Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase.

BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Satisfaction With and Adherence to Off-Label Corticosteroids in Adolescents and Adults With Eosinophilic Esophagitis: Results of a Web-Based Survey in the United States.

GOALS: We assessed satisfaction with and adherence to off-label corticosteroids in patients with eosinophilic esophagitis (EoE) in the United States. BACKGROUND: EoE is a chronic inflammatory disease for which there are currently no US Food and Drug Administration-approved swallowed topical corticosteroids. STUDY: This noninterventional, cross-sectional, web-based survey included caregivers of adolescents (aged 11 to 17 y) and adults (aged 18 years or older) with a self-reported [or caregiver-reported (adolescents)] physician diagnosis of EoE who were receiving corticosteroids. Participants were recruited through 2 nonprofit, patient advocacy groups. The 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) was used to assess satisfaction across effectiveness, convenience, and global satisfaction domains (scale: 1 to 100 per domain); higher scores indicated greater satisfaction. The 4-item Morisky Green Levine Medication Adherence Scale (MGL-4) was used to assess adherence; an MGL-4 score of <3 indicated adherence. Participants also reported reasons for nonadherence. RESULTS: Overall, 201 participants (caregivers of adolescents, n=98; adults, n=103) were included in this study. Mean TSQM-9 scores indicated low satisfaction with off-label corticosteroids across all 3 satisfaction domains in adolescents (≤61.1) and adults (≤55.7). Slightly fewer adolescents (37.1%) than adults (40.8%) were considered adherent. Forgetfulness was the most frequently reported reason for nonadherence; some patients chose not to take their medications, owing to poor palatability (adolescents), difficulty taking medications at specific times (adults), or feeling depressed/overwhelmed (adolescents and adults). CONCLUSIONS: Satisfaction with and adherence to off-label corticosteroids were low in this web-based survey of adolescents and adults with EoE in the United States.

Mutational landscape of primary spinal cord astrocytoma.

Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.

Tumor-derived KLK8 predicts inferior survival and promotes an immune-suppressive tumor microenvironment in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common lung cancer worldwide, leading to millions of deaths annually. Although immunotherapy has expanded the therapeutic choices for LUSC and achieved considerable efficacy in a subset of patients, many patients could not benefit, and resistance was pervasive. Therefore, it is significant to investigate the mechanisms leading to patients' poor response to immunotherapies and explore novel therapeutic targets. Using multiple public LUSC datasets, we found that Kallikrein-8 (KLK8) expression was higher in tumor samples and was correlated with inferior survival. Using a LUSC cohort (n = 190) from our center, we validated the bioinformatic findings about KLK8 and identified high KLK8 expression as an independent risk factor for LUSC. Function enrichment showed that several immune signaling pathways were upregulated in the KLK8 low-expression group and downregulated in the KLK8 high-expression group. For patients with low KLK8 expression, they were with a more active TME, which was both observed in the TCGA database and immune marker immunohistochemistry, and they had extensive positive relations with immune cells with tumor-eliminating functions. This study identified KLK8 as a risk factor in LUSC and illustrated the associations between KLK8 and cancer immunity, suggesting the potentiality of KLK8 as a novel immune target in LUSC.

Effects of radial extracorporeal shock wave therapy on flexor spasticity of the upper limb in post-stroke patients: A randomized controlled trial.

OBJECTIVE: This study aimed to assess the efficacy of radial extracorporeal shock wave therapy in treating upper limb spasticity after a stroke. DESIGN: Randomized controlled trial. SETTING: Zhujiang Hospital of Southern Medical University. SUBJECTS: This study included 95 people with stroke. INTERVENTION: The active (n = 47) and sham-placebo (n = 48) radial extracorporeal shockwave therapy groups received three treatment sessions (every third day). MAIN MEASURES: The Modified Ashworth Scale, Hmax/Mmax ratio, root mean square, co-contraction ratio, mechanical parameters of the muscle and temperature were measured at baseline and days 2, 5 and 8. RESULTS: Among the 135 potential participants screened, 100 were enrolled and allocated randomly, with 95 participants ultimately being included in the intent-to-treat analysis dataset. The active group showed significantly better improvements in upper limb spasticity and muscle function than did the sham-placebo group. Greater improvements in the Modified Ashworth Scale were observed in the active group than in the sham-placebo group (difference, -0.45; 95% CI, -0.69 to -0.22; P < 0.001). Moreover, significant differences in root mean square, co-contraction ratio and Hmax/Mmax ratio were observed between the two groups (all P < 0.001). The mechanical parameters of the biceps muscle were significantly better in the active group than in the sham-placebo group (P < 0.001). The active group had a higher temperature than the sham-placebo group, although the difference was not significant (P = 0.070). CONCLUSIONS: This study revealed that the treatment with extracorporeal shockwave therapy can relieve upper limb spasticity in people with stroke.

Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies.

Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

H3K4me3-related lncRNAs signature and comprehensive analysis of H3K4me3 regulating tumor immunity in lung adenocarcinoma.

BACKGROUD: The role of epigenetic modifications in tumorigenesis has been widely reported. However, the role and mechanism of H3K4me3 modification in lung adenocarcinoma (LUAD) are rarely reported systematically. We, therefore, sought to analyze the characteristics of LUAD associated with H3K4me3 modification, build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD and clarify the potential value of H3K4me3 in immunotherapy of LUAD. METHODS: We evaluated H3K4me3-lncRNA patterns and H3K4me3-lncRNA scores of 477 LUAD samples based on 53 lncRNAs closely correlated to H3K4me3 regulators and comprehensive analyzed the role of these patterns in tumorigenesis and tumor immunity. Using Gene set variation analysis (GSVA), we systematically evaluated the H3K4me3 level of every sample and deeply analyzed the effect of H3K4me3 on the prognosis of LUAD. In addition, we included two independent immunotherapy cohorts to study the impact of high H3K4me3 score on the prognosis of patients. We also used an independent cohort with 52 matched paraffin specimens of LUAD to verify the impact of high H3K3me3 expression on the prognosis of patients. RESULTS: We identified three H3K4me3-lncRNA patterns that exhibited specific immune characteristics. Characterized by immunosuppressive and increased TGFß-mediated epithelial-mesenchymal transition (EMT), patients with high H3K4me3-lncRNA score had a poor overall survival and decreased H3K4me3 score. H3K4me3 score was significantly positively correlated with CD4+T-cell and CD8+T-cell activation, programmed cell death and immune checkpoints (ICs) expression, and was negatively correlated with MYC pathway, TP53 pathway, and cell proliferation. Patients with high H3K4me3 score showed elevated expression of ICs, potentiated CD4 T-cell and CD8 T-cell activation, increased programmed cell death, and suppressed cell proliferation and TGFß-mediated EMT. Patients with high H3K4me3 score and high expression of CTLA4, ICOS, TIGIT, PDCD1LG2, IDO1, CD274, PDCD1, LAG3, or HAVCR2 had the best survival advantage. Two independent immunotherapy cohorts verified that patients with high H3K4me3 score showed an increased inflamed tumor microenvironment (TME) phenotype and enhanced anti-PD-1/L1 immunotherapy response. Immunohistochemistry (IHC) data from 52 matched paraffin specimens of LUAD confirmed that the protein level of H3K4me3 in tumor was significantly lower than that of paracancerous tissues and H3K4me3 brought significant survival benefits to patients with LUAD. CONCLUSIONS: We build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD. More importantly, this study revealed characteristics of H3K4me3 modification in LUAD and clarified the important potential role of H3K4me3 on tumor immunotherapy and patients' survival.

Risk Factors of Lower Extremity Deep Vein Thrombosis After Artificial Femoral Head Replacement for Elderly Femoral Neck Fractures and a Nomogram Model Construction.

Objective: To assess lower extremity deep vein thrombosis (DVT) risk factors after artificial femoral head replacement for elderly femoral neck fractures. A nomogram model was constructed to predict its risk. Methods: In analyzing 144 participants who underwent artificial femoral head replacement for elderly femoral neck fractures, researchers collected clinical data to identify factors associated with lower extremity DVT. The study collected numerous variables ranging from age and sex to history of lower extremity DVT and use of anticoagulant drugs after surgery. The patients were in two groups: those who developed DVT (n = 62) and those who did not (n = 82). Multivariate logistic regression analysis helped to identify factors influencing the occurrence of DVT after artificial femoral head replacement. The software packages used were R 4.1.0 and RMS. Results: Univariate and multivariate regression analysis identified age, ASA level, D-dimer of lower limb DVT, ALB, and PLT as predictive risk factors of lower extremity DVT after artificial femoral head replacement for elderly femoral neck fractures. Those risk factors were used to construct a clinical predictive nomogram. The calibration curves for hypertension in patients with OSAHS risk revealed excellent accuracy of the predictive nomogram model. The unadjusted concordance index (C-index) for the model was 0.877 [95% confidence interval (CI), 0.805-0.942]. The AUC was 0.8375002. Decision curve analysis showed that the predictive model could be applied clinically when the threshold probability was 20 to 80%. Conclusions: The researchers constructed and validated a clinical nomogram to predict the occurrence of lower extremity DVT after artificial femoral head replacement in elderly patients with femoral neck fractures. Age, ASA level, D-dimer, and history of lower limb DVT, ALB, and PLT were demonstrated to be predictive risk factors of lower extremity DVT in this circumstance. This practical prognostic nomogram may help improve clinical decision-making.

