The role of gut microbiota involved in prostate microenvironment and symptoms improvement in chronic prostatitis/chronic pelvic pain syndrome patients treated with low-intensity extracorporeal shock wave.

BACKGROUND: Low-intensity extracorporeal shockwave therapy (Li-ESWT) is emerging as a promising and safe treatment for Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). In this study, we aimed to investigate the role of the gut microbiota involved in the prostate microenvironment and symptom improvement during the Li-ESWT for CP/CPPS patients. METHODS: CP/CPPS patients not taking antibiotics or other treatments were included. NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF-5) were used to evaluate the effectiveness of Li-ESWT at the end of treatment. Visual analogue scale/score was used to evaluate the pain during procedure. Stool and semen samples were collected before and after Li-ESWT. Shotgun metagenomics analyzed gut microbiota, while ELISA and other diagnostic kits detected biochemical changes in seminal plasma. RESULT: Of the 60 enrolled patients, 52 completed treatment. Li-ESWT response rate was 78.8% (41/52) at end of treatment. Among responders, the subitems of the NIH-CPSI; IPSS; and IIEF-5 scores improved significantly, and the seminal plasma analysis showed decreased TNF-a and MDA levels and increased SOD and Zn2+ levels posttreatment. Gut microbiome analysis indicated that posttreatment, both α and ß diversity increased, and the abundance of certain specific species significantly increased. Fifty-eight pathways significantly enriched posttreatment, notably in branched-chain amino acid synthesis and butyrate synthesis. The abundance of several specific species was found to be significantly higher in non-responders than responders. Among responders, at the species level, some bacteria associated with NIH-CPSI and its subscales, IPSS, IIEF-5, and prostate microenvironment markers (TNF-a, MDA, Zn2+, and SOD) were identified. CONCLUSIONS: Our study demonstrates for the first time that Li-ESWT improves the prostate microenvironment and gut microbiota in CP/CPPS patients. Treatment nonresponse may be associated with a high abundance of specific pathogens before treatment. The gut microbiota could have a significant impact on Li-ESWT response and the prostate microenvironment.

Kidney Outcomes Following Angiotensin Receptor-Neprilysin Inhibitor vs Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy for Thrombotic Microangiopathy.

Importance: Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established. Objective: To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA. Design, Setting, and Participants: This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023. Exposures: Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge. Main Outcomes and Measures: The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes. Results: Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison. Conclusions and Relevance: In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Insulin-like growth factor-1 deficiency caused by hepatocellular adenoma leads to growth arrest, primary amenorrhea and metabolic syndrome: a case report and 4 years follow up.

BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign neoplasm, seldom ascribed as the cause of endocrine and metabolic derangement. We herein report a case of primary amenorrhea, growth arrest and metabolic syndrome. En bloc resection of the tumor normalized all the disturbances. CASE PRESENTATION: A 16-year-old girl complained of primary amenorrhea and growth arrest for the past 2 years. Her height and weight were at the 3rd percentile, whereas waist circumference was at the 90th percentile for chronological age. She was hypertensive on admission. Plasma cholesterol, triglyceride and uric acid were elevated. Evaluation of GH/IGF-1 axis showed extremely low IGF-1 concentration, which was unresponsive to hGH stimulation. Computer tomography identified a huge liver mass (18.2 cm×13.7 cm×21 cm). The patient underwent an uneventful open right hepatic lobectomy. The tumor was en bloc resected. Immunohistochemistry indicated an unclassified HCA, which was confirmed by genetic screening. IGF-1 concentration, blood pressure, lipid profile and ovarian function were all normalized after surgery, and the girl had reduction in waist circumference and gain in height during the follow up. CONCLUSION: We provide evidence that liver-derived IGF-1 has a direct effect on skeletal and pubertal development, blood pressure, visceral adiposity and dyslipidemia independent of insulin resistance and obesity in the circumstance of undernutrition. Though rare, we propose the need to look into HCA cases for the existence of IGF-1 deficiency and its impact on metabolic derangement.

