Mediator dynamics during heat shock in budding yeast.

The Mediator complex is central to transcription by RNA polymerase II (Pol II) in eukaryotes. In budding yeast (Saccharomyces cerevisiae), Mediator is recruited by activators and associates with core promoter regions, where it facilitates preinitiation complex (PIC) assembly, only transiently before Pol II escape. Interruption of the transcription cycle by inactivation or depletion of Kin28 inhibits Pol II escape and stabilizes this association. However, Mediator occupancy and dynamics have not been examined on a genome-wide scale in yeast grown in nonstandard conditions. Here we investigate Mediator occupancy following heat shock or CdCl2 exposure, with and without depletion of Kin28. We find that Pol II occupancy shows similar dependence on Mediator under normal and heat shock conditions. However, although Mediator association increases at many genes upon Kin28 depletion under standard growth conditions, little or no increase is observed at most genes upon heat shock, indicating a more stable association of Mediator after heat shock. Unexpectedly, Mediator remains associated upstream of the core promoter at genes repressed by heat shock or CdCl2 exposure whether or not Kin28 is depleted, suggesting that Mediator is recruited by activators but is unable to engage PIC components at these repressed targets. This persistent association is strongest at promoters that bind the HMGB family member Hmo1, and is reduced but not eliminated in hmo1Δ yeast. Finally, we show a reduced dependence on PIC components for Mediator occupancy at promoters after heat shock, further supporting altered dynamics or stronger engagement with activators under these conditions.

Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL.

PURPOSE: At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. METHODS: In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. RESULTS: Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. CONCLUSION: Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

Does COVID-19 vaccination affect post-traumatic stress symptoms via risk perception? A large cross-sectional study among the Chinese population.

OBJECTIVES: Although infection rates may increase after relaxation of the zero COVID strategy, the extensive vaccination campaign in China could potentially curb the spread of COVID-19, which may be associated with a low level of risk perception and post-traumatic stress symptoms (PTSS). However, the relationship between vaccination, risk perception and PTSS has not been studied extensively. This study aims to examine the associations between the number of COVID-19 vaccine doses, consistency in the type of each dose and time since vaccination with PTSS, and the mediating role of risk perception on such relationships in China. STUDY DESIGN: Cross-sectional sampling with a self-report questionnaire was used to measure vaccination, PTSS and risk perception. METHODS: The survey was conducted in Beijing, China, from 13 January to 9 February 2023. Linear regression analyses were conducted to test the relationship between vaccination, risk perception and PTSS. RESULTS: The analysis included 55,803 individuals. In total, 72.86 % of participants received two doses of the COVID-19 vaccine. Regression results indicated that people with two doses of the COVID-19 vaccine had a lower level of PTSS (ß = -1.232, 95 % confidence interval [CI]: -1.930, -0.534) than those who had not received any doses of the COVID-19 vaccine. Only the negative relationship between two-dose vaccination and PTSS was mediated by risk perception, while the negative relationship between the time since vaccination and PTSS was suppressed by risk perception. CONCLUSIONS: This study showed that receiving the COVID-19 vaccine reduced PTSS by decreasing perceived risk. Vaccination time was negatively associated with PTSS, but this relationship was suppressed by risk perception.

[Clinical significance of immune checkpoint inhibitors in neoadjuvant therapy for gastric cancer].

Multiple prospective clinical studies have demonstrated that chemotherapy combined with immune checkpoint inhibitors (ICIs) can prolong the survival of patients with far-advanced gastric cancer. For patients with locally advanced gastric cancer (LAGC), preoperative neoadjuvant chemotherapy combined with immunotherapy has also achieved some encouraging results which benefit some patients, achieve clinical downstage, attenuate hidden metastases, increase R0 resection rate and reduce postoperative recurrence rate, etc. How to apply ICIs or combine immunotherapy with other therapies correctly in the course of neoadjuvant comprehensive treatment for patients with LAGC is still a very challenging and difficult problem. There are three basic principles in immunotherapy to be grasped: (1) Based on high-level clinical practice guidelines; (2) Based on the results of high-quality evidence-based medical research; and (3) Based on molecular pathology and tumor biomarkers. Perioperative immunotherapy for gastric cancer can be correctly applied if these three principles are organically integrated. Referring to the results of domestic and international clinical research in recent years, the three basic principles are demonstrated in this article for readers.

