Spliceosomal GTPase Eftud2 deficiency-triggered ferroptosis leads to Purkinje cell degeneration.

Spliceosomal GTPase elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) syndrome comprising cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these symptoms remains elusive. Here, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia, and cerebellar atrophy, which recapitulates phenotypes observed in patients with MFDM. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity, thereby suppressing PC ferroptosis. Importantly, we identified transcription factor Atf4 as a downstream target to regulate anti-ferroptosis effects in PCs in a p53-independent manner. Inhibiting ferroptosis efficiently rescued cerebellar deficits in Eftud2 cKO mice. Our data reveal an important role of Eftud2 in maintaining PC survival, showing that pharmacologically or genetically inhibiting ferroptosis may be a promising therapeutic strategy for EFTUD2 deficiency-induced disorders.

Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2.

Defects in planar cell polarity (PCP) have been implicated in diverse human pathologies. Vangl2 is one of the core PCP components crucial for PCP signaling. Dysregulation of Vangl2 has been associated with severe neural tube defects and cancers. However, how Vangl2 protein is regulated at the posttranslational level has not been well understood. Using chemical reporters of fatty acylation and biochemical validation, here we present that Vangl2 subcellular localization is regulated by a reversible S-stearoylation cycle. The dynamic process is mainly regulated by acyltransferase ZDHHC9 and deacylase acyl-protein thioesterase 1 (APT1). The stearoylation-deficient mutant of Vangl2 shows decreased plasma membrane localization, resulting in disruption of PCP establishment during cell migration. Genetically or pharmacologically inhibiting ZDHHC9 phenocopies the effects of the stearoylation loss of Vangl2. In addition, loss of Vangl2 stearoylation enhances the activation of oncogenic Yes-associated protein 1 (YAP), serine-threonine kinase AKT, and extracellular signal-regulated protein kinase (ERK) signaling and promotes breast cancer cell growth and HRas G12V mutant (HRasV12)-induced oncogenic transformation. Our results reveal a regulation mechanism of Vangl2, and provide mechanistic insight into how fatty acid metabolism and protein fatty acylation regulate PCP signaling and tumorigenesis by core PCP protein lipidation.

Genomic and transcriptomic significance of multiple primary lung cancers detected by next-generation sequencing in clinical settings.

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

Prenatal diagnosis of dent disease type I with a nonsense pathogenic variant in CLCN5: a case study.

INTRODUCTION: Dent disease type I is a rare X-linked recessive renal tubular disease resulting from pathogenic variants in the CLCN5 gene. Due to the rarity of Dent disease type I and the diversity of its phenotypes, its clinical diagnosis is complex and poses a challenge to clinicians. METHODS: A foetus and a child from a 36-year-old pregnant woman with a birth history of abnormal children were enrolled in this study. Pregnant women undergo amniocentesis for prenatal diagnosis at the gestational age of 12+ 3 weeks. Chromosomal microarray (CMA) analysis and whole-exome sequencing (WES) were employed to investigate the chromosomal copy number and single gene variants. Literature retrieval and data analysis were performed for genotype and phenotype collection analysis. RESULTS: No chromosomal abnormalities or CNVs were detected in the entire family through karyotype and familial CMA analyses. WES identified a nonsense pathogenic variant in CLCN5 of the X chromosome, c.1942 C > T (exon 11, NM_000084), which was inherited from his mother, who exhibited regular clinical features. CONCLUSION: This study suggests that children with low-molecular-weight proteinuria and hypercalciuria should undergo prompt genetic testing to exclude Dent disease.

Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition.

The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.

Tissue-specific populations from amniotic fluid-derived mesenchymal stem cells manifest variant in vitro and in vivo properties.

