Single-cell analysis via manifold fitting: A framework for RNA clustering and beyond.

Single-cell RNA sequencing (scRNA-seq) data, susceptible to noise arising from biological variability and technical errors, can distort gene expression analysis and impact cell similarity assessments, particularly in heterogeneous populations. Current methods, including deep learning approaches, often struggle to accurately characterize cell relationships due to this inherent noise. To address these challenges, we introduce scAMF (Single-cell Analysis via Manifold Fitting), a framework designed to enhance clustering accuracy and data visualization in scRNA-seq studies. At the heart of scAMF lies the manifold fitting module, which effectively denoises scRNA-seq data by unfolding their distribution in the ambient space. This unfolding aligns the gene expression vector of each cell more closely with its underlying structure, bringing it spatially closer to other cells of the same cell type. To comprehensively assess the impact of scAMF, we compile a collection of 25 publicly available scRNA-seq datasets spanning various sequencing platforms, species, and organ types, forming an extensive RNA data bank. In our comparative studies, benchmarking scAMF against existing scRNA-seq analysis algorithms in this data bank, we consistently observe that scAMF outperforms in terms of clustering efficiency and data visualization clarity. Further experimental analysis reveals that this enhanced performance stems from scAMF's ability to improve the spatial distribution of the data and capture class-consistent neighborhoods. These findings underscore the promising application potential of manifold fitting as a tool in scRNA-seq analysis, signaling a significant enhancement in the precision and reliability of data interpretation in this critical field of study.

A novel nomogram to predict testicular torsion in children with acute scrotal pain: a single-center retrospective study in western China.

Background: Acute scrotal pain (ASP) is the most common urological emergency in pediatrics, and its causes include testicular torsion (TT), testicular appendage torsion, and epididymo-orchitis. Among them, TT requires prompt and accurate diagnosis and urgent surgical exploration to prevent testicular loss. Conservative anti-infective treatment is recommended for epididymo-orchitis, and surgery is considered only when scrotal abscess formation and sepsis occur. Improving the understanding of TT in primary care doctors, early diagnosis, and timely surgical exploration are essential to improve the survival rate of TT and avoid excessive treatment. This study aimed to explore the risk factors for TT in children with ASP and construct a predictive model. Methods: Clinical data of children who presented with ASP and underwent emergency scrotal exploration surgery were retrospectively analyzed, including general information, physical examination, laboratory tests, and color Doppler ultrasonography (CDU) findings. Based on surgical exploration, the outcomes were categorized as confirmed TT or not. Results: A total of 283 children were included in this study, among whom 134 had TT. The mean age of all patients was 105±47.9 months, with the majority being of Han ethnicity (87.6%) and residing in urban areas (83%). Most patients had normal C-reactive protein levels and negative results in urine routine white blood cell tests (63.3%). After conducting univariate and multivariate logistic regression analyses, we identified laterality, neutrophil count, mean erythrocyte sedimentation rate, epididymal blood flow signal, testicular parenchymal echogenicity, and testicular blood flow signal as independent risk factors influencing the occurrence of TT in ASP patients. Conclusions: This study is the report with the largest sample size on the construction of prediction models for ASP in children in southwestern China. The predictive model we developed demonstrated excellent performance and higher accuracy in predicting TT in children compared to the traditional Testicular Workup for Ischemia and Suspected Torsion (TWIST) score. It can assist pediatric surgeons in diagnosing and treating children with ASP.

Tumor microenvironment characteristics association with clinical outcome in patients with resected intestinal-type gastric cancer.

BACKGROUND: Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. METHODS: TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. RESULTS: Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). CONCLUSIONS: Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.

Enhancing clinical decision-making: A novel nomogram for stratifying cancer-specific survival in middle-aged individuals with follicular thyroid carcinoma utilizing SEER data.