A multicenter cross-sectional study in China revealing the intrinsic relationship between medical students' grade and their perceptions of the learning environment.

BACKGROUND: Medical school learning environment (MSLE) has a holistic impact on students' psychosomatic health, academic achievements, and personal development. Students in different grades perceive MSLE in different ways. Thus, it is essential to investigate the specific role of student's grade in the perception of MSLE. METHODS: Using the Johns Hopkins Learning Environment Scale (JHLES) as a quantification instrument for the perception level of MSLE, 10,901 medical students in 12 universities in China were categorized into low or high JHLES group according to their questionnaires. We investigated the relationship between student's grade and JHLES category by univariate analysis employing Pearson Chi-square test and Welch's ANOVA. Then multivariable logistic regression analysis confirmed the predictive efficacy of student's grade. A nomogram concerning the prediction of low JHLES score probability in medical students was also constructed. RESULTS: A significant difference between two JHLES categories among students in different grades was observed (p < 0.001), with the proportion of the high JHLES group dominating in grade 1, 5, and the graduate subgroups (p < 0.001). The mean JHLES score declined especially in the third and fourth graders compared to freshmen (p < 0.001), while the mean score among the fifth graders had a remarkable rebound from the third graders (p < 0.001). Most imperatively, identified by multivariable logistic regression analysis, students in grade 3 (OR = 1.470, 95% CI = 1.265-1.709, p < 0.001) and 4 (OR = 1.578, 95% CI = 1.326-1.878, p < 0.001) perceived more negatively than freshmen. The constructed nomogram provided a promising prediction model for student's low JHLES score probability, with accuracy, accordance, and discrimination (area under the curve (AUC) = 0.627). CONCLUSION: The student's grade was a significant influencing factor in medical students' perception of MSLE. The perceptions among the third and fourth graders got worse, probably due to the worrying changes in various aspects of MSLE during that period. The relevant and appropriate interventions to improve medical students' perceptions are urgently needed.

Good learning environment of medical schools is an independent predictor for medical students' study engagement.

Background: Study engagement is regarded important to medical students' physical and mental wellbeing. However, the relationship between learning environment of medical schools and the study engagement of medical students was still unclear. This study was aimed to ascertain the positive effect of learning environment in study engagement. Methods: We collected 10,901 valid questionnaires from 12 medical universities in China, and UWES-S was utilized to assess the study engagement levels. Then Pearson Chi-Square test and Welch's ANOVA test were conducted to find the relationship between study engagement and learning environment, and subgroup analysis was used to eradicate possible influence of confounding factors. After that, a multivariate analysis was performed to prove learning environment was an independent factor, and we constructed a nomogram as a predictive model. Results: With Pearson Chi-Square test (p < 0.001) and Welch's ANOVA test (p < 0.001), it proved that a good learning environment contributed to a higher mean of UWES scores. Subgroup analysis also showed statistical significance (p < 0.001). In the multivariate analysis, we could find that, taking "Good" as reference, "Excellent" (OR = 0.329, 95%CI = 0.295-0.366, p < 0.001) learning environment was conducive to one's study engagement, while "Common" (OR = 2.206, 95%CI = 1.989-2.446, p < 0.001), "Bad" (OR = 2.349, 95%CI = 1.597-3.454, p < 0.001), and "Terrible" (OR = 1.696, 95%CI = 1.015-2.834, p = 0.044) learning environment only resulted into relatively bad study engagement. Depending on the result, a nomogram was drawn, which had predictive discrimination and accuracy (AUC = 0.680). Conclusion: We concluded that learning environment of school was an independent factor of medical student's study engagement. A higher level of learning environment of medical school came with a higher level of medical students' study engagement. The nomogram could serve as a predictive reference for the educators and researchers.