Amniotic fluid derived mesenchymal stem cells (AFMSCs), shed along the fetal development, exhibit superior multipotency and immunomodulatory properties compared to MSCs derived from other somatic tissues (e.g., bone marrow and fat). However, AFMSCs display heterogeneity due to source ambiguity, making them an underutilized stem cells source for translational clinical trials. Consequently, there is an urgent need to identify a method to purify the AFMSCs for clinical use. We found that the AFMSCs can be categorized into three distinct groups: kidney-specific AFMSCs (AFMSCs-K), lung-specific AFMSCs (AFMSCs-L), and AFMSCs with an undefined tissue source (AFMSCs-X). This classification was based on tissue-specific gene expression pattern of single cell colony. Additionally, we observed that AFMSCs-X, a minority population within the AFMSCs, exhibited the highest multipotency, proliferation, resistance to senescence and immuno-modulation. Our results showed that AFMSCs-X significantly improved survival rates and reduced bacterial colony forming units (CFU) in cecal ligation and puncture (CLP)-induced septic mice. Therefore, our study introduces a novel classification method to enhance the consistency and efficacy of AFMSCs. These subpopulations, originating from different tissue source, may offer a valuable and innovative resource of cells for regenerative medicine purposes.

Prognostic Value of Immunohistochemistry-based Subtyping Before and After Neoadjuvant Chemotherapy in Patients with Triple-negative Breast Cancer.

To assess the predictive and prognostic value of a subtyping method based on immunohistochemistry in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC). This study included patients with TNBC treated with anthracycline- and taxane-based NAC and curative surgery. Immunohistochemical (IHC) subtyping was performed using core needle biopsy specimens before NAC (pre-NAC) and residual tumors after NAC (post-NAC). Logistic regression was performed to identify predictive biomarkers of pathological complete response (pCR). Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed using the log-rank test and Cox proportional hazards regression. A total of 230 patients were followed up for a median of 59 months. Clinical lymph node status and the pre-NAC subtype were independent predictors of pCR (P=0.006 and 0.005, respectively). The pre-NAC subtype was an independent prognostic factor for long-term survival (iDFS: P < 0.001, DDFS: P=0.010, and OS: P=0.044). Among patients with residual disease (RD) after NAC, approximately 45% of tumors changed their IHC subtype. Furthermore, the post-NAC subtype, but not the pre-NAC subtype, was strongly associated with the survival of patients with RD (iDFS: P < 0.001, DDFS: P=0.005, and OS: P=0.006). The IHC subtype predicted response to NAC and long-term survival in patients with early TNBC. In patients with RD, almost 45% of the tumors changed subtype after NAC. The IHC subtype should be considered when planning additional therapies pre- and post-NAC.

UCHL1-PKM2 axis dysregulation is associated with promoted proliferation and invasiveness of urothelial bladder cancer cells.

BACKGROUND: Bladder cancer is one of the most common type of cancers globally, and the majority of cases belong to urothelial bladder carcinoma (UBC) type. Current researches have demonstrated that multiple genomic abnormalities are related to the sensitivity of cisplatin-based chemotherapy in bladder cancer patients. Previous findings have indicated a controversial role of Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) in malignancy, so we aimed to further explore the role of UCHL1 in UBC. METHODS: UBC cell lines and The Cancer Genome Atlas (TCGA) in-silico datasets were utilized to investigate UCHL1 expression pattern and functional as well as prognostic impacts in UBC cancer cell line models and patients. UCHL1 overexpression and silencing vectors and subsequent immunoprecipitation/ubiquitination experiments in combination of cellular functional assays were conducted to explore UCHL1-PKM2 interaction axis and its significance in UBC malignancy. RESULTS: UCHL1 was significantly up-regulated in UBC cancer cells and UCHL1 high-expression was associated with higher pathology/clinical grade and significantly inferior overall prognosis of UBC patients. UCHL1 interacted with PKM2 and enhanced PKM2 protein level through inhibition of PKM2 protein degradation via ubiquitination process. UCHL1-PKM2 interaction significantly promoted UBC cellular proliferation, metastasis and invasion activities. CONCLUSION: UCHL1-PKM2 interaction played an interesting role in UBC tumor cell proliferation, migration and metastasis. Our study suggests PKM2-targeted treatment might have a potential value in metastatic malignancy therapy development in the future.

Associations of intrinsic capacity, fall risk and frailty in old inpatients.