Background: Thyroid cancer (TC) is the most common malignant tumor in the endocrine system, is also one of the head and neck tumor. Follicular Thyroid Carcinoma (FTC) plays an important role in the pathological classification of thyroid cancer. This study aimed to develop an innovative predictive tool, a nomogram, for predicting cancer specific survival (CSS) in middle-aged FTC patients. Methods: We collected patient data from the Surveillance, Epidemiology, and End Results (SEER) database. The data from patients between 2004 and 2015 were used as the training set, and the data from patients between 2016 and 2018 were used as the validation set. To identify independent risk factors affecting patient survival, univariate and multivariate Cox regression analyses were performed. Based on this, we developed a nomogram model aimed at predicting CSS in middle-aged patients with FTC. The consistency index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and the calibration curve were used to evaluate the accuracy and confidence of the model. Results: A total of 2470 patients were enrolled in this study, in which patients from 2004 to 2015 were randomly assigned to the training cohort (N = 1437) and validation cohort (N = 598), and patients from 2016 to 2018 were assigned to the external validation cohort (N = 435) in terms of time. Univariate and multivariate Cox regression analysis showed that marriage, histological grade and TNM stage were independent risk factors for survival. The C-index for the training cohort was 0.866 (95 % CI: 0.805-0.927), for the validation cohort it was 0.944 (95 % CI: 0.903-0.985), and for the external validation cohort, it reached 0.999 (95 % CI: 0.997-1.001). Calibration curves and AUC suggest that the model has good accuracy. Conclusions: We developed an innovative nomogram to predict CSS in middle-aged patients with FTC. Our model after a rigorous internal validation and external validation process, based on the time proved that the high level of accuracy and reliability. This tool helps healthcare professionals and patients make informed clinical decisions.

Naoxueshu Oral Liquid Accelerates Post-Craniotomy Hematoma Absorption in Patients: An Open-Label, Multicenter, and Randomized Controlled Trial.

OBJECTIVE: To investigate whether Naoxueshu Oral Liquid (NXS) could promote hematoma absorption in post-craniotomy hematoma (PCH) patients. METHODS: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18-80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS (10 mL thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage (ICH). RESULTS: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients (60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set (FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median (Q1, Q3): 85% (71%, 97%) vs. 76% (53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set (P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH (all P<0.05). CONCLUSIONS: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics. (Registration No. ChiCTR1800017981).

Evaluation of stromal myofibroblasts in oral submucous fibrosis and its malignant transformation: An immunohistochemical study.

BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous lesion, with oral squamous cell carcinoma (OSCC) being the most prevalent malignancy affecting the oral mucosa. The malignant transformation of OSF into OSCC is estimated to occur in 7-13% of cases. Myofibroblasts (MFs) play pivotal roles in both physiological and pathological processes, such as wound healing and tumorigenesis, respectively. This study aimed to explore the involvement of MFs in the progression of OSF and its malignant transformation. MATERIALS AND METHODS: In total, 94 formalin-fixed paraffin-embedded tissue blocks were collected, including normal oral mucosa (NOM; n = 10), early-moderate OSF (EMOSF; n = 29), advanced OSF (AOSF; n = 29), paracancerous OSF (POSF; n = 21), and OSCC (n = 5) samples. Alpha-smooth muscle actin was used for the immunohistochemical identification of MFs. RESULTS: NOM exhibited infrequent expression of MFs. A higher staining index of MFs was found in AOSF, followed by EMOSF and NOM. Additionally, a significant increase in the staining index of MFs was found from EMOSF to POSF and OSCC. The staining index of MFs in NOM, EMOSF, AOSF, POSF, and OSCC was 0.14 ± 0.2, 1.69 ± 1.4, 2.47 ± 1.2, 3.57 ± 2.6, and 8.86 ± 1.4, respectively. All results were statistically significant (P < 0.05). CONCLUSIONS: The expression of MFs exhibited a gradual increase as the disease progressed from mild to malignant transformation, indicating the contributory role of MFs in the fibrogenesis and potential tumorigenesis associated with OSF.

Sex and age disparities in multi-metal mixture exposure and cognitive impairment in urban elderly individuals: The mediation effect and biological function of metabolites.

