Ensartinib is effective in the treatment of advanced non-small-cell lung cancer with MET amplification after multi-line ALK-TKIs resistance: a case report.

Although patients with ALK-positive non-small cell lung cancer (NSCLC) are initially effective on treatment with ALK tyrosine kinase inhibitors (TKIs), resistance will inevitably develop. Of these patients, 2/3 will develop ALK-independent resistance and little is known about the mechanisms of ALK-independent resistance. In pre-clinical studies, the activation of several bypass signaling pathways has been implicated in the development of resistance, including the MET, EGFR, SRC and IGF1R pathways. Among these, the MET pathway is one of the signaling pathways that has recently been extensively studied, and activation of this pathway is one of the mechanisms of ALK-independent drug resistance. Here, we report a successful case of an advanced NSCLC patient who was resistant to treatment with ALK TKIs and developed MET amplification, who achieved 23 months of progression-free survival after post-line treatment with ensartinib.

Inosine and D-Mannose Secreted by Drug-Resistant Klebsiella pneumoniae Affect Viability of Lung Epithelial Cells.

The antibiotic resistance rates of Klebsiella pneumoniae have been steadily increasing in recent years. Nevertheless, the metabolic features of the drug-resistant Klebsiella pneumoniae and its associated benefits for bacterial pathogenicity are far from expounded. This study aims to unravel the unique physiological and metabolic properties specific to drug-resistant K. pneumoniae. Using scanning electron microscopy (SEM), we observed a thicker extracellular mucus layer around a drug-resistant K. pneumonia strain (Kp-R) than a drug-sensitive K. pneumonia strain (Kp-S). Kp-R also produced more capsular polysaccharide (CPS) and biofilm, and appeared to have a significant competitive advantage when co-cultured with Kp-S. Moreover, Kp-R was easier to adhere to and invade A549 epithelial cells than Kp-S but caused less cell-viability damage according to cell counting kit-8 (CCK-8) tests. Immunofluorescence revealed that both Kp-R and Kp-S infection destroyed the tight junctions and F-actin of epithelial cells, while the damage caused by Kp-S was more severe than Kp-R. We detected the extracellular metabolites secreted by the two strains with UHPLC-Q-TOF MS to explore the critical secretion products. We identified 16 predominant compounds that were differentially expressed. Among them, inosine increased the viability of epithelial cells in a dose-dependent manner, and an A2AR antagonist can abolish such enhancement. D-mannose, which was secreted less in Kp-R, inhibited the viability of A549 cells in the range of low doses. These findings provide potential targets and research strategies for preventing and treating drug-resistant K. pneumoniae infections.

Degradation mechanism and pathway of tetracycline in milk by heterojunction N-TiO2-Bi2WO6 film under visible light.

N-doped TiO2-Bi2WO6 (NTB) three-component photocatalyst was prepared using a glycol solvothermal method. The photocatalysts and films were characterized, and applied to the degradation of tetracycline (TC) in milk and its effect on the quality of milk. The results show that the NTB photocatalyst exhibits good photocatalytic activity under visible light, and its TC degradation rate is increased by 1.76, 1.49, 1.42, 1.16, and 1.13 times higher than that of TiO2, Bi2WO6, N-TiO2, N-Bi2WO6 and TiO2-Bi2WO6, respectively. Due to the N doping, the photogenerated electron-hole pair recombination rate of photocatalyst is greatly reduced, which improving its photocatalytic performance. Additionally, the absorption wavelength threshold is enlarged by 459 nm, the gap width is reduced to 2.69 eV, and the degradation rate of TC is still 83.24 % after 5 repetitions. HPLC-MS revealed the active species, intermediates and photodegradation pathways in the photocatalytic process.

Calcifications in triple-negative breast cancer: Molecular features and treatment strategies.

Despite the high prevalence of mammographic calcifications, our understanding remains limited regarding the clinical and molecular features of calcifications within triple-negative breast cancer (TNBC). To investigate the clinical relevance and biological basis of TNBC with calcifications of high suspicion for malignancy, we established a study cohort (N = 312) by integrating mammographic records with clinical data and genomic, transcriptomic, and metabolomic profiling. Despite similar clinicopathological features, patients with highly suspicious calcifications exhibited a worse overall survival than those without. In addition, TNBC with highly suspicious calcifications was characterized by a higher frequency of PIK3CA mutation, lower infiltration of immune cells, and increased abnormality of lipid metabolism. Overall, our study systematically revealed clinical and molecular heterogeneity between TNBC with or without calcifications of high suspicion for malignancy. These data might help to understand the clinical relevance and biological basis of mammographic calcifications.