Introduction: This study explored the associations of intrinsic capacity (IC), fall risk, and frailty in geriatric inpatients. Methods: A total of 703 hospitalized patients aged 75 years or older were recruited for this retrospective observational study from Zhejiang Hospital using a comprehensive geriatric assessment. The IC composite score was constructed from the scores of the Chinese version of the Mini-Mental State Examination, Short Physical Performance Battery, Short Form Mini Nutritional Assessment, 15-item Geriatric Depression Scale, and self-reported hearing and vision impairment. Adverse outcomes were recorded as the fall risk and frailty using the Morse Fall Scale and the Clinical Frailty Scale. Spearman's correlation coefficient analyses and multivariate logistic regression models were used to explore the associations between IC, high fall risk, and frailty. Results: Declined IC composite scores were associated with increased risks of falls [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.57-0.72] and frailty (OR = 0.45, 95%CI: 0.37-0.54) among older hospitalized patients after adjusting for the related potential confounders. In addition, decreased cognitive, vitality, locomotion, and psychological scores were associated with increased adverse health conditions, with ORs ranging from 0.26 to 0.70. Vision impairment was observed to increase the risk of frailty (OR = 0.42, 95%CI: 0.23-0.76) after adjusting for the related potential confounders. Discussion: This study indicated that declined IC was associated with fall risk and frailty in older inpatients. Further prospective studies are needed to explore the longitudinal associations between baseline IC and subsequent risk of falls and frailty.

The Cocrystal of Ubiquinol: Improved Stability and Bioavailability.

Coenzyme Q10 (CoQ10) exists in two forms, an oxidized form and a reduced form. Ubiquinol is the fully reduced form of CoQ10. Compared to the oxidized form, ubiquinol has a much higher biological absorption and better therapeutic effect. However, ubiquinol has an important stability problem which hampers its storage and formulation. It can be easily transformed into its oxidized form-ubiquinone-even at low temperature. In this work, we designed, synthesized, and characterized a new cocrystal of ubiquinol with vitamin B3 nicotinamide (UQ-NC). Compared to the marketed ubiquinol form, the cocrystal exhibited an excellent stability, improved dissolution properties, and higher bioavailability. The cocrystal remained stable for a long period, even when stored under stressed conditions. In the dissolution experiments, the cocrystal generated 12.6 (in SIF) and 38.3 (in SGF) times greater maximum ubiquinol concentrations above that of the marketed form. In addition, in the PK studies, compared to the marketed form, the cocrystal exhibited a 2.2 times greater maximum total coenzyme Q10 concentration and a 4.5 times greater AUC than that of the marketed form.

The predictive implication of programmed cell death ligand 1 expression in extranodal natural killer/T-Cell lymphoma and its correlation with clinicopathological features: a systematic review and meta-analysis.

Background: Although programmed cell death ligand 1 (PD-L1) expression and function in hematologic malignancies have aroused extensive attention, its prognostic value for extranodal natural killer/T-cell lymphoma (ENKTL) is still unknown. Therefore, we conducted this meta-analysis to explore the predictive value of neoplastic PD-L1 expression for ENKTL. Methods: The PubMed, Embase, Web of Science, and CNKI databases were searched to identify eligible observational studies reporting PD-L1 expression and survival outcomes of ENKTL patients. The search was conducted in accordance with the Meta-analyses Of Observative Studies in Epidemiology (MOOSE) guidelines. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were adopted to analyze survival outcomes, and the odds ratios (ORs) and 95% CIs were adopted for clinicopathological parameters. Review Manager 5.3 and STATA 17.0 were used for statistical analysis. Potential publication bias was evaluated by funnel plot and Egger's test. Results: A total of 433 patients with ENKTL were included across seven studies. The pooled results showed no significant relationship between neoplastic PD-L1 expression and overall survival (OS) (HR =1.35, 95% CI: 0.49-3.75, P=0.559). We also performed subgroup analyses. However, increased PD-L1 expression was associated with a low international prognostic index (IPI) score of 0-1 (OR =2.46; 95% CI: 1.11-5.45, P=0.03), good performance status (OR =1.97; 95% CI: 1.11-3.51, P=0.02), and a good treatment effect (OR =2.61; 95% CI: 1.01-6.70, P=0.05). Conclusions: PD-L1-positive expression in patients with ENKTL was correlated with favorable clinical features. Thus, PD-L1-positive expression appears to be a potential predictor of treatment benefits. Additional large-scale, high-quality studies are needed to further explore its predictive value.

