Remnant Cholesterol and Common Carotid Artery Intima-Media Thickness in Community Population with Normal Low-Density Lipoprotein Cholesterol.

INTRODUCTION: Remnant cholesterol is a risk factor for cardiovascular disease, especially when low-density lipoprotein cholesterol (LDL-C) levels are normal. However, there are few studies on the relationship between remnant cholesterol and subclinical atherosclerosis. Common carotid artery intima-media thickness (cIMT) is an imaging marker of subclinical atherosclerosis. This study aimed to investigate the relationship between remnant cholesterol and cIMT in a community population with normal LDL-C. METHODS: This study is a retrospective analysis; 1,101 community population with available carotid artery imaging and fasting lipid data with LDL-C <4.1 mmol/L were included in this analysis. Remnant cholesterol was calculated as total cholesterol minus LDL-C minus high-density lipoprotein cholesterol. Abnormal cIMT was defined as maximum cIMT value ≥1 mm. Logistic regression was used to assess the relationships between remnant cholesterol levels and abnormal cIMT. RESULTS: As the remnant cholesterol level increased from the lowest to the highest quartile, the rate of abnormal cIMT increased from 24.5% to 38.6% (p trend <0.001) in the community population with normal LDL-C level. In the unadjusted model, the odds ratios (ORs, 95% confidence intervals) in the highest quartile group were 1.937 (1.338-2.803) for abnormal cIMT compared with the lowest quartile. The multivariable-adjusted ORs (95% confidence intervals) for the highest versus lowest quartile of remnant cholesterol were 2.132 (1.420-3.202) for abnormal cIMT. CONCLUSION: Elevated fasting remnant cholesterol levels were positively associated with abnormal cIMT in community population with normal LDL-C levels. Remnant cholesterol may be an important indicator of risk stratification in community population with normal LDL-C level.

A dynamic predictive nomogram of long-term survival in primary gastric lymphoma: a retrospective study.

BACKGROUND: Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma (NHL). Due to the rarity of the disease, it is important to create a predictive model that provides treatment and prognosis for patients with PGL and physicians. METHODS: A total of 8898 and 127 patients diagnosed with PGL were obtained from the SEER database and from our Cancer Center as training and validation cohorts, respectively. Univariate and multivariate Cox proportional hazards models were used to investigate independent risk factors for the construction of predictive survival nomograms, and a web nomogram was developed for the dynamic prediction of survival of patients with PGL. The concordance index (C-index), calibration plot, and receiver operating characteristics (ROC) curve were used to evaluate and validate the nomogram models. RESULTS: There were 8898 PGL patients in the SEER cohort, most of whom were married men over the age of 60, 16.1% of the primary tumors were localized in the antrum and pylori of the stomach, which was similar to the composition of 127 patients in the Chinese cohort, making both groups comparable. The Nomogram of overall survival (OS) was compiled based on eight variables, including age at diagnosis, sex, race, marital status, histology, stage, radiotherapy and chemotherapy. Cancer-specific survival (CSS) nomogram was developed with eight variables, including age at diagnosis, sex, marital status, primary tumor site, histology, stage, radiotherapy and chemotherapy. The C-index of OS prediction nomogram was 0.948 (95% CI: 0.901-0.995) in the validation cohort, the calibration plots showed an optimal match and a high area below the ROC curve (AUC) was observed in both training and validation sets. Also, we established the first web-based PGL survival rate calculator ( https://yangjinru.shinyapps.io/DynNomapp/ ). CONCLUSION: The web dynamic nomogram provided an insightful and applicable tool for evaluating PGL prognosis in OS and CSS, and can effectively guide individual treatment and monitoring.

Prediction of central compartment nodal metastases in papillary thyroid cancer using TI-RADS score, blood flow, and multifocality.