Efgartigimod-associated Kaposi's varicelliform eruption and herpetic conjunctivitis in a patient with seropositive ocular myasthenia gravis: a case report and review.

Background: Efgartigimod (Efgartigimod alpha fcab, Vyvgart™) is a pioneering neonatal Fc receptor (FcRn) antagonist for the treatment of severe autoimmune diseases mediated by pathogenic immunoglobulin G (IgG) autoantibodies, including myasthenia gravis (MG). It is a well-tolerated drug with minor side effects, such as headache and upper respiratory (lung) and urinary tract infections. Here, we present a case of Kaposi's varicelliform eruption (KVE) and herpetic conjunctivitis related to efgartigimod in a 60-year-old patient with ocular MG (OMG). Case description: A 60-year-old Chinese male suffered from acetylcholine receptor antibody positive (AChR Ab+) OMG for 8 years. During this period, he underwent first-line treatment with systemic corticosteroids, cyclosporine, cyclophosphamide, and so on, but had poor symptom improvement. On the recommendation of his attending neurologist, he received one cycle of intravenous efgartigimod (10mg/kg, once weekly for 4 weeks). The patient experienced fever, widespread painful blisters, and edema on the face on the third day after his last intravenous infusion. The patient also complained of increased secretions and a foreign body sensation in both eyes. Laboratory tests confirmed infection with herpes simplex virus (HSV). A diagnosis of efgartigimod-associated KVE and herpetic conjunctivitis was made. After intravenous administration (5mg/kg, 3 times a day, every 8 hours) for 10 days, the patient was cured without residual complications. Conclusions: This case is the first report of a patient with KVE and herpetic conjunctivitis related to efgartigimod in PubMed. This is rare and unusual. Clinicians should be alert to the rare symptoms related to efgartigimod.

[Efficiency of different large language models in China in response to consultations about PCa-related perioperative nursing and health education].

OBJECTIVE: To evaluate the efficiency of the four domestic language models, ERNIE Bot, ChatGLM2, Spark Desk and Qwen-14B-Chat, all with a massive user base and significant social attention, in response to consultations about PCa-related perioperative nursing and health education. METHODS: We designed a questionnaire that includes 15 questions commonly concerned by patients undergoing radical prostatectomy and 2 common nursing cases, and inputted the questions into each of the four language models for simulation consultation. Three nursing experts assessed the model responses based on a pre-designed Likert 5-point scale in terms of accuracy, comprehensiveness, understandability, humanistic care, and case analysis. We evaluated and compared the performance of the four models using visualization tools and statistical analyses. RESULTS: All the models generated high-quality texts with no misleading information and exhibited satisfactory performance. Qwen-14B-Chat scored the highest in all aspects and showed relatively stable outputs in multiple tests compared with ChatGLM2. Spark Desk performed well in terms of understandability but lacked comprehensiveness and humanistic care. Both Qwen-14B-Chat and ChatGLM2 demonstrated excellent performance in case analysis. The overall performance of ERNIE Bot was slightly inferior. All things considered, Qwen-14B-Chat was superior to the other three models in consultations about PCa-related perioperative nursing and health education. CONCLUSION: In PCa-related perioperative nursing, large language models represented by Qwen-14B-Chat are expected to become powerful auxiliary tools to provide patients with more medical expertise and information support, so as to improve the patient compliance and the quality of clinical treatment and nursing.

Network pharmacology and molecular docking reveal potential mechanisms of ginseng in the treatment of diabetes mellitus-induced erectile dysfunction and asthenospermia.

