty liver constructed using human body composition analysis has good diagnostic efficacy and is suitable for screening fatty liver in different basic liver disease populations.

Integrated proteome and lipidome analysis of naturally aged safflower seeds varying in vitality.

Seed ageing has an important effect on germination and productivity. During natural ageing, seed vigour decreases rapidly but, to date, the molecular mechanisms underlying this decrease have not been fully elucidated. Using omics, some of the details regarding seed vigour decline during natural ageing might be elucidated through integrated analysis. Safflower seed germination and physio-biochemical changes during natural ageing (stored for 4, 16 and 28 months) were determined. Proteome and lipidome profiling during natural seed ageing was performed, and the differentially expressed proteins and lipid metabolite species analysed. The surface and internal structures of cotyledons were observed. An integrating analysis of the proteome and lipidome was also carried out. Natural seed ageing significantly decreased safflower seed germination and vigour. 4,184 proteins and 1,193 lipids were quantified, both of which show huge differences among the different naturally aged seeds. The surface of the cotyledons collapsed and cracked, and the oil bodies become looser during natural ageing. The total content of DAG and PA increased, while the content of TAG and PL (PC, PE, PS, PI and PL) significantly decreased during seeds ageing. Two lipase genes (HH-026818-RA and HH-025320) likely participated in this degradation of lipids. We conclude that the enzymes that participate in glycerolipid metabolism and fatty acid degradation probably lead to the degradation of oil bodies (TAG) and membrane lipids (PC, PE, PS, PI, PG) and, ultimately, destroy the structure, causing a decline in seed vigour during natural seed ageing.

[Value of serum parathyroid hormone in the diagnosis of primary aldosteronism].

Objective: To explore the value of serum parathyroid hormone (PTH) in the diagnosis of primary aldosteronism (PA) and to investigate an optimal cut-off of serum PTH to distinguish PA from nonfunctional adrenal tumor (NFA). Methods: The clinical data of patients with adrenal incidentaloma in Chinese PLA General Hospital from January 1, 2017 to December 31, 2019 were collected. The data of PA and NFA by clinical characteristics and evaluation on endocrine function were retrospectively analyzed. The logistic regression model was used to find the potential risk factors of elevated PTH. The receiver operating characteristic(ROC) curve was used to evaluate the efficacy of PTH in diagnosis of PA and to explore the best cut-off value. Results: A total of 773 patients were included. There were 356 PA patients (203 males, 57.0%), aged (50±11) years and 417 NFA patients (219 males, 52.5%), aged (51±12) years. The serum PTH level in patients with PA was significantly higher than that in patients with NFA [63.1 (48.4, 80.3) ng/L vs 41.7 (34.1, 51.7) ng/L, P<0.05], as well as the proportion of patients with elevated PTH level (47.8% vs 7.2%, P<0.05). Logistic regression analysis showed that having PA and deficiency of Vitamin D were risk factors for PTH elevation (both P<0.05). The ROC curve showed that the best cut-off value of PTH for the diagnosis of PA in patients with vitamin D deficiency was 56.44 ng/L, with a sensitivity of 66.5% and a specificity of 83.0%, and that in patients with normal vitamin D was 48.81 ng/L, with a sensitivity of 70.5% and a specificity of 72.6%. Conclusions: Patients with PA tend to show increased levels of serum PTH compared with NFA patients. The level of serum PTH can be used as one of the valuable indexes in screening of PA.

[A comparative study of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of primary hyperaldosteronism on left side].

Objective: To compare the therapeutic effect of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of left-sided primary hyperaldosteronism. Methods: From January 2017 to July 2019, the clinical data of 70 patients with left-sided primary hyperaldosteronism (PHA) who underwent surgery in the First Hospital of Lanzhou University and five other hospitals in Gansu Province were retrospectively analyzed. There are 43 male and 27 female patients. Among them,28 patients were performed transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy and 42 patients were performed transperitoneal paracolic sulci approach laparoscopic adrenal tumorectomy. The general information and perioperative data of the two groups were compared. Results: All 70 cases of surgery were successfully completed. As compared with the paracolic sulci approach group, the operation time was significantly shorter in the transmesenteric approach group[(26.7±8.8)vs (38.9±7.1)min,P<0.001)], and the estimated blood loss was less in the transmesenteric approach group[45(30,50) vs 50(40,60)ml,P=0.042]. There was no statistically significant difference in the postoperative hospitalization days between the two groups[(4.4±1.0)vs(4.5±1.0)d, P=0.669)]. The electrolytes and aldosterone to renin ratio returned to a healthy level in the postoperative one month, and the blood pressure also returned to a healthy level in 53 (75.7%) patients. Conclusion: Transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy is safe and feasible, with a short operation time and relatively less estimated blood loss.