[Call for attention to the value and challenge of liquid biopsy in diagnosis and treatment for peritoneal metastasis of gastric cancer].

Peritoneal metastasis is the common route of metastasis in gastric cancer and is a major cause of death in advanced gastric cancer. Early intervention with comprehensive treatment can effectively improve the prognosis of some patients with peritoneal metastasis. However, early peritoneal metastasis in gastric cancer is predominantly micro-metastasis, which cannot be effectively evaluated by imaging studies. Moreover, the detection of disseminated cancer cells in peritoneal lavage suffers from a low detection rate and significant heterogeneity. In recent years, the development and application of new liquid biopsy technologies such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have provided new means to assess potential peritoneal metastasis at the cellular and molecular levels, gradually becoming research hotspots in this field. This review will summarize the relevant progress of liquid biopsy in peritoneal metastasis, which holds significant importance for improving the prognosis of gastric cancer patients in China.

[Clinical study of the Cobb+1 to Cobb fusion strategy for Lenke 5C adolescent idiopathic scoliosis patients with the lower lumbar apex].

Objective: To investigate the indications and surgical outcome of Cobb+1 to Cobb fusion strategy in Lenke 5C adolescent idiopathic scoliosis (AIS) patients with the lower lumbar apex. Methods: The clinical data of Lenke 5C AIS patients treated in Nanjing Drum Tower Hospital from August 2015 to December 2018 were retrospectively analyzed. The patients were followed-up for at least 2 years after surgery and treated with selective Cobb+1 to Cobb fusion strategy. The patients were divided into the normal lumbar apex group (apex location of the main curve was between T12 and L1) and the lower lumbar apex group (apex location of the main curve was below the disc of L1/L2). The occurrence of proximal decompensation in the two groups was compared. In addition, according to whether the patients had proximal decompensation at the last follow-up, the patients in the lower lumbar apex group were further divided into proximal decompensation group and non-decompensation group. The radiographic parameters and Scoliosis Research Society-22 (SRS-22) scores of the two groups were compared. Results: A total of 52 patients (19 cases in the normal lumbar apex group and 33 cases in the lower lumbar apex group), aged (15.3±1.6) years, were followed up for 2-5 (3.2±1.2) years. Six patients (6/19) in the normal lumbar apex group and 5 cases (15.2%) in the lower lumbar apex group showed proximal decompensation during follow-up, and the incidence was significantly higher in the normal lumbar apex group (P=0.034). Within the lower lumbar apex group, the patients with proximal decompensation (n=5) showed similar Risser grade, baseline thoracic Cobb angle, and main Cobb angle as those without proximal decompensation(n=28), and the differences were all not statistically significant (all P>0.05). However, the baseline thoracic/lumbar apical vertebra translation (AVT) ratio was significantly larger in patients with proximal decompensation (0.6±0.2 vs 0.4±0.2, P=0.042), but the postoperative upper instrumented vertebra (UIV) tilt angle was similar (4.5°±2.3° vs 6.2°±3.4°, P=0.312). Conclusion: Cobb+1 to Cobb fusion strategy, selecting UIV at 1 level above upper end vertebra (UEV), could be performed in Lenke 5C patients with the lower lumbar apex location. In addition, UIV could be selected at UEV+1 in patients with small baseline thoracic curve.

[Characteristics and clinical analysis of MLH1 c.463dupC gene mutation in a Lynch syndrome family].