Comprehensive molecular analysis of a four-pyroptosis-gene signature with prognosis and immune landscape in lung adenocarcinoma.

Pyroptosis plays an important role in tumor immunity. However, the biological behavior and prognostic significance of pyroptosis remain unclear. We identified 41 pyroptosis regulators differently expressed in lung adenocarcinoma (LUAD). All cases of LUAD can be classified into two molecular subtypes using unsupervised clustering algorithm. Using multiple analyses, a four-pyroptosis-gene signature was constructed, and all LUAD patients were categorized as low-risk or high-risk with a longer overall survival (OS) time in the low-risk group(P < 0.001). This signature had power prognosis and stratification which was validated by six independent datasets and clinical subtypes. Besides, this signature showed distinct clinical outcomes, immune landscapes in different risk groups. Moreover, the low-risk group had a higher response against immunotherapy with a lower TIDE score. Importantly, this signature surpassed other biomarkers (TIDE, TMB, PD-L1) in predicting prognosis. Overall, the current study might help with precise prognostic prediction and crucial treatment strategies, eventually promoting tailored therapy for LUAD patients.

PSC subtyping based on TTF-1 and p40 expression reveals distinct molecular characteristics and therapeutic strategies.

Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n = 27), P40 positive subgroup (n = 15) and double-negative subgroup (n = 14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P = .034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P = .004) and the cell cycle pathway (P = .030). The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte fraction (LF) among several cancer types, and the tumor mutation burden (TMB) of the p40 positive subgroup ranked third in the TMB list, suggesting the applicability of immunotherapy for PSC. The study established a new subtyping method of PSC based on IHC results and reveals three subgroups with distinct molecular features, providing evidence for refined stratification in the treatment of PSC.

Primary adult sellar SMARCB1/INI1-deficient tumor represents a subtype of atypical teratoid/rhabdoid tumor.

Loss of function in SMARCB1/INI1 has been observed in a group of malignancies collectively defined as SMARCB1/INI1-deficient neoplasms. Primary intracranial SMARCB1/INI1-deficient tumors in adults are extremely rare. We collected eight primary adult sellar SMARCB1/INI1-deficient tumors to study their clinicopathological and (epi)genetic characteristics. We performed a comprehensive assessment of the clinical, radiological, morphological and immunohistochemical features. FISH analysis for the SMARCB1 locus and target exome sequencing for 425 cancer relevant genes were performed. Furthermore, six bona fide proximal epithelioid sarcoma (PES), fourteen atypical teratoid/rhabdoid tumors (ATRT) in brain and five pediatric poorly differentiated chordomas (PDC) in the clivus were collected for comparative analysis of differential diagnostic maker expression and DNA methylation profile. The median age was 47.1 years, ranging from 26 to 73 years. On morphology, tumors were characterized by sheets of monomorphic larger epithelioid-like cells, in two cases with rhabdoid cells. "Stag-horn" vasculatures were observed in five cases. The loss of INI1 protein expression, co-expression of epithelial makers and mesenchymal markers were observed in all cases. CD34 expression was observed in six cases. Heterozygous deletion of SMARCB1/INI1 was confirmed using FISH in six cases. The results of target exome sequencing showed three patients harbored heterozygous point mutations in SMARCB1. The epigenetic features of the primary adult sellar SMARCB1/INI1-deficient tumors resembled the ATRT-MYC subgroup, but clustered apart from PES and PDC. Based on epigenetic characteristics, primary adult sellar SMARCB1/INI1-deficient tumors represent a subtype of ATRT with similar epigenetic characteristics of ATRT-MYC subgroup. Our findings suggest that DNA methylation profiling should be utilized for differential diagnosis for the majority of epithelioid sarcoma and (sellar) rhabdoid tumor.