BACKGROUND: The relationship between the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) and the risk of lymph node metastases in papillary thyroid cancer (PTC) could improve the detection rate of lymph node metastases in thyroid cancer and provide a scientific basis for clinical diagnosis. PURPOSE: To evaluate the risk of lymph node metastases of PTC associated with the score from ACR TI-RADS adjusted for other correlative factors. MATERIAL AND METHODS: A total of 560 patients with pathologically confirmed PTC were included in the study and classified into a metastases group and a non-metastases group. Clinical and pathological manifestations of the patients were collected. RESULTS: The median TI-RADS score was 13 (p25-p75 = 11-14) among the patients with lymph node metastases, higher than those without metastases 9 (8-10) (P < 0.001). Multiple logistic regression indicated that TI-RADS score (odds ratio [OR] = 2.204), male sex (OR = 2.376), multifocality (OR = 4.170), and rich blood flow (OR = 3.656) were risk factors for lymph node metastases in patients with thyroid carcinoma. Some related factors such as TI-RADS score, age(<45years old), male, multifocality and rich blood flow were related to lymph node metastases in the central area of the neck which could provide therapeutic strategy for further treatment. CONCLUSION: it is not just the TI-RADS score but also multifocality, blood flow, and sex that influence the prediction of the risk of PTC central lymph node metastases.

Suggested amendment of TI-RADS classification of thyroid nodules by shear wave elastography.

BACKGROUND: The application of the ultrasound elastography and Thyroid Imaging Reporting and Data System (TI-RADS) classification further expands the scope of ultrasound differential diagnosis between benign and malignant thyroid nodules. PURPOSE: To investigate the value of the quantitative parameter of ultrasonic shear waves in optimizing the TI-RADS classification of thyroid nodules. MATERIAL AND METHODS: A total of 168 thyroid nodules, initially classified using TI-RADS and scanned by shear wave elastography (SWE), were retrospectively analyzed. All cases were diagnosed by fine needle aspiration and histology following surgery. RESULTS: The benign rate of TI-RADS 3 nodules was 76.5%, while the benign rate of TI-RADS 4a nodules was 71.7%. Furthermore, the malignant rate of TI-RADS 4b nodules was 69.7%, while the malignant rate of TI-RADS 4c nodules was 85.7%. In differentiating benign from malignant nodules, the combination of TI-RADS classification and Emean had the largest area under the receiver operating characteristic curve (AUC). Using an Emean value of 42.25 kpa as the cut-off point, the malignant rate of TI-RADS 4a nodules decreased from 28.3% to 23.5%, while the malignant rate of TI-RADS 4b nodules increased from 69.7% to 79.4%. Compared to conventional ultrasound alone, the sensitivity, negative predictive value, and AUC of conventional ultrasound combined with SWE in the diagnosis of benign and malignant thyroid nodules significantly improved (P=0.012, 0.029, 0.001). CONCLUSION: The SWE technique can be used to further determine the benign and malignant nature of TI-RADS 4 lesions, providing further reference for the choice of clinical treatment. The TI-RADS classification system corrected by SWE is more significant in the diagnosis of benign and malignant thyroid nodules.

Moderating role of job satisfaction on turnover intention and burnout among workers in primary care institutions: a cross-sectional study.

BACKGROUND: Global countries are suffering from a shortage of health professionals. Turnover intention is closely related to job satisfaction and burnout, making good use of these relationships could alleviate the crisis. Our research aims to examine the mediating role of job satisfaction in the relationship between burnout and turnover intention. METHODS: This research was conducted in Huangpi, China. The convenience sampling method and self-administereded questionnaires were used. 1370 of valid samples were collected with 97.72% effective rate. Descriptive analyses were conducted to describe social demographic factors. The structural equation model (SEM) was performed to adjust model fitting, and the mediation effect test was carried out by using the bootstrap method. Sobel-Z test was used to verify the significance of mediation effect. RESULTS: The mean age was 36.98 (SD = 9.84). The fitting indices of hypothetical model are not good. After the adjustments, χ2/df = 5.590, GFI = 0.932, AGFI = 0.901, CFI = 0.977, NFI = 0.973, IFI = 0.977, TLI = 0.970, RESEA = 0.058. The revised model fitted well, and the SEM was put up by using the bootstrap method. The mediating effect is partial, and Soble-Z test indicates that the mediation effect is significant. Burnout is negatively correlated with job satisfaction (p < 0.01) and the standardized path coefficient is - 0.41. Job satisfaction is also negatively correlated with turnover intention (p < 0.01) and the standardized path coefficient is - 0.18. Burnout is positively correlated with turnover intention (p < 0.01) and the standardized path coefficient is 0.83. CONCLUSIONS: Job satisfaction is a mediating variable that affects the relationship between burnout and turnover intention. The mediating effect was a partial mediating effect and has a low impact of 7.4%. Improving treatment and giving more promotion opportunities for workers to improve job satisfaction, conducting career planning course and paying attention to employee psychological health to reduce job burnout. The above measures may be helpful to reduce employee turnover rate and alleviating the current situation of a shortage of health personnel in China.