In this study, a case of Lynch syndrome (LS) family line with a novel mutation site in the MLH1 c.463dupC gene was reported and the clinical and pathogenic genetic features of this family were analyzed. A 40-year-old female patient with colon cancer diagnosed at the First Affiliated Hospital of Kunming Medical University on October 2, 2020 was retrospectively included. The clinical data of the family were collected and the family lineage was drawn. The family tumor history met the Amsterdam Criteria Ⅱ and the diagnostic criteria of LS in Chinese, which was a typical LS family lineage. A germline code-shift missense mutation c.463dupC in the MLH1 gene located in exon 6, a possible pathogenic variant, was detected by second-generation sequencing (NGS) in the patient. Subsequently, Sanger sequencing was performed on a total of 20 direct lineage members of the family of the MLH1 gene, 7 cases were found to harbor the mutation and included in the LS high-risk control. Follow-up to October 2023 showed that the patient had endometrial and cervical polyps, one case had colorectal cancer, and two cases had intestinal polyps, all were treated with early intervention and therapy; two cases did not show any clinical symptoms. This study is the first to report a new mutation site for the potentially pathogenic MLH1 c.463dupC, providing a rationale for the pathogenicity of the mutation and standardized health management for familial carriers.

[Analysis of clinical and prognostic characteristics of newly diagnosed multiple myeloma with myelofibrosis patients].

Objective: To investigate the clinical and prognostic characteristics of newly diagnosed multiple myeloma (NDMM) patients with myelofibrosis (MF). Methods: The clinical data of 160 NDMM patients admitted to Henan Provincial People's Hospital from January 2012 to July 2022 were analyzed retrospectively. They were divided into MF group(n=74) and non-MF group(n=86) according to whether combined with MF. Patients in MF group were further splited into MF-1 group (n=47) and MF-2/3 group (n=27). All patients were treated with bortezomib and immunomodulatory-based combination therapy. The efficacy was evaluated after 4 courses, and the clinical features and prognosis between the two groups were compared. The deadline for follow-up was December 30, 2022 and the median follow-up period [M (Q1, Q3)] was 23.5 (14.4, 40.5) months. Kaplan-Meier method was used for survival analysis, and Cox regression model was used to analyze the influencing factors of survival. Results: Among 160 patients with NDMM, 91 were males and 69 were females, with a median age [M (Q1, Q3)] of 59 (54, 69) years. In MF group, the bone marrow immature plasma cell percentage, total plasma cell percentage were 9.6% (3.2%, 28.5%) and 36.4% (18.5%, 51.1%), respectively, which were higher than 6.0% (1.2%, 17.2%) and 24.0% (12.0%, 46.0%) of the non-MF group (both P<0.05). Hb level was 84.0(74.5, 100.5)g/L and PLT was (151.99±90.68) ×109/L in the MF group, which were lower than 96.0 (81.0, 112.0)g/L and (180.38±85.32) ×109/L of non-MF group (both P<0.05). But there were no significant differences in ISS stage, karyotypic and fluorescence in situ hybridization (FISH) high-risk genetic abnormalities between the two groups (all P>0.05). Objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were not significantly different between the two groups (all P>0.05). The rate of 17p- was 25.9% (7/27) in MF-2/3 group, which was higher than 8.1% (7/86) of non-MF group (P=0.049). The median OS of the MF-2/3 group was 25.0 (95%CI: 23.6-26.4) months, which was shorter than that of the non-MF group (54.0 months, P=0.031). Multivariate Cox regression analysis showed that grade MF-2/3 was not a risk factor for OS in NDMM patients (HR=1.507, 95%CI: 0.624-3.993, P=0.425). Conclusions: The ratio of bone marrow immature plasma cells and total plasma cells in NDMM patients with MF are higher than that in patients without MF, and the Hb and PLT are lower than that in patients without MF. NDMM patients with grade 2/3 MF have shorter survival than those without MF.

[Effect of different observations on evaluation of cosmetic shoulder balance in adolescent idiopathic scoliosis patients with thoracic curve].