The RNA-binding protein PCBP1 represses lung adenocarcinoma progression by stabilizing DKK1 mRNA and subsequently downregulating ß-catenin.

BACKGROUND: PolyC-RNA-binding protein 1 (PCBP1) functions as a tumour suppressor and RNA regulator that is downregulated in human cancers. Here, we aimed to reveal the biological function of PCBP1 in lung adenocarcinoma (LUAD). METHODS: First, PCBP1 was identified as an important biomarker that maintains LUAD through The Cancer Genome Atlas (TCGA) project screening and confirmed by immunohistochemistry and qPCR. Via colony formation, CCK8, IncuCyte cell proliferation, wound healing and Transwell assays, we confirmed that PCBP1 was closely related to the proliferation and migration of LUAD cells. The downstream gene DKK1 was discovered by RNA sequencing of PCBP1 knockdown cells. The underlying mechanisms were further investigated using western blot, qPCR, RIP, RNA pulldown and mRNA stability assays. RESULTS: We demonstrate that PCBP1 is downregulated in LUAD tumour tissues. The reduction in PCBP1 promotes the proliferation, migration and invasion of LUAD in vitro and in vivo. Mechanistically, the RNA-binding protein PCBP1 represses LUAD by stabilizing DKK1 mRNA. Subsequently, decreased expression of the DKK1 protein relieves the inhibitory effect on the Wnt/ß-catenin signalling pathway. Taken together, these results show that PCBP1 acts as a tumour suppressor gene, inhibiting the tumorigenesis of LUAD. CONCLUSIONS: We found that PCBP1 inhibits LUAD development by upregulating DKK1 to inactivate the Wnt/ß-catenin pathway. Our findings highlight the potential of PCBP1 as a promising therapeutic target.

The Bioinformatical Identification of Potential Biomarkers in Heart Failure Diagnosis and Treatment.

Background: Heart failure (HF) is defined as the inability of the heart's systolic and diastolic function to properly discharge blood flow from the veins to the heart. The goal of our research is to look into the possible mechanism that causes HF. Methods: The GSE5406 database was used for screening the differentially expressed genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) network were applied to analyze DEGs. Besides, cell counting Kit-8 (CCK-8) was conducted to observe the knockdown effect of hub genes on cell proliferation. Results: Finally, 377 upregulated and 461 downregulated DEGs came out, enriched in the extracellular matrix organization and gap junction. According to GSEA results, Hoft cd4 positive alpha beta memory t cell bcg vaccine age 18-45 yo id 7 dy top 100 deg ex vivo up, Sobolev t cell pandemrix age 18-64 yo 7 dy dn, and so on were significantly related to gene set GSE5406. 7 hub genes, such as COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3 and MAPK1, were selected from PPI networks. CCK-8 indicated silencing of STAT3 promoted the proliferation of H9C2 cells and silencing of UBB inhibited the proliferation of H9C2 cells. Conclusion: Our analysis reveals that COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3, and MAPK1 might promote the progression of HF and become the biomarkers for diagnosis and treatment of HF.

Identification and validation of quantitative trait loci for the functional stay green trait in common wheat (Triticum aestivum L.) via high-density SNP-based genotyping.

KEY MESSAGE: This study identified QTLs associated with the functional stay green trait by a high-density genetic map. Two large effect QTLs, QSg.sau-2B.1 and QSg.sau-6A.2, were identified in multiple years and one of them was successfully validated. The functional stay green phenotype enables wheat to acclimate to stressful environments and prolongs the effectiveness of photosynthesis during the end-of-crop season. Despite the fact that stay green mutants in wheat have been reported, our knowledge of loci for the functional stay green trait remains limited. In this study, an RIL population containing 371 lines genotyped using the Wheat55K SNP array was used to map QTLs controlling the functional stay green trait in multiple years. In total, 21 and 19 QTLs were mapped using the BIP or MET modules of the ICIM method, respectively. Among them, two QTLs, QSg.sau-2B.1 and QSg.sau-6A.2, were considered large effect QTLs for the stay green trait and explained 11.43% and 15.27% of phenotypic variation on average, respectively. Two KASP markers were developed and tightly linked to QSg.sau-2B.1 and QSg.sau-6A.2, respectively, and the genetic effects of different genotypes in the RIL population were successfully confirmed. QSg.sau-2B.1 was also validated by linked KASP marker in different genetic backgrounds. QSg.sau-2B.1 and QSg.sau-6A.2 may influence heredity of the stay green trait and also exhibited a positive effect on the grain filling content. In the interval where QSg.sau-2B.1 and QSg.sau-6A.2 were located on the Chinese Spring and T. turgidum ssp. dicoccoides reference genomes, several genes associated with the leaf senescence process were identified. Altogether, our results identified two QTLs associated with the functional stay green trait and will be useful for the fine mapping and cloning of genes for stay green in the future.