Studies on the relationships between metal mixtures exposure and cognitive impairment in elderly individuals are limited, particularly the mechanism with metabolite. Few studies are available on the potential sex and age specific associations between metal exposure, metabolites and cognitive impairment. We examined plasma metal and blood metabolite concentrations among 1068 urban elderly participants. Statistical analysis included a battery of variable selection approaches, logistic regression for metal/metabolite associations, and Bayesian kernel machine regression (BKMR) to identify mixed effects of metals/metabolites on cognitive impairment risk. Our results showed that As was positively associated with cognitive impairment in the female (OR 95 % CI = 2.21 (1.36, 3.57)) and 60- to 70-year-old (OR 95 % CI = 2.60 (1.54, 4.41)) groups, Cr was positively associated with cognitive impairment in the male (OR 95 % CI = 2.15 (1.27, 3.63)) and 60- to 70-year-old (OR 95 % CI = 2.10 (1.24, 3.57)) groups, and Zn was negatively associated with cognitive impairment, especially in the female (OR 95 % CI = 0.46 (0.25, 0.84)), 60- to 70-year-old (OR 95 % CI =0.24 (0.12, 0.45)) and ≥ 80-year-old (OR 95 % CI = 0.19 (0.04, 0.86)) groups. Positive associations were observed between combined metals (Cr, Cu and As) and cognitive impairment, but Zn alleviated this tendency, especially in elderly individuals aged ≥80 years. Negative associations were observed between metabolites and cognitive impairment, especially in male, female and 60-70 years old groups. The mediation effects of metabolites on the association between metal exposure and cognitive impairment were observed, and the percentages of these effects were 15.60 % (Glu-Cr), 23.00 % (C5:1-Cu) and 16.36 % (Glu-Zn). Cr, Cu, and Zn could increase cognitive impairment risk through the "Malate-Aspartate Shuttle", "Glucose-Alanine Cycle", etc., pathways. Overall, we hypothesize that metabolites have mediation effects on the relationship between multi-metal exposure and cognitive impairment and that there are sex and age differences.

Brain tissue heterotopic in the adrenal gland in a child: a scarce case report.

Heterotopic brain tissue is rare and has not been reported. Our center made the first report. 4 years and 2 months old Girl presented with a cystic mass in the right adrenal gland 2 weeks after right upper abdominal pain. The operation was successful, and the diagnosis was confirmed by postoperative pathology. 6 months after the procedure, the incision healed well without recurrence. This case report has a detailed diagnosis and treatment process and satisfactory examination results. It can provide a reference for diagnosing and treating clinical HBT and reduce the risk of misdiagnosis and mistreatment.

Manifold fitting with CycleGAN.

Manifold fitting, which offers substantial potential for efficient and accurate modeling, poses a critical challenge in nonlinear data analysis. This study presents an approach that employs neural networks to fit the latent manifold. Leveraging the generative adversarial framework, this method learns smooth mappings between low-dimensional latent space and high-dimensional ambient space, echoing the Riemannian exponential and logarithmic maps. The well-trained neural networks provide estimations for the latent manifold, facilitate data projection onto the manifold, and even generate data points that reside directly within the manifold. Through an extensive series of simulation studies and real data experiments, we demonstrate the effectiveness and accuracy of our approach in capturing the inherent structure of the underlying manifold within the ambient space data. Notably, our method exceeds the computational efficiency limitations of previous approaches and offers control over the dimensionality and smoothness of the resulting manifold. This advancement holds significant potential in the fields of statistics and computer science. The seamless integration of powerful neural network architectures with generative adversarial techniques unlocks possibilities for manifold fitting, thereby enhancing data analysis. The implications of our findings span diverse applications, from dimensionality reduction and data visualization to generating authentic data. Collectively, our research paves the way for future advancements in nonlinear data analysis and offers a beacon for subsequent scholarly pursuits.

Correlation Between Risk Factors, Degree of Vascular Restenosis, and Inflammatory Factors After Interventional Treatment for Stroke: A Two-Center Retrospective Study.