Objective: To investigate the correlations between cosmetic and radiographic parameters of shoulder balance, as well as the variations in cosmetic shoulder balance observed from different perspectives, among patients with adolescent idiopathic scoliosis (AIS) characterized by thoracic curves. Methods: A total of 43 patients with thoracic curves treated from July to October in 2022 in Nanjing Drum Tower Hospital were recruited in this study. There were 9 males and 34 females with a mean age of (14.3±1.5) years. All participants underwent comprehensive radiographic assessments and were photographed both from posterior and anterior views, focusing on the shoulder region as well as a higher level (maintaining a consistent vertical distance of 180 cm from the ground). Six cosmetic parameters were measured on the photographs: shoulder angle(α1), axilla angle(α2), shoulder area index 1(SAI1), shoulder area index 2 (SAI2), inner shoulder height (SHi) and outer shoulder height (SHo). Eight radiographic parameters were measured on the radiographs: radiographic shoulder height difference (RSHD), first rib angle (FRA), clavicle-rib cage intersection (CRCI), coracoid process height (CPH), T1 tilt, clavicle angle(CA), clavicle chest cage angle difference (CCAD) and Cobb angle. Differences among bilateral cosmetic indicators from different perspectives were analyzed and compared, and their correlation with bilateral radiographic indicators was studied. Results: There was no significant differences between anterior cosmetic parameters and posterior cosmetic parameters at the same level of observation(all P>0.05). However, when observing SHi, SHo, α1, and α2 at the shoulder level, it became evident that they exhibited significantly higher values compared to the corresponding higher level on the same side of the patients' bodies. This contrast was observed in both the dorsal [SHo: (0.11±1.20) cm vs (-0.44±1.39) cm, P=0.005; SHi: (0.64±0.86) cm vs (0.32±0.56) cm, P=0.003; α1:-0.47°±2.27° vs -0.77°±2.49°, P=0.014; α2:-3.06°±3.23° vs -2.21°±3.03°, P=0.034] and ventral [SHo: (0.12±1.29) cm vs (-0.48±1.35) cm, P=0.007; SHi: (0.61±0.88) cm vs (0.30±0.59) cm, P=0.006; α1:-0.46°±2.18° vs -0.69°±2.35°, P=0.018; α2:-3.26°±3.12° vs -2.05°±2.97°, P=0.029] aspects of the patients. SHi and SHo were more sensitive to this difference of height. The correlation coefficients between radiographic parameters and cosmetic aspects at the shoulder level varied from 0.374 to 0.767. Similarly, the correlation coefficients between radiographic parameters and cosmetic factors at the higher level ranged from 0.273 to 0.579 (all P<0.05). Conclusions: The cosmetic parameters had significant difference between different perspective of observation, the cosmetic parameters are needed to be observed at the shoulder level in the evaluation of patients' shoulder balance.

[Influence of paraspinal muscle degeneration and postoperative Roussouly classification restoration on mechanical complications in female patients with degenerative scoliosis after surgery].

Objective: To investigate the impact of lumbar paraspinal muscle degeneration and postoperative failure to restore ideal Roussouly classification on the occurrence of mechanical complications (MC) following long-segment spinal correction surgery in female patients with degenerative scoliosis (DS). Methods: The clinical data of 72 female DS patients who underwent long-segment spinal correction surgery in Gulou Hospital from June 2017 to November 2021 were retrospectively analyzed. According to whether restoring the ideal Roussouly classification after surgery, the patients were divided into R group(recovery group) (n=51) and N group(non-recovery group) (n=21). According to whether mechanical complications occurred after operation within two years, the patients were divided into MC (mechanical complications)group (n=24) and NMC(non-mechanical complications) group (n=48). The RM group (n=14) experienced mechanical complications in the R group, while the RN group (n=37) did not. The NM group (n=10) experienced mechanical complications in the N group, while the NN group (n=11) did not.Radiographic assessment included Sagittal parameters of spine and pelvis, standardized cross-sectional area (SCSA) and fat infiltration rate (FI%) of paraspinal muscle at each lumbar disc level. Results: The age of DS patients in this study was (61.4±6.2) years.The incidence of MC was 33.33%(n=24)in all patients. The incidence of MC was 27.45%(n=14)in group R and 47.62%(n=10) in group N. The correction amount of pelvic tilt angle (PT) (-11.62°±10.06° vs -7.04°±8.45°, P=0.046) and T1 pelvic angle(TPA)(-12.88°±11.23° vs -7.31°±9.55°, P=0.031)during surgery were significantly higher in MC group compared to the NMC group. In group R, the FI% of paraspinal muscles in each lumbar segment of patients with postoperative MC was higher than that in patients without MC (P<0.05). In the R and N groups, there was no significant difference inthe SCSA of the lumbar paravertebral muscles between patients with postoperative MC and those without MC at each level (all P>0.05). Multivariate logistic regression analysis showed that the average FI% of lumbar PSM was correlated with the occurrence of MC after spinal fusion in DS patients.The average FI% of lumbar PSM≥22.63% was a risk factors for MC after spinal fusion (P=0.010,OR=1.088, 95%CI:1.020-1.160). Conclusions: Female DS patients with higher degree of preoperative paraspinal muscle degeneration have a higher incidence of postoperative mechanical complications. For these patients,.there is still a higher risk of mechanical complications after surgery even if the ideal Roussouly classification is restored after surgery.