Tumor Immunophenotyping-Derived Signature Identifies Prognosis and Neoadjuvant Immunotherapeutic Responsiveness in Gastric Cancer.

The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype-related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG-3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in-house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune-activated, and IPSHigh is immune-silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti-PD-1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

Impact of glucocorticoids on the efficacy of neoadjuvant chemoradiotherapy and survival of patients with locally advanced rectal cancer: a retrospective study.

BACKGROUND: Preclinical studies suggest that glucocorticoids (GCs) promote the proliferation and development of colorectal cancer. Because GCs are broadly prescribed for treatment-related adverse events in patients with locally advanced rectal cancer (LARC) receiving neoadjuvant chemoradiotherapy (NCRT), it's essential to assess the effect of GCs on clinical outcomes. METHODS: LARC cases treated with NCRT followed by surgery were assessed retrospectively. Evaluation of the relationship between GCs use (GCs vs. non-GCs) and neoadjuvant rectal (NAR) score (as a three-level categorical dependent variable) was performed using multivariable multinomial logistic regression (MLR). We also examined the relationship between the accumulated dose of GCs and NAR using multivariate MLR. Survival analysis of disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier method. Multivariate Cox regression was used to assess confounding factors that could influence OS and DFS. RESULTS: This retrospective cohort study included 790 patients with newly diagnosed non-metastatic LARC (T3-4/N + M0) who received NCRT followed by surgery between January 2012 and April 2017. The end of the follow-up period was May 11, 2022. Among the 790 patients with LARC, 342 (43.2%) received GCs treatment and 448 (56.8%) did not during the NCRT-to-surgery period. GCs medication was significantly different between mid-NAR (8-16) and low-NAR (< 8) (odds ratio [OR], 0.615; 95% CI, 0.420-0.901; P = 0.013), and the high-NAR (> 16) and low-NAR (0.563; 0.352-0.900; 0.016). Patients exposed to GCs, had a decreased 5-year OS (GCs vs. non-GCs = 80.01% (95% CI, 75.87%-84.37%) vs. 85.30% (82.06%-88.67%), P = 0.023) and poorer 5-year DFS (73.99% (69.45%-78.82%) vs. 78.7% (75.14%-82.78%), P = 0.045). The accumulated dose of GCs was an independent risk factor for OS (hazard ratio [HR], 1.007 [1.001-1.014], 0.036) and DFS (1.010 [1.004-1.017], 0.001). CONCLUSIONS AND RELEVANCE: Our study revealed that GCs were associated with reduced efficacy of NCRT and worse clinical outcomes in patients with LARC during the NCRT-to-surgery period.

Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth.

Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known to protect tumour cells from ferroptosis upon cysteine starvation through transamination. However, whether amino acids-produced metabolites participate in ferroptosis independent of the cysteine pathway is largely unknown. Here, the authors show that the tryptophan metabolites serotonin (5-HT) and 3-hydroxyanthranilic acid (3-HA) remarkably facilitate tumour cells to escape from ferroptosis distinct from cysteine-mediated ferroptosis inhibition. Mechanistically, both 5-HT and 3-HA act as potent radical trapping antioxidants (RTA) to eliminate lipid peroxidation, thereby inhibiting ferroptotic cell death. Monoamine oxidase A (MAOA) markedly abrogates the protective effect of 5-HT via degrading 5-HT. Deficiency of MAOA renders cancer cells resistant to ferroptosis upon 5-HT treatment. Kynureninase (KYNU), which is essential for 3-HA production, confers cells resistant to ferroptotic cell death, whereas 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) significantly blocks 3-HA mediated ferroptosis inhibition by consuming 3-HA. In addition, the expression level of HAAO is positively correlated with lipid peroxidation and clinical outcome. Together, the findings demonstrate that tryptophan metabolism works as a new anti-ferroptotic pathway to promote tumour growth, and targeting this pathway will be a promising therapeutic approach for cancer treatment.