Diabetes mellitus (DM) is a chronic metabolic disease that predisposes to chronic damage and dysfunction of various organs, including leading to erectile dysfunction (ED) and asthenospermia. Literature suggests that ginseng plays an important role in the treatment and management of DM. Ginseng may have a therapeutic effect on the complications of DM-induced ED and asthenospermia. The study aimed to explore the mechanisms of ginseng in the treatment of DM-induced ED and asthenospermia following the Traditional Chinese Medicine (TCM) theory of "treating different diseases with the same treatment." This study used network pharmacology and molecular docking to examine the potential targets and pharmacological mechanism of Ginseng for the treatment of DM-induced ED and asthenospermia. The chemical ingredients and targets of ginseng were acquired using the Traditional Chinese Medicine Systems Pharmacology database and analysis platform. The targets of DM, ED, and asthenospermia were extracted with the GeneCards and Online Mendelian Inheritance in Man databases. A protein-protein interaction network analysis was constructed. The Metascape platform was applied for analyzing the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways. AutoDock Vina was used to perform molecular docking. Network pharmacology revealed that the main active components of the target of action were kaempferol, beta-sitosterol, ginsenoside rh2, stigmasterol, and fumarine. Core targets of the protein-protein interaction network included TNF, IL-1ß, AKT1, PTGS2, BCL2, and JUN. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that they were mainly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, Lipid and atherosclerosis. The interactions of core active components and targets were analyzed by molecular docking. Ginseng may play a comprehensive therapeutic role in the treatment of DM-induced ED and asthenospermia through "multicomponent, multi-target, and multi-pathway" biological mechanisms such as inflammation and oxidative stress.

A multi-classifier system integrated by clinico-histology-genomic analysis for predicting recurrence of papillary renal cell carcinoma.

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.

Clinicopathological phenotype and outcomes of NCAM-1+ membranous lupus nephritis.

INTRODUCTION: No studies explored the long-term outcomes of neural cell adhesion molecule 1 (NCAM1) associated membranous lupus nephritis (MLN) patients. METHOD: We performed immunohistochemical studies on kidney biopsy specimens against NCAM1 in consecutive MLN patients. The clinical and histopathological characteristics and outcomes of cases of NCAM1 associated MLN patients are described and compared with NCAM1 negative patients. In addition, we detected serum circulating anti-NCAM1 antibodies through western blotting and indirect immunofluorescence assays. RESULTS: Among 361 MLN cases, 18 (5.0%) were glomerular NCAM1-positive. NCAM1 positive MLN patients were older [35 years (IQR 27-43) versus 28 (22-37); P = 0.050) and had lower systemic lupus erythematosus disease activity index [11 (IQR 8-12) versus 14 (10-18); P = 0.007], serum creatinine [60 µmol/L (IQR 50-70) versus 70 (54-114); P = 0.029], activity index [3 (IQR 2-6) versus 6 (3-9); P = 0.045] at kidney biopsy compared with NCAM1 negative patients. The percentage of positive anti-Sjogren's syndrome related antigen A antibodies in NCAM1 positive patients was significantly greater (83.3% versus 58.2%; P = 0.035) than in the NCAM1 negative patients. However, no evidence of neuropsychiatric disorders was found in these 18 patients. There were no significant differences in the treatment response and the risk of end stage renal diseases between NCAM1 positive and negative groups (P = 0.668 and P = 0.318, respectively). But the risk of death was much higher in the NCAM1 positive group than the NCAM1 negative group (27.8% vs. 8.1%, P = 0.007). Moreover, the risk of death was also much higher in the NCAM1 positive group than the matched NCAM1 negative group (Log-rank P = 0.013). Additionally, circulating anti-NCAM1 antibodies can be detected in 1/5 (20%) patients who had serum available. CONCLUSION: The prevalence of NCAM1 positivity was 5.0% in our cohort of MLN and the high mortality in these subgroup patients are needed to validate in future studies.

Annexin A1 protects epidermal stem cells against ultraviolet-B irradiation-induced mitochondrial dysfunction.