[Effects of normobaric hyperoxia intervention on renal ischemia-reperfusion injury in rats].

Objective: To investigate the effects of normobaric hyperoxia intervention on renal ischemia-reperfusion injury in rats and its possible mechanism. Methods: Twenty-one adult male SD rats were enrolled and their right kidneys were excised. After two weeks, they were randomly assigned to 3 groups, with 7 rats in each group, namely sham-operated group (Group S), ischemia-reperfusion group (Group I/R), and normobaric hyperoxia+ischemia-reperfusion group (Group NBHO+I/R). In group S, only the left renal pedicle was isolated, but no ischemic treatment was performed. However, in group I/R and group NBHO+I/R, left renal pedicles were separated and left renal ischemia was induced by noninvasive arterial clamp for 45 min, and after 24 h of reperfusion, rats in group S and group I/R inhaled regular concentration of oxygen (21%), while rats in group NBHO+I/R inhaled high concentration of oxygen (60%), 2 h at each time, once a day for 7 days. On the 7th day after surgery, blood urea nitrogen (BUN) and creatinine (Cr) levels were measured by taking blood from the orbital veins of rats. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) was detected from the left kidney tissues. The mRNA and protein contents of Keap1 and Nrf2 gene in kidney tissues were determined by qPCR and Western Blotting, respectively. Hematoxylin-eosin staining (HE) was employed to observe the pathological changes of kidney tissue. Immunohistochemical staining was used to measure the protein expression of Keap1 and Nrf2 in kidney tissues. Results: Compared with group S, the serum BUN [(10.7±1.7) mmol/L, (8.4±1.0) mmol/L vs (6.1±1.3) mmol/L, both P<0.05] and Cr [(81.0±3.7) µmol/L, (62.9±3.4) µmol/L vs (48.3±2.9) µmol/L, both P<0.05] levels of rats in the group I/R and group NBHO+I/R increased, and the I/R group had the most significant increase. Compared with group S, the MDA content of kidney tissue in the rats of group I/R and NBHO+I/R increased [(10.5±1.0) µmol/L, (8.6±0.8) µmol/L vs (6.5±0.5) µmol/L, both P<0.05], but the MDA content in group NBHO+I/R was lower than that of group I/R (P<0.05). Compared with group S, the SOD content in the kidney tissues of rats in both group I/R and group NBHO+I/R decreased. However, the SOD content of group NBHO+I/R was higher than that of group I/R (P<0.05). Compared with group S, the mRNA and protein contents of Keap1 gene in kidney tissues of group I/R and group NBHO+I/R decreased, and group NBHO+I/R had the most significant decrease (P<0.05). However, compared with group S, mRNA and protein expressions of Nrf2 gene increased in kidney tissues of group I/R and group NBHO+I/R, and NBHO+I/R group had the most significant increase (P<0.05). Postoperative pathological results suggested that compared with group S, the pathological damage of kidney tissues in group I/R and group NBHO+I/R increased, but the degree of damage in group NBHO+I/R was lower than that in group I/R. Conclusion: Normobaric hyperoxia intervention may have protective effects on renal ischemia-reperfusion injury in rats by activating Keap1-Nrf2 signaling pathway.

Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts. RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations. CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.

[Establishment of an auxiliary diagnosis system of newborn screening for inherited metabolic diseases based on artificial intelligence technology and a clinical trial].

