Recognition of Mycobacterium tuberculosis by macrophage Toll-like receptor and its role in autophagy.

BACKGROUND: The pathogen responsible for tuberculosis is called Mycobacterium tuberculosis. Its interaction with macrophages has a significant impact on the onset and progression of the disease. METHODS: The respiratory pathway allows Mycobacterium tuberculosis to enter the body's lungs where it battles immune cells before being infected latently or actively. In the progress of tuberculosis, Mycobacterium tuberculosis activates the body's immune system and creates inflammatory factors, which cause tissue inflammation to infiltrate and the creation of granulomas, which seriously harms the body. Toll-like receptors of macrophage can mediate host recognition of Mycobacterium tuberculosis, initiate immune responses, and participate in macrophage autophagy. New host-directed therapeutic approaches targeting autophagy for drug-resistant Mycobacterium tuberculosis have emerged, providing new ideas for the effective treatment of tuberculosis. CONCLUSIONS: In-depth understanding of the mechanisms by which macrophage autophagy interacts with intracellular Mycobacterium tuberculosis, as well as the study of potent and specific autophagy-regulating molecules, will lead to much-needed advances in drug discovery and vaccine design, which will improve the prevention and treatment of human tuberculosis.

Re-exploration of prognosis in type B thymomas: establishment of a predictive nomogram model.

OBJECTIVE: To explore the risk factors for disease progression after initial treatment of type B thymomas using a predictive nomogram model. METHODS: A single-center retrospective study of patients with type B thymoma was performed. The Cox proportional hazard model was used for univariate and multivariate analyses. Variables with statistical and clinical significance in the multivariate Cox regression were integrated into a nomogram to establish a predictive model for disease progression. RESULTS: A total of 353 cases with type B thymoma were retrieved between January 2012 and December 2021. The median follow-up was 58 months (range: 1-128 months). The 10-year progression-free survival (PFS) was 91.8%. The final nomogram model included R0 resection status and Masaoka stage, with a concordance index of 0.880. Non-R0 resection and advanced Masaoka stage were negative prognostic factors for disease progression (p < 0.001). No benefits of postoperative radiotherapy (PORT) were observed in patients with advanced stage and non-R0 resection (p = 0.114 and 0.284, respectively). CONCLUSION: The best treatment strategy for type B thymoma is the detection and achievement of R0 resection as early as possible. Long-term follow-up is necessary, especially for patients with advanced Masaoka stage and who have not achieved R0 resection. No prognostic benefits were observed for PORT.

Defensins: A novel weapon against Mycobacterium tuberculosis?

Tuberculosis (TB) is a serious airborne communicable disease caused by organisms of the Mycobacterium tuberculosis (Mtb) complex. Although the standard treatment antimicrobials, including isoniazid, rifampicin, pyrazinamide, and ethambutol, have made great progress in the treatment of TB, problems including the rising incidence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the severe toxicity and side effects of antimicrobials, and the low immunity of TB patients have become the bottlenecks of the current TB treatments. Therefore, both safe and effective new strategies to prevent and treat TB have become a top priority. As a subfamily of cationic antimicrobial peptides, defensins are rich in cysteine and play a vital role in resisting the invasion of microorganisms and regulating the immune response. Inspired by studies on the roles of defensins in host defence, we describe their research history and then review their structural features and antimicrobial mechanisms, specifically for fighting Mtb in detail. Finally, we discuss the clinical relevance, therapeutic potential, and potential challenges of defensins in anti-TB therapy. We further debate the possible solutions of the current application of defensins to provide new insights for eliminating Mtb.

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.

Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Real-world study of treatment and outcome of type B2 + B3 thymoma: The neglected part of thymoma.

BACKGROUND: This study aimed to examine the treatment and prognosis of patients with type B2 + B3 thymoma and compare it with those patients with type B2 and B3 thymoma. METHODS: We conducted a retrospective analysis of the results of 39 patients with type B2 + B3 thymoma, 133 patients with type B2 thymoma, and 64 patients with type B3 thymoma. The Kaplan-Meier technique was used to generate survival curves. For multivariate analysis, the Cox proportional hazard model was applied. RESULTS: With a median follow-up of 60 months (range: 1-128 months), the percentage of patients with tumor, node, metastasis (TNM) stage III and IV disease gradually increased from 19.5% to 25.6% to 35.9% among those with histological subtypes B2, B2 + B3, and B3, respectively, p = 0.045. Twenty-three patients experienced recurrence or metastasis. The total 10-year progression-free survival (PFS) rates were 86.0% overall (85.0% in type B2, 87.2% in type B2 + B3, and 87.5% in type B3). Age, R0 resection, and Masaoka-Koga stage were found to have a significant on PFS in all patients. There was no statistically significant difference in PFS between different histotypes of thymoma, p = 0.650. PFS was predicted by R0 resection in all histotypes and by the Masaoka-Koga stage in the type B2 subgroup. CONCLUSION: Combining the two staging methods to guide the diagnosis and treatment of patients with B2 + B3 thymoma is recommended. R0 resection is recommended to reduce recurrence. Patients with B2 + B3 thymoma have a prognosis similar to those with a B2 thymoma or a B3 thymoma alone.

Portal Biliopathy and Cavernous Transformation of the Portal Vein Revealed by 68Ga-FAPI PET/CT.