Ultraviolet-B (UV-B) radiation overexposure causes function impairment of epidermal stem cells (ESCs). We explored the mechanism of Annexin A1 (ANXA1) ameliorating UV-B-induced ESC mitochondrial dysfunction/cell injury. ESCs were cultured in vitro and irradiated with different doses of UV-B. Cell viability/ANXA1 protein level were assessed. After oe-ANXA1 transfection, ESCs were treated with oe-ANXA1/UV-B irradiation/CCCP/CCG-1423/3-methyladenine for 12 h. Cell viability/death, and adenosine triphosphate (ATP)/reactive oxygen species (ROS) levels were determined. Mitochondrial membrane potential (MMP) changes/DNA (mtDNA) content/oxygen consumption and RhoA activation were assessed. ROCK1/p-MYPT1/MYPT1/(LC3BII/I)/Beclin-1/p62 protein levels were determined. Mitochondrial morphology was observed. Mito-Tracker Green (MTG) and LC3B levels were determined. UV-B irradiation decreased cell viability/ANXA1 expression in a dose-dependent manner. UV-B-treated ESCs exhibited reduced cell viability/ATP content/MMP level/mitochondrial respiratory control ratio/mtDNA number/RhoA activity/MYPT1 phosphorylation/MTG+LC3B+ cells/(LC3BII/I) and Beclin-1 proteins, increased cell death/ROS/p62/IL-1ß/IL-6/TNF-α expression, contracted mitochondrial, disappeared mitochondrial cristae, and increased vacuolar mitochondria, which were averted by ANXA1 overexpression, suggesting that UV-B induced ESC mitochondrial dysfunction/cell injury/inflammation by repressing mitophagy, but ANXA1 promoted mitophagy by activating the RhoA/ROCK1 pathway, thus repressing UV-B's effects. Mitophagy activation ameliorated UV-B-caused ESC mitochondrial dysfunction/cell injury/inflammation. Mitophagy inhibition partly diminished ANXA1-ameliorated UV-B's effects. Conjointly, ANXA1 promoted mitophagy by activating the RhoA/ROCK1 pathway, thereby improving UV-B-induced ESC mitochondrial dysfunction/cell injury.

Empathy in undergraduate medical students: a multi-center cross-sectional study in China.

BACKGROUND: Fostering empathy has been continuously emphasized in the global medical education. Empathy is crucial to enhance patient-physician relationships, and is associated with medical students' academic and clinical performance. However, empathy level of medical students in China and related influencing factors are not clear. METHODS: This was a cross-sectional study among medical students in 11 universities. We used the Jefferson Scale of Empathy Student-version of Chinese version to measure empathy level of medical students. Factors associated with empathy were identified by the univariate and multivariate logistic regression analyses. Based on the variables identified above, the nomogram was established to predict high empathy probability of medical students. Receiver operating characteristic curve, calibration plot and decision curve analysis were used to evaluate the discrimination, calibration and educational utility of the model. RESULTS: We received 10,901 samples, but a total of 10,576 samples could be used for further analysis (effective response rate of 97.02%). The mean empathy score of undergraduate medical students was 67.38 (standard deviation = 9.39). Six variables including gender, university category, only child or not, self-perception doctor-patient relationship in hospitals, interest of medicine, Kolb learning style showed statistical significance with empathy of medical students (P < 0.05). Then, the nomogram was established based on six variables. The validation suggested the nomogram model was well calibrated and had good utility in education, as well as area under the curve of model prediction was 0.65. CONCLUSIONS: We identify factors influencing empathy of undergraduate medical students. Moreover, increasing manifest and hidden curriculums on cultivating empathy of medical students may be needed among medical universities or schools in China.

Glomerular Exostosin-Positivity is Associated With Disease Activity and Outcomes in Patients With Membranous Lupus Nephritis.