Objective: To establish a disease risk prediction model for the newborn screening system of inherited metabolic diseases by artificial intelligence technology. Methods: This was a retrospectively study. Newborn screening data (n=5 907 547) from February 2010 to May 2019 from 31 hospitals in China and verified data (n=3 028) from 34 hospitals of the same period were collected to establish the artificial intelligence model for the prediction of inherited metabolic diseases in neonates. The validity of the artificial intelligence disease risk prediction model was verified by 360 814 newborns' screening data from January 2018 to September 2018 through a single-blind experiment. The effectiveness of the artificial intelligence disease risk prediction model was verified by comparing the detection rate of clinically confirmed cases, the positive rate of initial screening and the positive predictive value between the clinicians and the artificial intelligence prediction model of inherited metabolic diseases. Results: A total of 3 665 697 newborns' screening data were collected including 3 019 cases' positive data to establish the 16 artificial intelligence models for 32 inherited metabolic diseases. The single-blind experiment (n=360 814) showed that 45 clinically diagnosed infants were detected by both artificial intelligence model and clinicians. A total of 2 684 cases were positive in tandem mass spectrometry screening and 1 694 cases were with high risk in artificial intelligence prediction model of inherited metabolic diseases, with the positive rates of tandem 0.74% (2 684/360 814)and 0.46% (1 694/360 814), respectively. Compared to clinicians, the positive rate of newborns was reduced by 36.89% (990/2 684) after the application of the artificial intelligence model, and the positive predictive values of clinicians and artificial intelligence prediction model of inherited metabolic diseases were 1.68% (45/2 684) and 2.66% (45/1 694) respectively. Conclusion: An accurate, fast, and the lower false positive rate auxiliary diagnosis system for neonatal inherited metabolic diseases by artificial intelligence technology has been established, which may have an important clinical value.

Strength of patient cohorts and biobanks for cardiomyopathy research.

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.

TIR-domain-containing adapter-inducing interferon-ß contributes to TLR3/TLR4 triggered apoptosis and inflammation in nucleus pulposus cells.

The senescence and degeneration of the intervertebral disc are closely related to the reduction of nucleus pulposus (NP) cells caused by apoptosis. TIR-domain-containing adapter-inducing interferon-ß (TRIF) is an adapter for Toll-like receptors 3/4 (TLR3/4), which involves in cell apoptosis. The aim of this study is to detect the role of TRIF in the apoptotic progress of NP cells. The expression of collagen II, aggrecan, TLR3/4, and TRIF were analyzed in different degrees of degenerated human NP samples from patients. NP cells were isolated from mild degenerated tissues and cultured with IL-1ß to accelerate the degradation, and treated with TLR3/4 protein. siRNA was used to silence TRIF gene expression, and TRLF-plasmid was used to upregulate TRLF gene expression. We used flow cytometry assay to analyze cell apoptosis. The expression of collagen II, aggrecan, TLF3/4, TRIF, caspase-8/3, MMP-13, TNF-α was determined by immunofluorescence, Western blot, or RT-PCR. That the expression of collagen II and aggrecan markedly decreased, but TLF3/4, TRIF, caspase-8/3, MMP-3, TNF-α, and IL-1ß were increased in severely degenerated disc tissues. IL-1ß treatment induced NP cell degeneration and TLF3/4, TRIF, caspase-8/3, MMP-3, TNF-α overexpression. TLF3/4 protein treatment promoted NP cell degeneration and apoptosis by upregulation of TRIF, caspase-8/3, MMP-3, and TNF-α. Furthermore, TRIF silencing reversed the negative effect of TLF3/4 overexpression, and TRIF overexpression played the same role in NP cell apoptosis. Based on these results, we believe that TRIF is activated in a degenerated intervertebral disc. TLF3/4 promotes NP cell apoptosis and inflammation through the TRLF adaptor. TRLF expression is positively related to the apoptosis and inflammation in NP cells. These results suggest a therapeutic potential of the TRIF in the treatment of disc degeneration.

LINC00662 promotes glycolysis and cell survival by regulating miR- 375/HIF-1α axis in ovarian cancer.