[Association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40-89 in selected areas of China].

Objective: To investigate the association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40 to 89 years in selected areas of China. Methods: The research was based on the survey of the impact of soil quality of agricultural land on human health in typical areas conducted in 2019-2020. A total of 5 600 middle-aged and older adults aged 40 to 89 years were included by using a multi-stage stratified random sampling method. Baseline characteristics of the subjects were collected and physical examinations were performed. Random midstream urine was collected to measure urinary cadmium and urinary creatinine and fasting venous blood was collected to measure the leukocyte count, neutrophil count, lymphocyte count, monocyte count and eosinophil count. The linear mixed effect model was used to analyse the association of urinary cadmium levels with leukocyte classification counts, and the dose-response relationship between them was analyzed by using the restricted cubic spline (RCS) function. Results: The age of the subjects was (63.17±12.02) years; 2 851 (50.91%) were males; and the M (Q1, Q3) of urinary creatinine-corrected urinary cadmium levels was 2.69 (1.52, 4.69) µg/g·creatinine. After adjusting for confounding factors, the results of linear mixed effects model analysis showed that for each 1-unit increase in urinary creatinine-corrected urinary cadmium level, the percentage change [% (95%CI)] of leukocyte count and lymphocyte count was -1.70% (-2.61%, -0.79%) and -1.57% (-2.86%, -0.26%), respectively. RCS function showed a negative linear relationship between urinary creatinine-corrected urinary cadmium levels and leukocyte counts and lymphocyte counts, respectively (all Pnon-linear>0.05). Conclusion: Urinary cadmium levels are negatively associated with leukocyte count and lymphocyte count among middle-aged and older adults aged 40 to 89 years in selected areas of China.

[Epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023].

Objective: To understand the epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023. Methods: The data of this study were collected from the ARI surveillance data from 16 provinces in China from 2009 to 2023, with a total of 28 278 ARI cases included in the study. The clinical specimens from ARI cases were screened for HRSV nucleic acid from 2009 to 2023, and differences in virus detection rates among cases of different age groups, regions, and months were analyzed. Results: A total of 28 278 ARI cases were enrolled from January 2009 to September 2023. The age of the cases ranged from<1 month to 112 years, and the age M (Q1, Q3) was 3 years (1 year, 9 years). Among them, 3 062 cases were positive for HRSV nucleic acid, with a total detection rate of 10.83%. From 2009 to 2019, the detection rate of HRSV was 9.33%, and the virus was mainly prevalent in winter and spring. During the Corona Virus Disease 2019 (COVID-19) pandemic, the detection rate of HRSV fluctuated between 6.32% and 18.67%. There was no traditional winter epidemic peak of HRSV from the end of 2022 to the beginning of 2023, and an anti-seasonal epidemic of HRSV occurred from April to May 2023. About 87.95% (2 693/3 062) of positive cases were children under 5 years old, and the difference in the detection rate of HRSV among different age groups was statistically significant (P<0.001), showing a decreasing trend of HRSV detection rate with the increase of age (P<0.001). Among them, the HRSV detection rate (25.69%) was highest in children under 6 months. Compared with 2009-2019, the ranking of HRSV detection rates in different age groups changed from high to low between 2020 and 2023, with the age M (Q1, Q3) of HRSV positive cases increasing from 1 year (6 months, 3 years) to 2 years (11 months, 3 years). Conclusion: Through 15 years of continuous HRSV surveillance analysis, children under 5 years old, especially infants under 6 months old, are the main high-risk population for HRSV infection. During the COVID-19 pandemic, the prevalence and patterns of HRSV in China have changed.