Single-cell morphological and topological atlas reveals the ecosystem diversity of human breast cancer.

Digital pathology allows computerized analysis of tumor ecosystem using whole slide images (WSIs). Here, we present single-cell morphological and topological profiling (sc-MTOP) to characterize tumor ecosystem by extracting the features of nuclear morphology and intercellular spatial relationship for individual cells. We construct a single-cell atlas comprising 410 million cells from 637 breast cancer WSIs and dissect the phenotypic diversity within tumor, inflammatory and stroma cells respectively. Spatially-resolved analysis identifies recurrent micro-ecological modules representing locoregional multicellular structures and reveals four breast cancer ecotypes correlating with distinct molecular features and patient prognosis. Further analysis with multiomics data uncovers clinically relevant ecosystem features. High abundance of locally-aggregated inflammatory cells indicates immune-activated tumor microenvironment and favorable immunotherapy response in triple-negative breast cancers. Morphological intratumor heterogeneity of tumor nuclei correlates with cell cycle pathway activation and CDK inhibitors responsiveness in hormone receptor-positive cases. sc-MTOP enables using WSIs to characterize tumor ecosystems at the single-cell level.

Molecular classification of hormone receptor-positive HER2-negative breast cancer.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2- breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2- breast cancer.

The association between smoking during pregnancy and hypertensive disorders of pregnancy: A systematic review and meta-analysis.

BACKGROUND: Smoking is a major public health problem. However, its association with hypertensive disorders of pregnancy (HDP) is inconclusive. OBJECTIVE: To find the association between smoking during pregnancy and HDP. SEARCH STRATEGY: We searched PubMed, Ovid and Cochrane Library up to March, 2021, using terms including "smoking" and "HDP". SELECTION CRITERIA: Observational studies that assessed the relationship between smoking during pregnancy and HDP were included. DATA COLLECTION AND ANALYSIS: Odds ratios (OR) and 95% confidence intervals (CI), and other necessary data were extracted. Stata16.0 MP was used to analyze statistics. MAIN RESULTS: A total of 13 studies were included. Meta-analysis revealed that smoking during pregnancy was a protective factor for HDP (OR 0.78, 95% CI 0.67-0.92), gestational hypertension (OR 0.74, 95% CI 0.69-0.79), and pre-eclampsia (OR 0.65, 95% CI 0.58-0.73). Subgroup analysis showed that smoking during pregnancy was a risk factor for HDP in Asia but a protective factor in Europe and North America. Neither quitting smoking before pregnancy nor during pregnancy had a statistically significant association with HDP. CONCLUSION: This meta-analysis revealed that smoking during pregnancy might prevent HDP, gestational hypertension, and pre-eclampsia. Smoking during pregnancy was a risk factor for HDP in Asia but a protective factor in Europe and North America.

Diabetes and Risks of Right-Sided and Left-Sided Colon Cancer: A Meta-Analysis of Prospective Cohorts.

Background and Aims: Diabetes is associated with an increased risk of colon cancer (CC). Epidemiologic studies previously reported a higher risk for right-sided colon cancer (RCC) compare to left-sided colon cancer (LCC), although data are conflicting. We performed a meta-analysis to investigate this issue. Methods: We systematically searched the PubMed, EMBASE, Web of Science and Cochrane Library database for prospective cohort studies published up to June 2021. Studies were included if they reported site-specific estimates of the relative risk (RR) between diabetes and the risks of RCC and LCC. Random effects meta-analyses with inverse variance weighting were used to estimate the pooled site-specific RRs and the RCC-to-LCC ratio of RRs (RRRs). Results: Data from 10 prospective cohort studies, representing 1,642,823 individuals (mainly white) and 17,624 CC patients, were included in the analysis. Diabetes was associated with an increased risk of both RCC (RR =1.35, 95% CI = 1.24-1.47) and LCC (RR = 1.18, 95% CI = 1.08-1.28). After adjusting for major risk factors, individuals with diabetes had a greater risk for RCC than for LCC (RRR = 1.13, 95% CI = 1.02-1.26), with no significant heterogeneity between studies (I2 = 0%). Conclusions: This meta-analysis indicates that diabetes is associated with a higher risk for RCC than for LCC. Our findings suggest that colonoscopic surveillance in diabetic patients with careful examination of the right colon is warranted.

Occupational exposure to organic solvents and breast cancer risk: a systematic review and meta-analysis.