Ovarian cancer (OC) is one of the most common gynecological malignancies, with the highest mortality rate in women worldwide. LINC00662, a long non-coding RNA (lncRNA), was shown to play a vital role in many malignancies, while little is known about its role in OC. Firstly, our study determined the expression of LINC00662 in OC tissues and cells. Upregulation or downregulation of LINC00662 were performed in OC cells to explore its effects on cell proliferation and glycolysis of OC. The interaction between LINC00662 and miR-375 was verified using luciferase assays and RNA immunoprecipitation. Results showed that LINC00662 was highly expressed in OC tissues and cells, and patients with increased expression of LINC00662 were associated with shorter overall survival. Furthermore, functional assays proved that LINC00662 was essential for OC cell proliferation and glycolysis. Subsequently, our study further revealed that LINC00662 acted as a competitive RNA and it could modulate the expression of HIF-1α through directly binding with miR- 375. Collectively, upregulation of LINC00662 in ovarian cancer tissues is closely correlated to poor survival. LINC00662 might regulate HIF-1α expression via miR-375. These findings suggested that LINC00662 has the potential to be explored as a diagnostic biomarker for OC.

The validity of ICD-11 PTSD and Complex PTSD in East Asian cultures: findings with young adults from China, Hong Kong, Japan, and Taiwan.

Background: The ICD-11 classifies posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as two distinct diagnoses. Few studies have tested the validity of ICD-11 CPTSD in non-Western settings, particularly in Asia. Objective: This study assessed the factorial, concurrent, and discriminant validity of CPTSD symptoms with four samples of young adults from mainland China, Hong Kong, Japan, and Taiwan. Method: Young adults aged 18-24 years were recruited by convenience sampling and provided their data anonymously online. Study measures included the International Trauma Questionnaire (ITQ) to measure PTSD and CPTSD, and measures of childhood adversity, depression, anxiety, age, and sex. Confirmatory factor analysis (CFA) was performed for each sample to evaluate the validity of two CPTSD measurement models. Structural equation modelling (SEM) was used to determine the multivariate associations between study variables for the full sample. Results: A total of 1,346 young adults completed the survey. CFA showed both models of CPTSD examined fit the data well across all four samples. SEM findings showed that number of childhood adversities significantly associated with both PTSD and CPTSD factors; depression significantly associated with CPTSD factors but not PTSD, whereas anxiety significantly associated with both. Conclusions: Study findings provide evidence for PTSD and CPTSD as separate and valid diagnoses in Asia. More cross-cultural comparisons are needed to understand whether risks for either condition differ by geographical or sociocultural norms.

Antecedentes: La CIE-11 clasifica el trastorno de estrés postraumático (TEPT) y el trastorno de estrés postraumático complejo (TEPT-C) como dos diagnósticos distintos. Pocos estudios han probado la validez del TEPT-C de la CIE-11 en escenarios no occidentales, particularmente en Asia.Objetivo: Este estudio evaluó la validez factorial, concurrente y discriminante de los síntomas de TEPT-C de 4 muestras de adultos jóvenes de China continental, Hong Kong, Japón y Taiwán.Método: Fueron reclutados adultos jóvenes entre 18 y 24 años de edad a través de una muestra por conveniencia y proveyeron sus datos en forma anónima en línea. Las mediciones del estudio incluyeron el Cuestionario Internacional de Trauma (ITQ por sus siglas en inglés) para medir TEPT y TEPT-C y mediciones de adversidad en la infancia, depresión, ansiedad, edad y sexo. Se realizó el análisis factorial confirmatorio (CFA por sus siglas en inglés) para cada muestra para evaluar la validez de los dos modelos de medición de TEPT-C. Se usó el modelado de ecuaciones estructurales (SEM por sus siglas en inglés) para determinar las asociaciones multivariadas entre las variables del estudio para la muestra completa.Resultados: un total de 1.346 adultos jóvenes completaron la encuesta. La CFA mostró que ambos modelos de TEPT-C examinados se ajustan bien los datos en las cuatro muestras. Los hallazgos del SEM mostraron que el número de adversidades en la infancia se asociaba significativamente tanto con los factores de TEPT y TEPT-C; la depresión se asociaba significativamente para TEPT-C pero no para TEPT; mientras que la ansiedad se asociaba significativamente con ambos.Conclusiones: los hallazgos del estudio proveen evidencia para TEPT y TEPT-C como dos diagnósticos separados y válidos en Asia. Se necesitan más comparaciones transculturales para comprender si los riesgos de cualquiera de estas condiciones difieren geográficamente o por normas socioculturales.