OBJECTIVE: To study the correlation between risk factors, degree of vascular restenosis, and inflammatory factors after interventional treatment for stroke. METHODS: The clinical data of 96 stroke patients who received interventional therapy in our hospital from April 2020 to June 2021 were selected for retrospective study, and the postoperative follow-up was 1 year. Univariate and multivariate regression were used to analyze identified factors associated with interventional stroke efficacy. At the same time, the value of inflammatory factor levels in predicting vascular restenosis after interventional stroke was analyzed. RESULTS: According to our findings, several risk factors, including body mass index ≥ 25.51 kg/m 2 , smoking, drinking, hypertension, and diabetes, were identified as contributors to poor postoperative efficacy following stroke intervention ( P <0.05). Furthermore, a notable association was observed between the severity of vascular stenosis ( P <0.001) and the levels of interleukin 6, interleukin 2, TNF-α, and C-reactive protein. The combined assessment of these serum inflammatory factors exhibited excellent predictive capability for postoperative vascular restenosis and stenosis severity, yielding a sensitivity of 84.30%, a specificity of 81.20%, and an area under the curve of 0.882. CONCLUSIONS: Obesity, smoking, alcohol consumption, hypertension, and diabetes have been found to be associated with suboptimal outcomes following interventional treatment for stroke. The assessment of preoperative levels of inflammatory factors holds promise in predicting the likelihood of postoperative restenosis to a certain degree.

Predicting Progestin Therapy Response With PTEN, PAX2, and ß-Catenin in Patients With Endometrioid Precancer.

This study investigates the predictive value of biomarkers PTEN, PAX2, and ß-catenin for therapeutic outcomes in patients with atypical endometrial hyperplasia or endometrioid intraepithelial neoplasia undergoing progestin therapy. In a retrospective study of 128 patients, we analyzed a total of 351 endometrial biopsy samples and categorized outcomes into responders (absence of residual disease) and nonresponders (presence of residual disease). We found aberrant biomarker expression in pretreatment cases: 48% for PTEN, 65% for PAX2, and 36% for ß-catenin. Approximately 77.3% of patients responded to progestin treatment, with nonresponders showing significantly higher initial PTEN loss (75.86% vs 39.79%, P < 0.001). Nonresponders also demonstrated significant PTEN loss (53.33% vs 20.55%, P < 0.001), PAX2 loss (57.33% vs 41.22%, P < 0.05), and ß-catenin nuclear staining (53.45% vs 27.91%, P < 0.01) in follow-up samples. In addition, nonresponders exhibited lower recovery of intact PTEN and PAX2, along with higher ß-catenin aberrancy in cases initially showing normal ß-catenin levels. We conclude that persistent aberrant PTEN and PAX2 expression, coupled with emerging aberrant ß-catenin in follow-ups, indicates a greater likelihood of treatment failure. Conversely, the absence of these aberrations suggests successful progestin therapy. Our findings highlight the utility of this 3-marker panel in assessing residual disease status and predicting progestin treatment outcomes, thus offering critical insights for patient management.

Prognostic significance of surgery and radiotherapy in elderly patients with localized prostate cancer: establishing and time-based external validation a nomogram from SEER-based study.