[Role of Hippo signaling pathway in mice hypospadias induced by vinclozolin].

OBJECTIVE: To observe the role of Hippo signaling pathway in mice hypospadias induced by vinclozolin. METHODS: After 8 weeks of ICR mice were conceived, they were divided randomly into the treatment and the control groups(10 for each group). Vinclozolin was orally administraed to the pregnant mice in the treatment group with 400 mg/(kg·d) during gestation days 12-18, while those of the control group were treated with equal volume of soybean oil. About 60 days after birth, 20 penises of the mouse offspring were taken randomly from both of the two groups separately. And furthermore, the relative expression abundance of Hippo signaling pathway key genes(Mst1, Lats1, Taz, Yap), androgen receptor gene Ar of all the samples were measured by the real-time quantity reverse transcript polymerase chain reaction(qPCR). The Yes-related protein(Yap) and its phosphorylation in the downstream of Hippo signaling pathway were measured by Western blot. RESULTS: Compared with the male mice of the control group, the anal genital distances of the treatment group were significantly shortened((9. 2501±2. 5504) vs. (16. 1253±1. 3562) mm, P<0. 05), the quality of the penises was significantly less than((0. 0293±0. 0075) vs. (0. 4731±0. 004) g, P<0. 05), the length of the penises was shorter((5. 3875±0. 4524) vs. (12. 4688±1. 2290) mm, P<0. 05), and the diameters of the penises were also less than the control((1. 5513±0. 1158) vs. (2. 6013±0. 1469) mm, P<0. 05). All the genes in the penises of the control group were expressed. The Yap and Ar in the treatment group's penises were not expressed, the expression abundance of Mst1 and Lats1 was higher than that of the control(6. 6097±1. 3188 vs. 0. 3517±0. 1524, 5. 7071±2. 7210 vs. 0. 1235±0. 0658, P<0. 05), and the expression abundance of Taz was lower than that of the control(0. 3937±0. 1519 vs. 3. 2329±0. 4339, P<0. 05). The expression of Yap was decreased in the treatment group(0. 3348±0. 0639 vs. 0. 8023±0. 4275, P<0. 05), and the phosphorylation level of Yap was higher than that of the control group(3. 9940±0. 2177 vs. 0. 3128±0. 0867, P<0. 05). CONCLUSION: In the model of mice hypospadias induced by vinclozolin, the Ar was not expressed, the Hippo signaling pathway was activated and the phosphorylation of Yap was increased. This pathway may play an important role in the model.

[Effect of flutamide exposed during pregnancy on reproductive organs development and oxidative stress responsein in male mice offspring].

OBJECTIVE: To investigate the effects of flutamide on the reproductive organs development and oxidative stress response of male offspring after exposure to pregnant mice, and to provide further evidence for the application of the model and mechanism research. METHODS: Choose 7-week-old ICR mice, female mice were randomly divided into experimental group and control group after pregnancy, thenflutamide was orally administered to pregnant mice with dose 300 mg/( kg·d) during gestation days 12-18, while the control group was treated with equal volume of soybean oil. More than 7 weeks after birth, 40 male mice were randomly chosen to observe the urethral development and test the anogenital distance( AGD), testicular volume and penile length, and then some of these mice's reproductive organs were took for histopathological examination. After grind and centrifuge to obtain the supernatant, twelve penis and testes were randomly selected for examining the level of malondialdehyde( MDA), superoxide dismutase( SOD), and glutathioneperoxidase( GSH-Px) use corresponding kit and microplate reader. The abundance of oxidative stress related genes Noxo1, Sod1 and Gpx1 were detected by qPCR. RESULTS: The incidence of hypospadias in male mice in the treatment group was 100%( 91/91). AGD in the treatment group was( 10. 22 ± 1. 53) mm, which was significantly lower than the control( 17. 46 ± 1. 25) mm( P < 0. 05). The volume of testicles in the treatment group was( 166. 34 ± 26. 59) vs. ( 178. 25 ± 25. 77) mm~3 in the control group( P < 0. 05). The length of the penis in the treatment group was( 7. 46 ± 0. 76) vs. ( 12. 60 ± 0. 80) mm in the control group( P <0. 05). In the testicles, the level of SOD was( 171. 08 ± 57. 24) vs. ( 102. 79 ± 15. 31) U/mg pro, MDA was( 4. 45 ± 1. 67) vs. ( 2. 93 ± 1. 00) nmol/mg pro, GSH-Px was( 41. 55± 12. 15) vs. ( 78. 27 ± 7. 60) U/mg pro( P < 0. 05). The abundance of Noxo1 in the testis from the treatment group was higher than that in the control group, while the expressions of Sod1 and Gpx1 in testis from the treatment group were lower than those in the control group( P < 0. 05). There is no significant difference in SOD, MDA, GSH-Px levels and Sod1, Noxo1, and Gpx1 expressions were found in the penises of both groups. CONCLUSION: Prenatal exposure of flutamide may cause developmental abnormalities such as hypospadias and shortening of the penis in male offspring, and abnormal testicular function of oxidation and anti-oxidation. However, there is no significant effect on penis oxidative/anti-oxidant function.