[Subphenotypes and precision medicine in acute respiratory distress syndrome].

The presence of significant complex heterogeneity among patients with acute respiratory distress syndrome (ARDS) is a major reason for the failure of drug treatments. Precision medicine seeks to elucidate the potential mechanisms of ARDS heterogeneity, define subtypes of ARDS patients with specific characteristics, and rapidly identify the patient groups most likely to benefit from targeted treatments, thereby maximizing treatment efficiency and minimizing adverse reactions. This review discusses on the current state of research on ARDS subtypes from multiple perspectives, including etiology, onset time, radiology, pathology, oxygenation index, respiratory mechanics, protein biomarkers, genetics, transcriptomics, and microbiomics, with the aim of deepening the understanding of the pathogenesis of ARDS and thereby guiding precision treatment of ARDS.

[Role of mitochondrial autophagy and the curative effect of rehmannia glutinosa leaves total glycoside capsules on nucleos(t)ide drug-induced renal injury].

Objective: To study the curative effect of rehmannia glutinosa leaves total glycoside capsules and the role of mitochondrial autophagy on nucleos(t)ide drug-induced renal injury. Methods: Adefovir dipivoxil (ADV) was used to construct a hepatitis B virus (HBV) transgenic mouse model for renal injury. Renal function was measured in each group at one and two weeks of modeling. Mitochondrial autophagy indicators were measured at two weeks of modeling in renal tissue. Transmission electron microscopy was used to detect mitochondrial autophagy phenomena in renal tissue. The model was established for two weeks. Mouse with renal injury were treated with rehmannia glutinosa leaves total glycoside capsules or isotonic saline for eight weeks by intragastric administration. Renal function was measured. Renal tissue morphology was observed. Mitochondrial autophagy indicators were detected in renal tissue. The protective effect of different concentrations of verbascoside (the main active ingredient of rehmannia glutinosa capsule) was observed on HK-2 cell damage induced by ADV. HK-2 cells were divided into control, ADV, and ADV plus verbascoside groups. The effects of verbascoside at different times and concentrations were observed on the HK-2 mitochondrial autophagy indicators. Fifty patients with chronic hepatitis B were collected who presented with renal injury after treatment with nucleos(t)ide analogs. The random number method was used to divide 29 cases into a control group that received conventional treatment. The treatment group of 21 cases was treated with rehmannia glutinosa leaves total glycoside capsules on the basis of the control group. Serum creatinine (Scr) and urinary protein were detected at eight weeks.The χ(2) test or t-test was used for statistical analysis. Results: Compared with the control group, two weeks of modeling in the ADV group induced renal function injury in HBV mice. The expression of autophagy indicators was higher in the renal tissue of the ADV group than that of the control group. Transmission electron microscopy had revealed mitochondrial autophagy in the renal tissue of the ADV group. Compared with the control group, the renal function of HBV mice treated with rehmannia glutinosa leaves total glycoside capsules improved for two months, and the expressions of autophagy indicators were down-regulated.Verbascoside promoted proliferation in ADV-damaged HK-2 cells, and the expression of autophagy indicators was down-regulated compared with the ADV alone group. In 50 patients with renal function injury, the urinary protein improvement was significantly superior in the treatment group than that in the control group, with eighteen and three cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with a statistically significant difference (χ(2) = 9.975 0, P = 0.001 6). Serum creatinine was decreased in the treatment group compared with the control group, with 11 and 10 cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with no statistically significant difference (χ(2) = 0.593 5, P = 0.441 1). Conclusion: Rehmannia glutinosa leaves total glycoside capsule can improve the nucleos(t)ide drug-induced renal function injury in chronic hepatitis B, possibly playing a role via inhibiting PINK1/Parkin-mediated mitochondrial autophagy.

[Diagnostic value of whole blood cell parameters logistic regression model for radiation injury on radiation workers].