OBJECTIVE: Prostate cancer (PC) is a significant disease affecting men's health worldwide. More than 60% of patients over 65 years old and more than 80% are diagnosed with localized PC. The current choice of treatment modalities for localized PC and whether overtreatment is controversial. Therefore, we wanted to construct a nomogram to predict the risk factors associated with cancer-specific survival (CSS) and overall survival (OS) in elderly patients with localized PC while assessing the survival differences in surgery and radiotherapy for elderly patients with localized PC. METHODS: Data of patients with localized PC over 65 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models were used to determine independent risk factors for CSS and OS. Nomograms predicting CSS and OS were built using multivariate Cox regression models. The consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve were used to test the accuracy and discrimination of the prediction model. Decision curve analysis (DCA) was used to test the potential clinical value of this model. RESULTS: A total of 90,434 patients over 65 years and diagnosed with localized PC from 2010 to 2018 were included in the study. All patients were randomly assigned to the training set (n = 63,328) and the validation set (n = 27,106). Univariate and multivariate Cox regression model analysis showed that age, race, marriage, T stage, surgical, radiotherapy, prostate-specific antigen (PSA), and Gleason score (GS) were independent risk factors for predicting CSS in elderly patients with localized PC. Age, race, marriage, surgery, radiotherapy, PSA, and GS were independent risk factors for predicting OS in elderly patients with localized PC. The c-index of the training and validation sets for the predicted CSS is 0.802(95%CI:0.788-0.816) and 0.798(95%CI:0.776-0.820, respectively). The c-index of the training and validation sets for predicting OS is 0.712(95%:0.704-0.720) and 0.724(95%:0.714-0.734). It shows that the nomograms have excellent discriminatory ability. The AUC and the calibration curves also show good accuracy and discriminability. CONCLUSION: We have developed new nomograms to predict CSS and OS in elderly patients with localized PC. After internal validation and external temporal validation with reasonable accuracy, reliability and potential clinical value, the model can be used for clinically assisted decision-making.

Clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in Chinese population with mismatch repair deficient urothelial carcinoma: a real-world study.

Urothelial carcinoma (UC) with deficient mismatch repair (dMMR) is a specific subtype of UC characterized by the loss of mismatch repair (MMR) proteins and its association with Lynch syndrome (LS). However, comprehensive real-world data on the incidence, clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in the Chinese patients with dMMR UC remains unknown. We analyzed 374 patients with bladder urothelial carcinoma (BUC) and 232 patients with upper tract urothelial carcinoma (UTUC) using tissue microarrays, immunohistochemistry, and targeted next-generation sequencing. Results showed the incidence of dMMR UC was higher in the upper urinary tract than in the bladder. Genomic analysis identified frequent mutations in KMT2D and KMT2C genes and LS was confirmed in 53.8% of dMMR UC cases. dMMR UC cases displayed microsatellite instability-high (MSI-H) (PCR method) in 91.7% and tumor mutational burden-high (TMB-H) in 40% of cases. The density of intratumoral CD8+ T cells correlated with better overall survival in dMMR UC patients. Positive PD-L1 expression was found in 20% cases, but some patients positively responded to immunotherapy despite negative PD-L1 expression. Our findings provide valuable insights into the characteristics of dMMR UC in the Chinese population and highlights the relevance of genetic testing and immunotherapy biomarkers for treatment decisions.

Development and validation of a nomogram to predict cancer-specific survival in nonsurgically treated elderly patients with prostate cancer.

Prostate Cancer (PC) is the most common male nonskin tumour in the world, and most diagnosed patients are over 65 years old. The main treatment for PC includes surgical treatment and nonsurgical treatment. Currently, for nonsurgically treated elderly patients, few studies have evaluated their prognostic factors. Our aim was to construct a nomogram that could predict cancer-specific survival (CSS) in nonsurgically treated elderly PC patients to assess their prognosis-related independent risk factors. Patient information was obtained from the Surveillance, Epidemiology and End Results (SEER) database, and our target population was nonsurgically treated PC patients who were over 65 years old. Independent risk factors were determined using both univariate and multivariate Cox regression models. A nomogram was built using a multivariate Cox regression model. The accuracy and discrimination of the prediction model were tested using the consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve. Decision curve analysis (DCA) was used to examine the potential clinical value of this model. A total of 87,831 elderly PC patients with nonsurgical treatment in 2010-2018 were included in the study and were randomly assigned to the training set (N = 61,595) and the validation set (N = 26,236). Univariate and multivariate Cox regression model analyses showed that age, race, marital status, TNM stage, chemotherapy, radiotherapy modality, PSA and GS were independent risk factors for predicting CSS in nonsurgically treated elderly PC patients. The C-index of the training set and the validation set was 0.894 (95% CI 0.888-0.900) and 0.897 (95% CI 0.887-0.907), respectively, indicating the good discrimination ability of the nomogram. The AUC and the calibration curves also show good accuracy and discriminability. We developed a new nomogram to predict CSS in elderly PC patients with nonsurgical treatment. The model is internally validated with good accuracy and reliability, as well as potential clinical value, and can be used for clinical aid in decision-making.

