Whole-genome sequencing to characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in Yichang city of China.

Objective: The burden of both general and drug-resistant tuberculosis in rural areas is higher than that in urban areas in China. To characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in rural China, we used whole genome sequencing to analyze clinical strains collected from patients in two counties of Yichang for three consecutive years. Methods: From 2018 to 2020, sputum samples were collected for cultures from patients with suspected tuberculosis in Yidu and Zigui county, and DNA was extracted from the positive strains for genome sequencing. The online SAM-TB platform was used to identify the genotypes and drug resistance-related mutations of each strain, establish a phylogenetic tree, and calculated the genetic distances between pairwise strains. Twelve single nucleotide polymorphisms (SNPs) were used as thresholds to identify transmission clusters. The risk of related factors was estimated by univariable and multivariable logistic regression. Results: A total of 161 out of the collected 231 positive strains were enrolled for analysis, excluding non-tuberculous mycobacterium and duplicate strains from the same patient. These strains belonged to Lineage 2 (92, 57.1%) and Lineage 4 (69, 42.9%), respectively. A total of 49 (30.4%) strains were detected with known drug resistance-related mutations, including 6 (3.7%) multidrug-resistant-TB (MDR-TB) strains and 11 (6.8%) RIF-resistant INH-susceptible TB (Rr-TB) strains. Six of the MDR/Rr-TB (35.3%) were also resistant to fluoroquinolones, which made them pre-extensively drug-resistant TB (pre-XDR-TB). There were another seven strains with mono-resistance to fluoroquinolones and one strain with resistance to both INH and fluoroquinolones, making the overall rate of fluoroquinolones resistance 8.7% (14/161). A total of 50 strains (31.1%) were identified as transmission clusters. Patients under 45 years old (adjusted odds ratio 3.46 [95% confidential intervals 1.28-9.35]), treatment-naive patients (6.14 [1.39-27.07]) and patients infected by lineage 4 strains (2.22 [1.00-4.91]) had a higher risk of transmission. Conclusion: The drug resistance of tuberculosis in rural China, especially to the second-line drug fluoroquinolones, is relatively serious. The standardized treatment for patients and the clinical use of fluoroquinolones warrant attention. At the same time, the recent transmission risk of tuberculosis is high, and rapid diagnosis and treatment management at the primary care needs to be strengthened.

Prognostic and immunological role of CD36: A pan-cancer analysis.

CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

Clinical evidence for association of neoadjuvant chemotherapy or chemoradiotherapy with efficacy and safety in patients with resectable esophageal carcinoma (NewEC study).

BACKGROUND: The efficacy and safety of neoadjuvant treatment over surgery alone and that of neoadjuvant chemoradiotherapy (NCRT) over neoadjuvant chemotherapy (NCT) in resectable esophageal carcinoma remains inconclusive. This study (NewEC) used global data to comprehensively evaluate these comparisons and to provide a preferable strategy for patient subsets. METHODS: This study included a meta-analysis of randomized controlled trials (RCTs) identified from inception to May 2019 from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congresses and a registry-based cohort study with patients from Massachusetts General Hospital (Massachusetts, USA) and Guangdong Provincial People's Hospital (Guangzhou, China) recruited from November 2000 and June 2017, to cross-validate the comparisons among NCRT versus NCT versus surgery. The GRADE approach was used to assessed quality of evidence in meta-analysis. Neural network machine learning propensity score-matched analysis was used to account for confounding by patient-level characteristics in the cohort study. The primary endpoint was overall survival (OS). The study was registered with PROSPERO CRD42017072242 and ClinicalTrials.gov NCT04027543. FINDINGS: Of 22,070 studies assessed, there were 38 (n = 6,993 patients) eligible RCTs. Additionally, 423 out of 467 screened patients were included in the cohort study. The results from trials showed that NCT had a better OS than surgery alone (hazard ratio [HR] 0·88, 95% confidence interval [CI] 0·79-0·98; high quality) and was only favorable for adenocarcinoma (HR 0·83, 95% CI 0·72-0·96; moderate quality). High-quality evidence showed a significantly better OS for NCRT than surgery alone (HR 0·74, 95% CI 0·66-0·82) for both adenocarcinoma (HR 0·73, 95% CI 0·62-0·86) and squamous cell carcinoma (SCC) (HR 0·73, 95% CI 0·65-0·83). The OS benefit of NCRT over NCT was seen in the pairwise (HR 0·78, 95% CI 0·62-0·99; high quality) and network (HR 0·82, 95% CI 0·72-0·93; high quality) meta-analyses, with similar results before (HR 0·60, 95% CI 0·40-0·91) and after (HR 0·44, 95% CI 0·25-0·77) matching in the cohort study, leading to a significantly increased 5-year OS rate in both adenocarcinoma and SCC before and after matching. The increased benefits from NCT or NCRT were not associated with the risk of 30-day or in-hospital mortality. INTERPRETATION: NewEC Study provided high-quality evidence supporting the survival benefits of NCRT or NCT over surgery alone, with NCRT presenting the greatest benefit for resectable esophageal carcinoma. FUNDING: National Science and Technology Major Project, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, the Guangzhou Science and Technology Major Program, the Medical artificial intelligence project of Sun Yat-Sen Memorial Hospital, the Guangdong Science and Technology Department, the Guangdong Province Medical Scientific Research Foundation, and Guangdong Provincial People's Hospital Intermural Program.

Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer.

BACKGROUND: Previous preclinical and clinical studies have shown that levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in non-small cell lung cancer (NSCLC), and survival after therapy; however, this finding remains controversial. We performed a meta-analysis, to evaluate, systematically, the clinical utilization of TIL subtypes in patients with NSCLC. METHODS: The PubMed, ISI Web of Science, EMBASE, and Cochrane Library databases were searched to identify relevant studies. We pooled estimates of treatment effects, and hazards were summarized using random or fixed effects models to evaluate survival outcomes. RESULTS: A total of 24 relevant studies involving 7,006 patients were eligible. The median percentage of lymph node positivity was 45.7% (95% confidence interval [CI], 37.1-56.4%). Pooled analysis shows that high levels of CD8+ TILs had a good prognostic effect on survival with a hazard ratio (HR) of 0.91 (P = 0.013) for death and 0.74 (P = 0.001) for recurrence, as did high levels of CD3+ and CD4+ TILs, with HRs of 0.77 (P = 0.009) and 0.78 (P = 0.005) for death, respectively. By contrast, high levels of FoxP3+ regulatory TILs had a worse prognostic effect for overall and recurrence-free survival, with HRs of 1.69 (P = 0.042) and 1.79 (P = 0.001), respectively. No individual study affected the results, and no publication bias was found. CONCLUSIONS: Our findings support the hypothesis that TILs could be a prognostic marker in NSCLC. High-quality randomized studies are needed to verify statistically the effect of TILs on prognosis in future research.