Objective: To explore the diagnostic value of whole blood cell parameters logistic regression model for radiation injury on radiation workers by comparing the differences of whole blood cell parameters between occupational radiation injury population and occupational health examination population. Methods: In February 2023, 184 radiation workers who received occupational health examinations in our hospital and occurrenced chromosome aberration from July 2021 to July 2022 were retrospectively selected as the radiation injury group. And other 184 radiation workers encountered in the same period without chromosome aberration occurrence were selected as the control group. Collected whole blood cell parameters from two groups of research subjects, conducted comparative analysis, constructed a logistic regression model, and evaluated the diagnostic value of the logistic regression model for radiation injury on radiation workers by receiver operating characteristic curve (ROC) and area under curve (AUC) . In addition, with the same standard, 60 radiation workers with chromosome aberration and 60 radiation workers without chromosome aberration from August 2022 to January 2023 were included in the validation queue to validate the logistic regression model. Results: Neu_X, Neu_Y, Neu_Z, Lym_X, Lym_Y, Lym_Z, Mon_X, Mon_Y, Mon_Z, Micro, MCHC in the radiation injury group were significantly higher than those in the control group, and the difference was statistically significant (P<0.05) . And MCV and Macro in the radiation injury group were lower than those in the control group, and the difference was statistically significant (P<0.05) . Moreover, logistic regression analysis showed that Lym_X, Lym_Y, Lym_Z, MCHC, Micro were all independent risk factors for diagnosing radiation injury on radiation workers (OR=1.08、1.02、0.99、1.06、51.32, P<0.05) . ROC curve analysis showed that the AUC, sensitivity, specificity, and accuracy of the logistic regression model based by Lym_X, Lym_Y, Lym_Z, MCHC and Micro in diagnosing radiation injury on radiation workers were 0.80, 85.9%, 65.8% and 75.9% respectively. The validation queue verified the logistic regression model and the AUC, sensitivity, specificity, and accuracy of the logistic regression model were 0.80, 81.7%, 71.7% and 76.7% respectively, the model fitted well. Conclusion: Radiation damage can cause changes in multiple whole blood cell parameters of radiation workers. The logistic regression model based by Lym_X, Lym_Y, Lym_Z, MCHC and Micro showed good diagnosis ability and can be used for the screening of radiation injury on radiation workers.

Prediction of knee pain improvement over two years for knee osteoarthritis using a dynamic nomogram based on MRI-derived radiomics: a proof-of-concept study.

OBJECTIVES: To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics. METHODS: Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model. RESULTS: The nomogram showed favorable discrimination performance [AUCtraining, 0.79 (95% CI: 0.72-0.79), AUCvalidation, 0.83 (95% CI: 0.70-0.96)] as well as a good calibration. Additional contributing value of fusion radiomics signature to the nomogram was statistically significant (NRI, 0.23; IDI, 0.14, P < 0.001 in training cohort and NRI, 0.29; IDI, 0.18, P < 0.05 in validating cohort). Decision curve analysis confirmed the clinical usefulness of nomogram. CONCLUSION: The radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Uniaxial cyclic stretch enhances osteogenic differentiation of OPLL-derived primary cells via YAP-Wnt/ß-catenin axis.

The pathogenesis of posterior longitudinal ligament ossification (OPLL) remains inadequately understood. Mechanical stimulation is one of the important pathogenic factors in OPLL. As one of the mechanical stimulation transduction signals, the yes-associated protein (YAP) interacts with the Wnt/ß-catenin signalling pathway, which plays an important role in osteogenic differentiation. This study aimed to demonstrate the role of YAP-Wnt/ß-catenin axis in cell differentiation induced by mechanical stress. Primary cells extracted from posterior longitudinal ligament tissues from OPLL or non-OPLL patients were subjected to sinusoidal uniaxial cyclic stretch (5 %, 0.5 Hz, 3 d). The expression of runt-related transcription factor 2, collagen I, osterix, osteocalcin and alkaline phosphatase were compared between the static and the experimental groups. In addition, the cytoskeleton was detected using phalloidin staining while YAP phosphorylation states and nuclear location were identified using immunofluorescence. The results showed that mechanical stretching loading increased the expression of osteogenic genes and proteins in the OPLL group, while it had no significant effect on the control group. When OPLL cells were stretched, YAP exhibited an obvious nuclear translocation and the Wnt/ß-catenin pathway was activated. Knocking down YAP or ß-catenin could weaken the impact upon osteogenic differentiation induced by mechanical stimulation. YAP-mediated mechanical stimulation promoted osteogenic differentiation of OPLL cells through Wnt/ß-catenin pathway and this progress was independent of the Hippo pathway.