FCGR2B as a prognostic and immune microenvironmental marker for gliomas based on transcriptomic analysis.

To explore the expression and prognosis of Fc fragment of IgG low affinity IIb receptor (FCGR2B) in glioma and its relationship with immune microenvironment, so as to provide potential molecular targets for the treatment of glioma. We analyzed the gene expression of FCGR2B using the Cancer Genome Atlas database, Chinese Glioma Genome Atlas, Gene Expression Omnibus database and other glioma related databases. Moreover, we generated survival receiver operating characteristic curve, carried out univariate and multivariate Cox analysis and nomograph construction, and analyzed the relationship between FCGR2B and prognosis. According to the median of FCGR2B gene expression value, the differential expression analysis was carried out by high and low grouping method, and the gene ontology, Kyoto encyclopedia of genes and genomes, and gene set enrichment analysis enrichment analysis were carried out to explore the possible mechanism. Then, the correlation between immune score of glioma and prognosis, World Health Organization grade and FCGR2B expression was analyzed. Finally, the correlation between FCGR2B expression and the proportion of tumor infiltrating immune cells, immune checkpoints, tumor mutation load and immune function was analyzed. The expression of FCGR2B in gliomas was higher than that in normal tissues and was associated with poor prognosis. Independent prognostic analysis showed that FCGR2B was an independent prognostic factor for glioma. The analysis of gene ontology and gene set enrichment analysis showed that FCGR2B was closely related to immune-related functions. The analysis of immune scores and prognosis, World Health Organization grade and FCGR2B expression in gliomas indicated that patients with high immune scores had significantly poorer overall survival and higher tumor pathological grade. In addition, immune scores were significantly positively correlated with the expression of FCGR2B. The analysis of tumor infiltrating immune cells suggested that the expression level of FCGR2B affected the immune activity of TME. In addition, the expression of FCGR2B was positively correlated with almost all immune checkpoint molecules including CD28, CD44, TNFSF14, PDCD1LG2, LAIR1, and CD48 and was significantly positively correlated with tumor mutation load. All immunobiological functions of the high expression group of FCGR2B were significantly inhibited. FCGR2B may play an important role in the occurrence, development and invasion of tumor by influencing the tumor microenvironment of immunosuppression. FCGR2B may be an important target for the treatment of glioma.

Characteristics of glioblastomas and immune microenvironment in a Chinese family with Lynch syndrome and concurrent porokeratosis.

Background: Lynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs. Methods: Immunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations. Results: In the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis. Conclusion: LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Congenital giant fibroepithelial polyp of the scrotum in an infant: the first case report from China.

Giant fibroepithelial polyp (FP) of the scrotum in infants is a rare disease. We reported the first case of FP in China. The child was only 9 months and 12 days old and was admitted to the hospital due to rapid growth and rupture of the scrotal mass. The patient underwent scrotal exploration under general anesthesia, and the mass was cystic-solid with clear boundaries. The tumor did not invade the sarcolemma of the scrotum and testicular tissue. The intraoperative pathological frozen section tended to be benign, and the scrotum's tumor and subcutaneous pedicle tissue were removed entirely after 0.5 cm from the boundary of the mass. The operation was successful. The mass was confirmed as FP by postoperative pathology. 6 months after the operation, the incision healed well without recurrence. This case report has a detailed diagnosis and treatment process and adequate examination results. It can provide a reference for diagnosing and treating FP in infants and reduce the risk of misdiagnosis and mistreatment.

Efficacy and Safety of Panax notoginseng Saponins in the Treatment of Adults With Ischemic Stroke in China: A Randomized Clinical Trial.

Importance: Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15. Interventions: Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months. Main Outcomes and Measures: The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Results: Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85). Conclusions and Relevance: In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.

TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2.

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.