Doppler perfusion index and contrast-enhanced ultrasound in patients with colorectal cancer liver metastases.

BACKGROUND/AIMS: To assess the value of the Doppler perfusion index (DPI) and contrast agent for the detection of liver metastases in patients with colorectal cancer. METHODOLOGY: DPI was measured in 18 patients with colorectal cancer liver metastases and 18 control subjects. Sixteen patients were underwent contrast-enhanced ultrasonography (CEUS). RESULTS: patients with liver metastases had significantly greater DPI than control group (0.39 +/- 0.10 vs. 0.19 +/- 0.07, p < 0.05). Sixteen liver metastasis lesions underwent a rapid wash-out of contrast agent during the portal venous phase followed by a complete wash-out of SonoVue during the sinusoidal phase and were differentiated as "fast-in and fast-out" contrast enhancement patter. Another 3 lesions which were not found by baseline ultrasonography were detected to be enhancement defects at sinusoidal phases by CEUS. CONCLUSIONS: DPI is a sensitive index in detection of colorectal liver metastases; if used combined with contrast agent, much more occult liver metastasis would be detected by ultrasonography.

Can rectal MRI and endorectal ultrasound accurately predict the complete response to neoadjuvant immunotherapy for rectal cancer?

Background: Standardized assessments of clinical complete response (cCR) to neoadjuvant chemoradiotherapy (nCRT) for rectal cancer have been established, but their utility and accuracy remain unclear. This study aimed to evaluate the clinical diagnostic value of rectal magnetic resonance imaging (MRI) and endorectal ultrasonography (ERUS) for the determination of cCRs after neoadjuvant immunotherapy and to investigate the concordance between cCR and pathological complete response (pCR). Methods: Ninety-four patients with rectal cancer treated with neoadjuvant radiotherapy with or without immunotherapy were included. The sensitivity, specificity, and accuracy of each evaluation method were calculated. Results: Combined MRI and ERUS assessments found cCR in seven of the 94 patients in our cohort. In the non-immunotherapy group, the sensitivity, specificity, and accuracy of MRI for diagnosing cCR were 50.0%, 85.2%, and 77.1%, respectively, whereas those of ERUS were 50.0%, 92.6%, and 82.9%, respectively; those of combined MRI and ERUS were 25.0%, 96.3%, and 87.5%, respectively. In the immunotherapy group, the sensitivity, specificity, and accuracy with which MRI identified CR were 51.7%, 76.7%, and 64.4%, respectively; those of ERUS were 13.8%, 90.0%, and 52.5%, respectively, and those of combined MRI and ERUS were 10.3%, 96.7%, and 54.2%, respectively. We also found that 32 of 37 patients with pCR did not meet the cCR evaluation criteria. Of these pCR patients, 78.4% (29/37) received immunotherapy. In the entire cohort, there were five pCRs among the seven cCRs. Of the four cCRs that occurred in the immunotherapy group, three were pCRs. Conclusions: Rectal MRI and/or ERUS did not provide sufficiently accurate assessments of cCR in patients with rectal cancer receiving neoadjuvant therapy, especially immunotherapy, and cCR did not predict pCR.

Significant response to pembrolizumab plus lenvatinib in Epstein-Barr-virus-associated intrahepatic cholangiocarcinoma: a case report.