ABSTRACT: A 47-year-old man presented with right upper abdominal pain for 1 month. Contrast-enhanced CT revealed hilar bile duct stenosis with dilatation of the intrahepatic bile ducts, and his serum CA19-9 and CA242 levels were significantly elevated. 18F-FDG and 68Ga-FAPI PET/CT were performed for differential diagnosis. 18F-FDG PET/CT showed only mild FDG uptake in the hepatic hilum. Astonishingly, in 68Ga-FAPI PET/CT, intense radioactivity was presented on the same region, which indicated massive fibroblasts aggregation in hepatic hilum. The patient was finally diagnosed as portal biliopathy caused by cavernous transformation of the portal vein.

Comparative analysis of the long-term outcomes of segmentectomy and lobectomy for stage IA1 lung adenocarcinoma in patients with or without previous malignancy of other organs: a population-based study.

BACKGROUND: For early stage non-small cell lung cancer, whether limited resection can yield comparable outcomes to those of lobectomy hasn't been established. We compared Overall survival (OS) and lung cancer-specific survival (LCSS) after segmentectomy or lobectomy in stage IA1 (≤10 mm) lung adenocarcinoma (LUAD) patients. RESEARCH DESIGN AND METHODS: We retrospectively recruited patients who'd been diagnosed with lung cancer for the first time and treated with segmentectomy or lobectomy, with or without previous other malignancy. RESULTS: 1788 patients were included. After propensity score matching: 5-year OS were 85.6% for segmentectomy and 84.7% for lobectomy (p=0.951); 5-year LCSS were 93.5% for segmentectomy; and 93.0% for lobectomy (p=0.726). Cox regression analysis revealed segmentectomy was comparable to lobectomy in OS and LCSS. Having a second lung cancer later in life was associated with a worse LCSS for lobectomy (p<0.05) rather than segmentectomy. After patients were stratified according to malignancy history, subgroup analyses showed no significant prognosis differences between two surgeries. CONCLUSIONS: For stage IA1 LUAD patients who were diagnosed with lung cancer for the first time, with or without previous other malignancy, segmentectomy yields comparable outcomes to those of lobectomy. It may provide better outcomes for patients with multiple suspicious nodules.

Preoperative Prediction of Lymph Node Metastasis in Patients With Early-T-Stage Non-small Cell Lung Cancer by Machine Learning Algorithms.

Background: Lymph node metastasis (LNM) is difficult to precisely predict before surgery in patients with early-T-stage non-small cell lung cancer (NSCLC). This study aimed to develop machine learning (ML)-based predictive models for LNM. Methods: Clinical characteristics and imaging features were retrospectively collected from 1,102 NSCLC ≤ 2 cm patients. A total of 23 variables were included to develop predictive models for LNM by multiple ML algorithms. The models were evaluated by the receiver operating characteristic (ROC) curve for predictive performance and decision curve analysis (DCA) for clinical values. A feature selection approach was used to identify optimal predictive factors. Results: The areas under the ROC curve (AUCs) of the 8 models ranged from 0.784 to 0.899. Some ML-based models performed better than models using conventional statistical methods in both ROC curves and decision curves. The random forest classifier (RFC) model with 9 variables introduced was identified as the best predictive model. The feature selection indicated the top five predictors were tumor size, imaging density, carcinoembryonic antigen (CEA), maximal standardized uptake value (SUVmax), and age. Conclusions: By incorporating clinical characteristics and radiographical features, it is feasible to develop ML-based models for the preoperative prediction of LNM in early-T-stage NSCLC, and the RFC model performed best.

Glutathione S-Transferase Gene Polymorphisms are Associated with an Improved Treatment Response to Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis.

BACKGROUND Previous studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC. MATERIAL AND METHODS A literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed. RESULTS Twenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074-1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468-0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients. CONCLUSIONS Meta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.

C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis.

Activation of transforming growth factor ß1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (Col4a1-a5), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. Col4a1-a5 expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of Col4a1a2, Col4a3a4 and Col4a5 were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal Col4a1-a5 mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit Col4a1-a5 mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.

The association of matrix metalloproteinase-9 promoter polymorphisms with gastric cancer risk: a meta-analysis.

PURPOSE: A variety of studies have observed that the single nucleotide polymorphisms (SNPs) matrix metalloproteinase-9 (MMP-9) gene may be associated with the risk of gastric cancer(GC), and a cytosine (C) to thymine (T) mutation at the -1562 site of the MMP-9 gene promoter is reported to be closely related to the susceptibility. However, because of the conflicting results of these studies, we undertook a systematic meta-analysis to assess the association between the SNPs and the risk of gastric cancer. MATERIALS AND METHODS: A computerised literature search was conducted within the databases of PubMed, EMBASE, and ISI Web of Knowledge for studies on the genetic association of MMP-9-1562C/T and gastric cancer published from 2004 to 2015. The pooled odds ratio (OR) and 95% confidence intervals (CI) were estimated for each genotype using the dominant, recessive, co-dominant, and allelic models of the matrix metalloproteinase 9. RESULTS: Our analysis indicated a significant association of MMP-9-1562C/T with gastric cancer (dominant model [CT+TT/CC]: OR = 1.121, 95% CI = 0.965-1.304; recessive model [CC+CT/TT]: OR = 1.663, 95% CI = 1.148-2.408; co-dominant model [TT/CC]: OR = 1.666, 95% CI = 1.127-2.461; [CT/CC]: OR = 1.078, 95% CI = 0.923-1.259; allelic model [T/C]: OR = 1.150, 95% CI =1.014-1.304). CONCLUSIONS: Our meta-analysis results demonstrated that MMP-9-1562C/T promoter polymorphisms increase the risk of developing gastric cancer.