Introduction: The relationship of exostosin 1 and exostosin 2 (EXT1/EXT2) expression and outcomes in membranous lupus nephritis (MLN) was controversial. Methods: EXT1/EXT2 was performed by immunohistochemistry (IHC) in 283 consecutive patients with MLN. Clinicopathological characteristics and outcomes of EXT1/EXT2-positive patients were compared with EXT1/EXT2-negative patients. The primary end points were adverse renal events, including death, dialysis, and renal transplantation. Results: Of the patients with MLN, 29.3% were positive for EXT1/EXT2. The prevalence of EXT1/2-positive MLN was significantly higher in pure class V MLN than those for mixed class V MLN (44.2% vs. 19.4%, P < 0.001). For EXT1/EXT2-positive patients, the median time between onset of lupus and renal biopsy, and lupus nephritis and renal biopsy is shorter (6 [interquartile range, IQR: 2-25] months vs. 12 [IQR: 3-49] months, P = 0.008 and 3 [IQR: 2-18] months vs. 6 [IQR: 2-23] months, P = 0.039) and they had significantly lower systemic lupus erythematosus Disease Activity Index (SLEDAI) scores (P = 0.015) and lower serum creatinine levels (P < 0.001), higher hemoglobin (P = 0.006) as well as lower blood pressure. The EXT1/EXT2-positive patients had significantly fewer chronicity features (glomerulosclerosis, P < 0.001; interstitial fibrosis, P = 0.006; and tubular atrophy, P = 0.002) and fewer activity indicators (endocapillary hypercellularity, P = 0.012; cellular crescents, P = 0.007; and fibrocellular crescents, P < 0.001) on renal biopsy. After a median follow-up of 65 (28-126) months, EXT1/EXT2-positive patients were less likely to experience adverse renal events (2.4% vs. 16.0%, P = 0.001). Conclusion: Compared with EXT1/EXT2-negative patients, the EXT1/EXT2-positive patients presented with lower disease activity and were less likely to experience adverse renal events in relationship with the chronicity index.

Enhancing antitumor response by efficiently generating large-scale TCR-T cells targeting a single epitope across multiple cancer antigens.

The need to contrive interventions to curb the rise in cancer incidence and mortality is critical for improving patients' prognoses. Adoptive cell therapy is challenged with quality large-scale production, heightening its production cost. Several cancer types have been associated with the expression of highly-immunogenic CTAG1 and CTAG2 antigens, which share common epitopes. Targeting two antigens on the same cancer could improve the antitumor response of TCR-T cells. In this study, we exploited an efficient way to generate large-fold quality TCR-T cells and also demonstrated that the common epitopes of CTAG1 and CTAG2 antigens provide an avenue for improved cancer-killing via dual-antigen-epitope targeting. Our study revealed that xeno/sera-free medium could expand TCR-T cells to over 500-fold, posing as a better replacement for FBS-supplemented media. Human AB serum was also shown to be a good alternative in the absence of xeno/sera-free media. Furthermore, TCR-T cells stimulated with beads-coated T-activator showed a better effector function than soluble T-activator stimulated TCR-T cells. Additionally, TCR-T cells that target multiple antigens in the same cancer yield better anticancer activity than those targeting a single antigen. This showed that targeting multiple antigens with a common epitope may enhance the antitumor response efficacy of T cell therapies.

Network analysis of the comorbidity between post-traumatic stress, depression and anxiety symptoms among frontline healthcare workers during the COVID-19 pandemic.