Visible-Light-Induced Tandem Reaction of Allenes with Selenesulfonates Leading to (E)-2,3-Disulfonylpropene Derivatives.

A visible-light-induced tandem reaction of allenes with selenesulfonates was developed, providing (E)-2,3-disulfonylpropene derivatives in moderate to good yields. This reaction was featured with simple operation, good regioselectivity and stereoselectivity, and wide functional group tolerance. Photoinduced radical additions via energy transfer were proposed.

CDH1 overexpression predicts bladder cancer from early stage and inversely correlates with immune infiltration.

BACKGROUND: Bladder cancer (BC) seriously endangers public health, but effective biomarkers for BC diagnosis, particularly in the early stage, are still lacking. Identification of reliable biomarkers associated with early-stage BC is of great importance to early treatment and an improved outcome. METHODS: Differentially expressed genes (DEGs) were identified using four publicly available early-stage BC gene-expression profiles. Protein-protein interaction (PPI) and survival analysis for hub genes was evaluated. The correlation between methylation of genes and prognosis was evaluated using the MethSurv database. Co-expressed genes were explored using Cancer Cell Line Encyclopedia database and the corresponding expression were assessed in vitro. The competing endogenous RNA network and the immune cell infiltration in BC were generated using data of The Cancer Genome Atlas. RESULTS: Ten hub genes of the 213 integrated DEGs were identified, including CDH1, IGFBP3, PPARG, SDC1, EPCAM, ACTA2, COL3A1, TPM1, ACTC1, and ACTN1. CDH1 appeared to increase from tumor initiation stage and negatively correlated with methylation. Six methylated sites in CDH1 indicated a good prognosis and one site indicated an aberrant prognosis. High CDH1 expression was negatively correlated with infiltrations by most immune cells, such as plasmacytoid dendritic cells (pDCs), regulatory T cells, macrophages, neutrophils, DCs, and natural killer cells. CDH1 was highly positively correlated with EPCAM and appeared to be directly regulated by miR-383. CONCLUSIONS: The identified oncogenic alterations provide theoretical support for the development of novel biomarkers to advance early-stage BC diagnosis and personalized therapy.

Basilar invagination without atlantoaxial dislocation: treatment by correction of clivus canal angle with interfacet distraction and fixation.

BACKGROUND: This study reports on the surgical technique used and clinical outcomes obtained during the treatment of basilar invagination (BI) without atlantoaxial dislocation (AAD) through the correction of the clivus canal angle (CCA) using interfacet distraction and fixation. METHODS: Nineteen cases with BI without AAD treated by the correction of the clivus canal angle were retrospectively analyzed. Pre- and postoperative computed tomography scans and three-dimensional reconstruction views were obtained to measure the size of the CCA, pB-C2 distance, and degree of BI. Chiari malformation and syringomyelia were evaluated by magnetic resonance imaging (MRI). The clinical outcomes for all patients were measured using the Japanese Orthopedic Association (JOA) scale. The CCA was corrected by using interfacet distraction and fixation techniques. The Wilcoxon test was used to compare pre- and postoperative measurements. RESULTS: All the patients were followed up for 24.95 ± 5.22 months (range 12-36 months); no patient suffered intraoperative nerve or vascular injury. Clinical symptoms improved in 17 patients (89.5%). The mean JOA score increased from 12.32 ± 1.89 to 14.37 ± 1.30 (Z = -3.655, P < 0.001). The mean CCA improved from 129.34 ± 8.52° preoperatively to 139.75 ± 8.86° postoperatively (Z = -3.824, P < 0.001). The mean pB-C2 decreased from 7.47 ± 2.21 to 5.68 ± 3.13 (Z = -3.060, P = 0.002). Syringomyelia was significantly reduced in 10 out of 13 patients by the first follow-up year. All patients achieved bony fusion. CONCLUSION: Posterior interfacet distraction and fixation to correct the CCA is a feasible and effective method for treating BI without AAD.