BACKGROUND: The prognosis for advanced intrahepatic cholangiocarcinoma (iCCA) is poor, and there remains an urgent need to develop efficient systemic therapy. The efficacy of Pembrolizumab immunotherapy combined with lenvatinibin in iCCA is still unclear. The role of Epstein-Barr-virus (EBV) as a biomarker in iCCA for response to immunotherapy needs further exploration. CASE PRESENTATION: We report a case of a 60-year-old female with EBV-associated advanced iCCA (EBVaiCCA) who progressed after first-line therapy. She accomplished an available response to the combination therapy of pembrolizumab with lenvatinib, with overall survival of 20 months. CONCLUSIONS: As far as we know, this is the first case report about the application of Pembrolizumab with lenvatinib for EBVaiCCA patients. This case indicates that the combination of immunotherapy and antiangiogenic therapy provides a glimmer of hope for advanced EBVaiCCA patients.

Recruitment or activation of mast cells in the liver aggravates the accumulation of fibrosis in carbon tetrachloride-induced liver injury.

Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-ß1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis.

Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy.

Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.

[Study on preparation of quercetin nanostructured lipid carriers and their physicochemical properties].

OBJECTIVE: To prepare quercetin nanostuctured lipid carriers (QT-NLC), and detect their physicochemical properties. METHOD: QT-NLC was prepared by emulsification ultrasonic dispersion method, and the optimum prescription was screened out by orthogonal design. Transmission electron microscope was used to observe QT-NLC morphology. Granulometer was applied to determine zeta potential, particle size and distribution. DSC was adopted for phase analysis. Centrifugal ultra-filtration method was used to determine entrapment efficiency. Dialysis method was adopted to detect drug release in vitro of preparations. RESULT: QT-NLC prepared under optimum conditions was mostly spherical grains, with the average particle size of (175 +/- 25) nm, which were distributed evenly, and zeta potential was (-23 +/- 0.3) mV. DSC results indicated that the drug was dispersed in nano-particles in a non-crystalline state, with an entrapment efficiency of (95.43 +/- 0.23)% and a drug-loading capacity of (2.38 +/- 0.24)%. The in vitro drug release was 32.2% in 2 hours, which was followed by a sustained release. CONCLUSION: Emulsification ultrasonic dispersion method is applicable for preparing QT-NLC, as nano-particles are distributed evenly, with good reliability. This processing technology is safe, reliable and highly reproducible.

Accentuated Hippo pathway and elevated miR-132 and miR-195a lead to changes of uteri and ovaries in offspring mice following prenatal exposure to vinclozolin.

Vinclozolin (VCZ) has been identified as a broad-spectrum fungicide and an environmental endocrine disruptor. Also, the Hippo signaling pathway controls organ size by regulating cell proliferation and apoptosis, and moreover, overexpression of microRNA-132 (miR-132) and microRNA-195 (miR-195) inhibits cell proliferation and promotes apoptosis. So, in this study, the experimental mice were orally given 400 mg/kg/day VCZ (suspended in corn oil) at gestational day 12-18, while those of the control group were fed with corn oil of equal volume. Then unilateral ovaries and mid-uteri were isolated from 10 randomly-selected mice at the postnatal 1st week (7 days), 3rd week (20-21 days), and 7th week (48-49 days) respectively to observe gene levels, while 6 of the contralateral ovaries and uteri were subsequently examined for proteins respectively. Besides, 16 from both groups were determined with serum estradiol (E2) at week 7, of which 6 were randomized for histological observation. Here we found the levels of E2 reduced in VCZ-group at week 7, with fewer follicles and injured endometrium. Meanwhile, in VCZ mice of all ages, increased miR-132 and miR-195a, decreased G protein-coupled estrogen receptor (GPER), elevated phosphorylated large tumor suppressor (pLATS) and phosphorylated yes-associated protein (pYAP), and decreased yes-associated protein (YAP) were observed in their ovaries and uteri. These findings suggested ovarian and uterine dysplasia in the offspring induced by gestational VCZ-exposure were mainly attributed to higher miR-132 and miR-195a and accentuated Hippo-pathway.

Characterization of the renal tubular transport of creatinine by activity-based protein profiling and transport kinetics.