Background: Coronavirus disease 2019 pandemic pointed out significant mental symptoms of frontline healthcare workers (HCWs). Objective: We aimed to estimate the prevalence and comorbidity of post-traumatic stress symptoms (PTSS), depression and anxiety symptoms in HCWs from Fangcang shelter hospitals during the pandemic. Design: Demographic information, post-traumatic stress disorder checklist for DSM-5 (PCL-5), Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Questionnaire (GAD-7) were obtained online based on stratified random sampling design during April 2022, with 284 eligible responses. Method: Hierarchical regression analyses were applied to investigate independent variables associated with psychological status outcomes (PHQ-9, GAD-7 and PCL-5), and the network analyses were applied to explore the comorbidity using all items of PCL-5, PHQ-9 and GAD-7. Results: (1) 10.56%, 13.03% and 8.10% of HCWs reported PTSS, depression and anxiety symptoms. Fifty-three (18.66%) HCWs experienced at least one mental health disorder, among which 26.42-37.74% HCWs had comorbidity of two or three mental disorders; (2) several influence factors of mental health were identified, including medical professions, working hours, contacted patients (p < 0.05); (3) prominent bridge symptoms between PTSS and depression were sleep problems, suicide ideation, concentration difficulties and recklessness. Comorbidity between PTSS and anxiety was thought to mainly stem from negative affect, such as afraid, anxious, annoyed and worrying. Depressed mood and worry might be good targets during treatment of comorbidity of depression and anxiety. Conclusion: Our data suggest mild level of PTSS, depression and anxiety symptoms among HCWs during the pandemic and might give novel insights into assessment and intervention of comorbidity.

A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS: Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS: The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS: TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

Clinical evaluation of pulmonary quantitative computed tomography parameters for diagnosing eosinophilic chronic obstructive pulmonary disease: Characteristics and diagnostic performance.

Aims: To investigate the characteristics and diagnostic performance of quantitative computed tomography (QCT) parameters in eosinophilic chronic obstructive pulmonary disease (COPD) patients. Methods: High-resolution CT scans of COPD patients were retrospectively analyzed, and various emphysematous parenchyma measurements, including lung volume (LC), lung mean density (LMD), lung standard deviation (LSD), full-width half maximum (FWHM), and lung relative voxel number (LRVN) were performed. The QCT parameters were compared between eosinophilic and noneosinophilic COPD patients, using a definition of eosinophilic COPD as blood eosinophil values ≥ 300 cells·µL-1 on at least three times. Receiver operating characteristic curves and area under the curve (ROC-AUC) and python were used to evaluate discriminative efficacy of QCT. Results: Noneosinophilic COPD patients had a significantly lower TLMD (-846.3 ± 47.9 Hounsfield Unit [HU]) and TFWHM(162.5 ± 30.6 HU) compared to eosinophilic COPD patients (-817.8 ± 54.4, 177.3 ± 33.1 HU, respectively) (p = 0.018, 0.03, respectively). Moreover, the total LC (TLC) and TLSD were significantly lower in eosinophilic COPD group (3234.4 ± 1145.8, 183.8 ± 33.9 HU, respectively) than the noneosinophilic COPD group (5600.2 ± 1248.4, 203.5 ± 20.4 HU, respectively) (p = 0.009, 0.002, respectively). The ROC-AUC values for TLC, TLMD, TLSD, and TFWHM were 0.91 (95% confidence interval [CI], 0.828-0.936), 0.66 (95% CI, 0.546-0.761), 0.64 (95% CI, 0.524-0.742), and 0.63 (95% CI, 0.511-0.731), respectively. When the TLC value was 4110 mL, the sensitivity was 90.7% (95% CI, 79.7-96.9), specificity was 77.8% (95% CI, 57.7-91.4) and accuracy was 86.4%. Notably, TLC demonstrated the highest discriminative efficiency with an F1 Score of 0.79, diagnostic Odds Ratio of 34.3 and Matthews Correlation Coefficient of 0.69, surpassing TLMD (0.55, 3.66, 0.25), TLSD (0.56, 3.95, 0.26), and TFWHM (0.56, 4.16, 0.33). Conclusion: Eosinophilic COPD patients exhibit lower levels of emphysema and a more uniform density distribution throughout the lungs compared to noneosinophilic COPD patients. Furthermore, TLC demonstrated the highest diagnostic efficiency and may serve as a valuable diagnostic marker for distinguishing between the two groups.

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route.

BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC. METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells. RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast. CONCLUSION: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

Baohuoside I suppresses the NLRP3 inflammasome activation via targeting GPER to fight against Parkinson's disease.

BACKGROUND: Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS: The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS: Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1ß) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION: Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.