Breast cancer is the most common cancer worldwide. Recent studies suggest that organic solvent exposure could be closely related to breast cancer, although the evidence remains controversial. Thus, we evaluated existing epidemiological evidence for the association between occupational solvent exposure and breast cancer. PubMed, Embase, and Cochrane Library were searched to identify published case-control and cohort studies that addressed occupational exposure to organic solvents and breast cancer, up to April, 2021. Meta-analyses using random-effects models were conducted to obtain the pooled odds ratios (OR) and 95% confidence intervals (CI) on the incidence of breast cancer in relation to occupational exposure. The pooled OR of breast cancer among workers exposed to organic solvents overall was 1.18 (95%CI, 1.11 ~ 1.25; I2 = 76.3%; 24 studies), compared to those with no exposure. After stratification by menopause and study location, it was revealed that the association between occupational exposure to organic solvents and the risk of breast cancer in postmenopausal women (OR, 1.35; 95% CI, 1.09 ~ 1.67; I2 = 73.4%; 7 studies) was significant, and there was also a clear association in workers in Europe (OR, 1.21; 95% CI, 1.12 ~ 1.32; I2 = 82.9%; 13 studies). We observed a significant association between occupational exposure to organic solvents and breast cancer in both cohort and case-control studies.

Identification and Validation of a Prognostic Immune-Related Alternative Splicing Events Signature for Glioma.

BACKGROUND: Glioma is the most common malignant brain tumor in adults, with its tumor-promoting immune microenvironment always being intricate to handle with. Amounts of evidence has accumulated to suggest that alternative splicing (AS) is related to tumor immune microenvironment. However, comprehensive analysis of immune-related AS events and their clinical significance are still lacking in glioma. METHODS: AS events and transcriptome data of 653 glioma patients were downloaded online. ssGSEA was performed on transcriptome data of 653 patients to divided them into low, medium and high immune cell infiltration groups. Immune-related AS events were filtrated based on this grouping. Then lasso Cox regression analysis and multivariate Cox regression analysis were done to achieve an immune-related AS events prognostic signature for glioma. Kaplan-Meier analysis, ROC analyses, univariate Cox regression and multivariate Cox regression were performed to reveal the independent prognostic role of this signature. Meanwhile, a nomogram was constructed to achieved better prognostic value for glioma patients. Besides, functional enrichment analyses and correlation analyses with immune cells infiltration were used to validated the immune-related characteristic of this signature. RESULTS: 36 immune-related AS events were achieved based on the grouping mentioned above. A nine-immune-related alternative splicing event signature was built for glioma patients. This signature showed an independent prognostic value and a nomogram containing gender, age, Karnofsky performance score, grade, IDH status, MGMT promoter status and risk score derived from the signature was constructed with a higher predictive ability for overall survival. Association with the infiltration of immune cell subtypes was validated and functional enrichment analysis found that the signature was mainly enriched in immune-related and pro-tumor functions. CONCLUSION: Our research presented all immune-related AS events in glioma, identified an immune-related prognostic AS events risk model and a nomogram was constructed to predict the prognosis individually and more precisely. Tight connection was verified between this signature and clinical characteristics. Also, immune cells infiltration and immune checkpoints expression level were proved to link to risk scores, which enhanced the understanding of relationship between AS events and glioma immune microenvironment, firstly revealing the potential role of AS in immunotherapy of glioma.

Transcriptome Changes of Mycobacterium marinum in the Process of Resuscitation From Hypoxia-Induced Dormancy.

Nearly one-third of the world's population is latently infected with Mycobacterium tuberculosis (M. tb), which represents a huge disease reservoir for reactivation and a major obstacle for effective control of tuberculosis. During latent infection, M. tb is thought to enter nonreplicative dormant states by virtue of its response to hypoxia and nutrient-deprived conditions. Knowledge of the genetic programs used to facilitate entry into and exit from the nonreplicative dormant states remains incomplete. In this study, we examined the transcriptional changes of Mycobacterium marinum (M. marinum), a pathogenic mycobacterial species closely related to M. tb, at different stages of resuscitation from hypoxia-induced dormancy. RNA-seq analyses were performed on M. marinum cultures recovered at multiple time points after resuscitation. Differentially expressed genes (DEGs) at each time period were identified and analyzed. Co-expression networks of transcription factors and DEGs in each period were constructed. In addition, we performed a weighted gene co-expression network analysis (WGCNA) on all genes and obtained 12 distinct gene modules. Collectively, these data provided valuable insight into the transcriptome changes of M. marinum upon resuscitation as well as gene module function of the bacteria during active metabolism and growth.