Serum creatinine is widely used to adjust the dosing of drugs eliminated by the kidney in patients with renal dysfunction, as it is a readily accessible indicator of kidney function. However, there are many limitations for drug dosage adjustment based on serum creatinine levels, one of which is the limited understanding of creatinine's tubular transport. Thus, we aimed to complement and advance the renal tubular transport of creatinine by activity-based protein profiling (ABPP) and transporter-overexpression technology. Renal tubular transporters were not identified via ABPP due to the low-affinity interaction between transporters and creatinine. The uptake of isotopically labeled d3-creatinine was significantly increased in OCT2-overexpressing cell lines (p<0.01), and the Km and Vmax of d3-creatinine uptake mediated by OCT2 was 3.1 mM and 408 pmol/mg protein/min, respectively. In the OCT2-overexpressing cell lines, the IC50 of creatinine for d3-creatinine uptake was 10.3 mM, and that of the OCT2 inhibitor cimetidine for d3-creatinine uptake was 99.04 µM. Different dosages of creatinine did not affect the renal excretion of d3-creatinine in mice (p>0.05), while cimetidine significantly reduced the renal excretion of d3-creatinine (p<0.01) without affecting the glomerular filtration rate. Molecular docking in silico showed that the OCT2 amino acid GLN242 could form a hydrogen bond of 2.5 Å with creatinine, and there may be a π-π interaction between TYR362 and creatinine. A site mutation experiment demonstrated that TYR362 and GLN242 were important sites for the OCT2-creatinine interaction. These results demonstrate that OCT2 mediates the renal tubular secretion of creatinine with low affinity and is a minor contributor to creatinine secretion.

Gentamicin alleviates cholestatic liver injury by decreasing gut microbiota-associated bile salt hydrolase activity in rats.

Intrahepatic cholestasis lacks effective therapeutic drugs. The gut microbiota-associated bile salt hydrolases (BSH) may be a potential therapeutic target. In this study, oral administration of gentamicin (GEN) decreased the serum and hepatic levels of total bile acid in 17α-ethynylestradiol (EE)-induced cholestatic male rats, significantly improved the serum levels of hepatic biomarkers and reversed the histopathological changes in the liver. In healthy male rats, the serum and hepatic levels of total bile acid were also decreased by GEN, the ratio of primary to secondary bile acids, and conjugated to unconjugated bile acids was significantly increased, and the urinary excretion of total bile acid was elevated. 16S rDNA sequencing of the ileal contents revealed that GEN treatment substantially reduced the abundance of Lactobacillus and Bacteroides both of which expressed BSH. Consistently, BSH activity analysis by the generation of d5-chenodeoxycholic acid from d5-taurochenodeoxycholic acid in situ showed BSH was significantly inhibited in the ileal contents of rats treated with GEN. This finding led to an increased proportion of hydrophilic conjugated bile acids and facilitated the urinary excretion of total bile acids, thereby decreasing serum and hepatic total bile acids and reversing liver injury related to cholestasis. Our results provide important evidence that BSH can be a potential drug target for treating cholestasis.

Application of Real-Time Sound Touch Elastography for Evaluating Chronic Kidney Disease of Transplanted Kidneys.

BACKGROUND: If chronic allograft nephropathy can be detected early and treated, the long-term survival rate of the transplanted kidney may be effectively improved. PURPOSE: To compare the application value of real-time sound touch elastography (STE), strain elastography, and color Doppler flow imaging in evaluating chronic kidney disease of transplanted kidneys. MATERIALS AND METHODS: A total of 101 patients with renal transplantation were divided into a normal group (serum creatinine <134 mol/L, 58 patients) and a chronic allograft nephropathy group after renal transplantation over 6 months (serum creatinine >134 mol/L, 43 patients). The maximum elastic modulus (Emax) was determined, and receiver operator characteristics were used to compare the diagnostic efficacy of STE ultrasound. RESULTS: Emean, Emax, B/A (the strain rate of the internal oblique muscle tissue/ the strain rate of the central renal cortex) of cortical standard strain ratio in strain elastography, and resistance index (RI) between normal and chronic allograft nephropathy groups have statistical significance (P < .05). Emax is superior to B/A and arcuate artery RI in the chronic cortex in the diagnosis of renal dysfunction, and the area under the receiver operator characteristics curve is 0.88. The estimated glomerular filtration rate was negatively correlated with renal cortex Emax, B/A, and arcuate artery RI, among which Emax was the strongest (r = - 0.713, P < .001). The renal cortical Emax cut-off was 30.95 kPa, the sensitivity was 92%, the specificity was 88%, and the accuracy was 88%. CONCLUSION: The STE technique to evaluate chronic renal dysfunction after renal transplantation is more sensitive than traditional strain-type elastography and hemodynamic parameters, with renal function decline, renal cortex Emax, renal cortical B/A, and arcuate artery RI gradually increased, and renal cortex Emax was particularly obvious.