Rheumatoid arthritis and the risk of major cardiometabolic diseases: a Mendelian randomization study.

OBJECTIVE: Rheumatoid arthritis (RA) is suggested to be implicated in the development of cardiometabolic diseases. We conducted a Mendelian randomization (MR) study to assess potential causality for associations of RA with the risk of cardiometabolic diseases, including type 2 diabetes (T2D), coronary artery disease (CAD), and ischaemic stroke. METHOD: Seventy independent single-nucleotide polymorphisms (SNPs) associated with RA were identified as instrumental variables from a genome-wide association study (GWAS) of 58 284 European subjects. Summary-level data for the associations of the 70 genetic variants with T2D, CAD, and ischaemic stroke were taken from three GWASs with a total of 1 529 131 participants. Inverse-variance weighted (IVW) MR was used in the main analyses. RESULTS: The main IVW MR analysis showed that genetically determined RA was associated with higher risks of T2D [odds ratio (OR): 1.04, 95% confidence interval (CI) 1.02-1.05; p < 0.001] and CAD (OR: 1.02, 95% CI 1.00-1.03; p = 0.012), but not ischaemic stroke (OR: 1.00, 95% CI 0.99-1.02; p = 0.961). Sensitivity analyses with multiple MR methods confirmed these associations. MR-Egger regression showed no evidence of pleiotropy in the association between genetically determined RA and the risk of T2D, CAD, and ischaemic stroke. Leave-one-out sensitivity analysis showed that the association between genetically determined RA and the risk of T2D, CAD, and ischaemic stroke was not driven by any individual SNP. CONCLUSION: Genetically determined RA was associated with increased risks of T2D and CAD, suggesting that RA plays a crucial role in the pathogenesis of T2D and CAD.

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.

CircOMA1 modulates cabergoline resistance by downregulating ferroptosis in prolactinoma.

PURPOSE: Prolactinomas are one of the most common pituitary neuroendocrine tumors (PitNETs), accounting for approximately 50% of all pituitary tumors. Dopamine agonists are the main treatment for prolactinoma, but a small number of patients are still resistant to pharmacotherapy. Recent discoveries have revealed that ferroptosis is involved in regulating tumor drug resistance. However, the role of ferroptosis in prolactinoma has not been reported. In this study, we aimed to explore the mechanism of a circRNA in ferroptosis in prolactinoma. METHODS: The expression of circOMA1 in prolactinoma tissues was examined by quantitative reverse transcription PCR (qRT-PCR). The biological function of circOMA1 was evaluated in vitro and in vivo. To explore the role of ferroptosis in prolactinoma, we used qRT-PCR and western blotting. Glutamate-cysteine ligase, modifier subunit (GCLM) was predicted to be a direct target gene of miR-145-5p by bioinformatics analysis, which was confirmed by luciferase reporter assays. RESULTS: circOMA1 was overexpressed in drug-resistant prolactinoma tissues compared with sensitive prolactinoma samples. We further found that circOMA1 promoted MMQ cells growth in vivo and in vitro. In addition, GCLM was directly targeted by miR-145-5p and indirectly regulated by circOMA1. Importantly, circOMA1 induced ferroptosis resistance through the increased expression of Nrf2, GPX4, and xCT, and circOMA1 attenuated CAB-induced ferroptosis in MMQ cells in vivo and in vitro. CONCLUSION: The present study demonstrates that circOMA1 attenuates CAB efficacy through ferroptosis resistance and may be a new therapeutic target for the individualized treatment of DA-resistant prolactinoma patients.