Transcriptional expression of CXCL10 and STAT1 in lupus nephritis and the intervention effect of triptolide.

OBJECTIVE: This study screened out the key genes associated with the occurrence and development of lupus nephritis (LN) using bioinformatics methods, and then explored the expression of key genes in LN and the inhibitory effect of triptolide. METHODS: The GEO2R online tool in the GEO database was used to perform differential analysis of gene expression in LN tissues and normal kidney tissues. The GO function and KEGG pathway enrichment analysis of differentially expressed genes (DEGs), STRING, and Cytoscape software were used to build a protein-protein interaction network (PPI) to screen out the Hub gene. Mouse glomerular mesangial cells (MMC) were randomly divided into a control group, an interferon-γ (IFN-γ) stimulation group, and a triptolide intervention group. The relative expression of CXCL10 mRNA in each group was detected by real-time fluorescent quantitative PCR (RT-PCR). CXCL10 secretion was detected by enzyme-linked immunosorbent assay (ELISA), and Western blot was used to detect the expression of the JAK/STAT1 signaling pathway-related proteins STAT1 and p-STAT1 in each group. RESULTS: Bioinformatics showed that there were 22 DEGs expression differences in the GEO database. The GO enrichment analysis showed that biological process (BP) such as the type I interferon signaling pathway, innate immune response, IFN-γ-mediated signaling pathway, virus defense response, and immune response were significantly regulated by DEGs. Through the combination of String database analysis and cytoscape software, it was found that STAT1 and CXCL10 are closely related to LN. Experimental results showed that IFN-γ induces the expression of CXCL10 mRNA and protein by activating the JAK/STAT1 signaling pathway, while triptolide inhibits the expression of CXCL10 mRNA and protein by inhibiting the JAK/STAT1 signaling pathway. CONCLUSION: STAT1 and CXCL10 are the key genes in the occurrence and development of LN. IFN-γ induces the expression of CXCL10 by activating the JAK/STAT1 signaling pathway, while triptolide inhibits the expression of CXCL10 by blocking the JAK/STAT1 signaling pathway. Inhibition of the JAK/STAT1 signaling pathway and CXCL10 expression is expected to become a potential target for the treatment of LN. Key Points • Bioinformatics showed that there were 22 DEGs expression differences in the GEO database. • Through the combination of String database analysis and Cytoscape software, it was found that STAT1 and CXCL10 are closely related to LN. • Experimental results showed that IFN-γ induces the expression of CXCL10 mRNA and protein by activating the JAK/STAT1 signaling pathway, while triptolide inhibits the expression of CXCL10 mRNA and protein by inhibiting the JAK/STAT1 signaling pathway.

In situ correction of various ß-thalassemia mutations in human hematopoietic stem cells.

ß-thalassemia (ß-thal) is the most common monogenic disorder caused by various mutations in the human hemoglobin ß (HBB) gene and affecting millions of people worldwide. Electroporation of Cas9 and single-guide RNA (sgRNA)-ribonucleoprotein (RNP) complex-mediated gene targeting in patient-derived hematopoietic stem cells (HSCs), followed by autologous transplantation, holds the promise to cure patients lacking a compatible bone marrow donor. In this study, a universal gene correction method was devised to achieve in situ correction of most types of HBB mutations by using validated CRISPR/sgRNA-RNP complexes and recombinant adeno-associated viral 6 (rAAV6) donor-mediated homology-directed repair (HDR) in HSCs. The gene-edited HSCs exhibited multi-lineage formation abilities, and the expression of ß-globin transcripts was restored in differentiated erythroid cells. The method was applied to efficiently correct different mutations in ß-thal patient-derived HSCs, and the edited HSCs retained the ability to engraft into the bone marrow of immunodeficient NOD-scid-IL2Rg-/- (NSI) mice. This study provides an efficient and safe approach for targeting HSCs by HDR at the HBB locus, which provides a potential therapeutic approach for treating other types of monogenic diseases in patient-specific HSCs.

Evaluation of voice function after BABA robotic thyroid lobectomy: A comparative analysis with endoscopic thyroid lobectomy.