Gut Streptococcus is a microbial marker for the occurrence and liver metastasis of pancreatic cancer.

Background: Gut microbiome plays an indispensable role in the occurrence and progression in various diseases. The incidence of pancreatic cancer (PC) and liver metastasis (PCLM) are high, most of them are found in advanced stage. Therefore, it is particularly necessary to search for predictive biomarkers, which are helpful for early detection and treatment, and thus improve the survival rate and quality of life of PC patients. Methods: We retrospectively analyzed 44 pancreatic cancer patients (P group, n = 44) and 50 healthy people (N group, n = 50) from March 21, 2021 and August 2, 2022. Among all PC patients, we divided them into liver metastasis group (LM group, n = 27) and non-liver metastasis group (non-LM group, n = 17). DNA was extracted and 16S ribosomal RNA (16S rRNA) gene sequencing was performed. SPSS was used for statistical analyses and all bioinformatics analyses were based on QIIME2, p < 0.05 were considered statistically significant. Results: The microbial richness and diversity of group P and LM were higher than that of group N and non-LM. LEfSe analysis found that Streptococcus was a significantly different microorganism, which was further identified by random forest (RF) model, and its ability to predict PC and PCLM was verified by ROC curve. Conclusion: We demonstrated significant differences in intestinal microbiome composition between PC patients and healthy people, and found that Streptococcus is a potential biomarker for early prediction of PC and PCLM, which is critical for early diagnosis of diseases.

Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress.

The accumulation of uric acid (UA) in the body can lead to the occurrence of hyperuricemia or uric acid nephropathy. Mast cells (MCs) increase oxidative stress and release renin to promote the production of Ang II. The aim of this study was to investigate the effect of UA on MCs in rat kidneys and the association between MCs and renal injury. Our results show that UA accumulation in the kidney stimulated the degranulation of MCs and the release of renin to promote Ang II production, resulting in renal oxidative stress, mitochondrial structural damage, and microvascular system damage. The expression of urate-related transporters was regulated by the UA level and serum urinary toxins levels were substantially elevated in hyperuricemia. Administration of the MCs membrane stabilizer sodium cromoglycate (SCG) or the angiotensin receptor antagonist Valsartan decreased the production of renin and Ang II and relieved renal oxidative stress, mitigated mitochondrial structural damage and microvascular system damage, and promoted the excretion of UA and urinary toxins by increasing the expression of urate-related transporters. These results demonstrate that the accumulation of UA in the kidney can trigger the degranulation of MCs and promote the development of renal oxidative stress. Administration of SCG and Valsartan ameliorated UA-induced renal injury by inhibiting MCs degranulation and reducing renal oxidative stress by inhibiting renin and Ang II production and accelerating renal clearance of UA and uremic toxins.

Pretreatment high cholesterol and low neutrophils predict complete pathological response after neoadjuvant short­course radiotherapy followed by chemotherapy and immunotherapy in locally advanced rectal cancer.

The present study was aimed at looking for hematological indicators that could predict pathological complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with short-course radiotherapy (SCRT) followed by chemotherapy and immunotherapy. A total of 171 patients were enrolled in this observational retrospective study. Pretreatment values of albumin, total cholesterol, lactate dehydrogenase, neutrophil, platelet and lymphocytes were available. Univariate and multivariate logistics analyses were used to determine the prognostic factor for pCR. SCRT followed by chemotherapy and immunotherapy was demonstrated to double the pCR rate (50.5%) compared with long-course chemoradiotherapy. For the former group, baseline high platelet to lymphocyte ratio (P=0.047), high cholesterol (P=0.026) and low neutrophils (P=0.012) level were associated with high pCR rate and baseline high cholesterol (P=0.016) and low neutrophils (P=0.020) level were the independent prognostic factors for pCR. In conclusion, pretreatment high cholesterol and low neutrophils were the independent prognostic predictors of pCR in patients with LARC treated with SCRT followed by chemotherapy and immunotherapy. Clinical trial no. NCT04928807, June 16, 2021.