Quadriceps strength is negatively associated with knee joint structural abnormalities-data from osteoarthritis initiative.

OBJECTIVE: The aim of this study was to explore the longitudinal associations between baseline quadriceps strength and knee joint structural abnormalities in knee osteoarthritis (KOA). METHODS: This study is a longitudinally observational study based on Osteoarthritis Initiative (OAI) cohort, including men and women aged 45-79. Quadriceps strength was measured by isometric knee extension testing at baseline. Knee joint structural abnormalities, including cartilage damage, bone marrow lesions (BMLs), effusion-synovitis and Hoffa-synovitis, were evaluated by Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) at baseline and 1-year follow-up. Generalized estimating equations were employed to examine the associations between quadriceps strength and knee structural abnormalities. All analyses were stratified by sex. RESULTS: One thousand three hundred thirty-eight participants (523 men and 815 women) with a mean age of 61.8 years and a mean BMI of 29.4 kg/m2 were included in this study. For men, no significantly longitudinal association of quadriceps strength with structural abnormalities was detected. In contrast, quadriceps strength was significantly and negatively associated with changes in cartilage damage and BMLs in lateral patellofemoral joint (PFJ) (cartilage damage: OR: 0.91, 95% CI 0.84 to 0.99, P = 0.023; BMLs: OR: 0.85, 95% CI 0.74 to 0.96, P = 0.011) and effusion-synovitis (OR = 0.88, 95% CI 0.78 to 0.99, P = 0.045) among females longitudinally. Higher quadriceps strength was significantly associated with less progression of lateral PFJ cartilage damage, BMLs and effusion-synovitis in females. CONCLUSIONS: Higher quadriceps strength was associated with changes in cartilage damage and BMLs within the lateral PFJ and effusion-synovitis among females, suggesting the potential protective role of quadriceps strength on joint structures in women.

LANCL1 as the Key Immune Marker in Neuropathic Pain.

Objective: This study is to explore key immune markers and changes of immune microenvironment in neuropathic pain (NeuP). Method: The data sets of GSE145199 and GSE145226 in Gene Expression Omnibus (GEO) database was used to analyze, and the key immune markers were verified by GSE70006 and GSE91396, and the infiltration degree of immune cells in different samples were analyzed by CIBERSORT analysis package. Results: In this study, we found a key immune marker, namely, LANCL1. Regulatory axis closely related to LANCL1 has also been found, namely, miR-6325/LANCL1 axis. In the immune infiltration analysis, we also found that the LANCL1 is positively correlated with T cells CD4 naïve (r = 0.880, p < 0.05). Conclusion: In this study, we found that LANCL1 may be a protective factor for NeuP, and the miR-6325/LANCL1 axis may be involved in the occurrence and development of NeuP. Cascade reactions including mast cells, macrophages, and T cells may be an important reason for the aggravation of nerve damage.

High S100A7 expression is associated with early muscle invasion and poor survival in bladder carcinoma.

Muscle-invasive bladder carcinoma (MIBC) accounts for 25% of newly diagnosed bladder carcinomas (BCs) and presents a high risk of progression and metastasis. This study aimed to identify reliable biomarkers associated with muscle invasion and prognosis to identify potential therapeutic targets for MIBC. Four gene datasets were downloaded from the Gene Expression Omnibus, and the integrated differentially expressed genes (DEGs) were then subjected to gene ontology (GO) terms and pathway enrichment analyses. Correlation analysis between the expression of the top-ranking DEGs and pathological T stages was performed to identify the genes associated with early muscle invasion. The corresponding prognostic values were evaluated, and co-expressed genes mined in the cBioPortal database were loaded into ClueGo in Cytoscape for pathway enrichment analysis. Using data mining from the STRING and TCGA databases, protein-protein interaction and competitive endogenous RNA networks were constructed. In total, 645 integrated DEGs were identified and these were mainly enriched in 26 pathways, including cell cycle, bladder cancer, DNA replication, and PPAR signaling pathway. S100A7 expression was significantly increased from the T2 stage and showed significantly worse overall survival and disease-specific survival in patients with BC. In total, 144 genes co-expressed with S100A7 in BC were significantly enriched in the IL-17 pathway. S100A7 was predicted to directly interact with LYZ, which potentially shows competitive binding with hsa-mir-140 to affect the expression of six lncRNAs in MIBC. In conclusion, high S100A7 expression was predicted to be associated with early muscle invasion and poor survival in patients with BC.