The purpose of this study was to compare the effect of robotic thyroid lobectomy via Bilateral Axlio-Breast Approach (BABA) and endoscopic thyroid lobectomy on the voice function. A total of 125 patients with thyroid cancer from March 2021 to July 2022 were divided into the robotic thyroid lobectomy group and the endoscopic thyroid lobectomy group. Acoustic index and voice handicap index (VHI-10) were compared between the 2 groups before and after (1 week, 1 month, 3 month) the surgery. In the robotic group, VHI-10 score was not significantly different before and after the surgery. In the endoscopic group, VHI-10 score after the surgery was significantly higher than that before the surgery. In the endoscopic group, the fundamental frequency (F0) declined significantly 1 week and 1 month after the surgery compared with that before the surgery. One week after surgery, F0 in the endoscopic group was (197.91 ±â€…24.15) Hz, which was significantly lower than that (206.77 ±â€…20.13) Hz in the robotic group. In the robotic group, there was no obvious decline in F0 and MPT in each follow-up period after surgery compared with those before surgery. In the endoscopic group, MPT declined significantly 1 week after the surgery compared with that before surgery. One week after surgery, MPT in the endoscopic group was (13.02 ±â€…9.28) s, which was significantly lower than that (17.55 ±â€…9.25) s in the robotic groups. There were no significant differences in Shimmer, Jitter, DSI and NHR during all postoperative follow-up periods compared with those before surgery in both groups. The voice function of robotic thyroid lobectomy via BABA is superior to endoscopic thyroid lobectomy.

Residual tumor model in esophageal squamous cell carcinoma after neoadjuvant immunochemotherapy: Frequently involves the mucosa and/or submucosa.

Objectives: The efficacy and safety of neoadjuvant immunochemotherapy (nICT) are widely explored in locally advanced esophageal squamous cell carcinoma (ESCC). Whether the "wait-and-see" strategy is applicable in ESCC after nICT is still lacking a theoretical basis. This study aimed to preliminarily explore the distribution of residual tumors and the regression pattern of ESCC after nICT. Methods: Patients undergoing radical esophagectomy after nICT in Fujian Medical University Union Hospital between January 2020 and March 2022 were identified. The resection specimens were re-evaluated by one experienced pathologist. The pathological response was assessed by tumor regression grade (TRG) (modified Ryan scheme). The TRG grade was divided into grades 0 (pathological complete response), 1, 2, and 3. The pathological stage was evaluated in the Eighth Edition AJCC. In the non-pCR group, the residual model was divided into four types: Type I, regression towards the lumen; type II, regression towards the invasive front; type III, concentric regression; and type IV, scattered regression. Results: A total of 95 consecutive patients were included for analysis. Seventy-six (80.0%) of 95 patients were in non-pCR (pathological complete response), and nine patients (9/76, 11.84%) had isolated residual tumors in lymph nodes. There was no significant difference in baseline characteristics between the pCR group and the non-pCR group (p > 0.05). The overall distribution of TRG for all esophageal wall layers was TRG 0 = 28 (28/95, 29.5%), TRG 1 = 17 (17/95, 17.9%), TRG 2 = 18 (18.9%, 18/95), and TRG 3 = 32 (32/95, 33.7%). In 67 patients with residual tumors in the esophageal wall (TRG ≧1), 63 (63/67, 94.0%) had residual tumor cells in the mucosa and/or submucosa, and four had isolated residual tumors in the muscle layer (4/67, 6.0%). Further analysis showed eight (8/67, 11.9%) patients with submucosal involvement but without mucosal involvement. The distribution of regression patterns was type I (n = 35, 52.2%), type II (n = 3, 4.5%), type III (n = 8, 11.9%), and type IV (n = 21, 31.3%). Conclusions: The mucosa and/or submucosa are frequently involved in residual malignancy, and the frequent regression models are regression toward the lumen and random regression. There is an opportunity to carefully test the residual tumors in a subgroup of the population with ESCC following nICT. However, some patients had residual tumors only in the muscle layer or lymph nodes. The clinical application of the wait-and-see strategy in ESCC after nICT should be explored using an appropriate evaluation protocol.