Plasma metabolomics identifies S-adenosylmethionine as a biomarker and potential therapeutic target for vascular aging in older adult males.

Brachial-ankle pulse wave velocity (baPWV) is a noninvasive index of vascular aging. However, the metabolic profile underlying vascular aging has not yet been fully elucidated. The current study aimed to identify circulating markers of vascular aging as assessed by baPWV and to elucidate its mechanism from a metabolomic perspective in older adults. A total of 60 and 61 Chinese male participants aged ≥80 years were recruited to the metabolome and validation cohorts, respectively. The baPWV of participants was measured using an automatic waveform analyzer. Plasma metabolic profile was investigated using ultra-performance liquid chromatography coupled with triple quadrupole linear ion trap tandem mass spectrometry. Orthogonal partial least squares (OPLS) regression modeling established the association between metabolic profile and baPWV to determine important metabolites predictive of vascular aging. Additionally, an enzyme-linked immunosorbent assay was employed to validate the metabolites in plasma and culture media of vascular smooth muscle cells in vitro. OPLS modeling identified 14 and 22 metabolites inversely and positively associated with baPWV, respectively. These 36 biomarkers were significantly enriched in seven metabolite sets, especially in cysteine and methionine metabolism (p <0.05). Notably, among metabolites involved in cysteine and methionine metabolism, S-adenosylmethionine (SAM) level was inversely related to baPWV, with a significant correlation coefficient in the OPLS model (p <0.05). Furthermore, the relationship between SAM and vascular aging was reconfirmed in an independent cohort and at the cellular level in vitro. SAM was independently associated with baPWV after adjustments for clinical covariates (ß = -0.448, p <0.001) in the validation cohort. In summary, plasma metabolomics identified an inverse correlation between SAM and baPWV in older males. SAM has the potential to be a novel biomarker and therapeutic target for vascular aging.

Application of a Comprehensive Model Based on CT Radiomics and Clinical Features for Postoperative Recurrence Risk Prediction in Non-small Cell Lung Cancer.

RATIONALE AND OBJECTIVES: We constructed a comprehensive model by combining the radiomics and clinical features of tumors to predict the recurrence risk of patients with operable stage IA-IIIA non-small cell lung cancer (NSCLC). Our aim was to improve the accuracy of prognostic prediction and provide personalized treatment plans to enhance patient outcomes. MATERIALS AND METHODS: We retrospectively analyzed 152 surgically treated patients with pathologically confirmed stage IA-IIIA NSCLC. These patients were randomly divided into a training cohort and a test cohort in an 8:2 ratio. Using the 3D Slicer image computing platform, we manually delineated the regions of interest (ROI) for all lesions and extracted radiomics features using Python. We used the Least Absolute Shrinkage and Selection Operator (LASSO) to select the radiomics features, while the COX multivariate regression model was employed to identify independent clinical risk factors for recurrence. Finally, we utilized logistic regression (LR) to build the model and validated it using the receiver operating characteristic curve (ROC). The predictive performance of the model was evaluated using the concordance index (C-index), and the clinical value of the model was compared through decision curve analysis (DCA). RESULTS: We extracted a total of 1562 radiomics features. After feature selection, we retained 29 features. The COX multivariate regression model demonstrated that the N stage was an independent risk factor for postoperative recurrence. In the training and test cohorts, the area under the curve (AUC) values of the radiomics-clinical comprehensive model were 0.972 and 0.937, respectively, while the C-index values were 0.815 and 0.847. These values surpassed those of the standalone clinical model or radiomics model. CONCLUSION: Our study demonstrates that a comprehensive model based on CT radiomics and clinical features can effectively stratify the risk of postoperative recurrence in patients with operable NSCLC. It provides a powerful tool for accurately stratifying the risk of high-risk patients after surgery.

Complete response to first-line osimertinib monotherapy in a complex epidermal growth factor receptor mutant ( L833V / H835L ) lung adenocarcinoma patient: a case report.

Although uncommon epidermal growth factor receptor (EGFR) mutations account for 10-15% EGFR mutant non-small cell lung cancer (NSCLC) patients, clinical evidence for uncommon EGFR mutations, such as complex mutations remain limited. In this study, we reported a NSCLC patient harboring complex EGFR L833V / H835L mutation in exon 21, who had a complete response to first-line osimertinib monotherapy. The patient admitted to our hospital for space-occupying lesions of right lower lung during an annual health checkup, and was diagnosed as stage IIIA lung adenocarcinoma. Targeted next-generation sequencing (NGS) on tumor samples showed a complex EGFR mutation: L833V / H835L in exon 21. Therefore, she was treated with osimertinib monotherapy and complete remission achieved soon. During follow-up period, no metastasis was found and serum carcinoembryonic antigen returned to normal. In addition, NGS monitoring of mutations in circulating tumor DNA maintained negative. The patient remain benefitted for osimertinib monotherapy over 22 months with no disease progression. Our case firstly provided clinical evidences of first-line osimertinib therapy in lung cancer patients with rare L833V / H835L EGFR mutation.

Molecular characteristics of multiple primary pulmonary nodules under a three-dimensional reconstruction model and relevant multi-omics analyses: a case report.

Background: In addition to CT images and pathological features, many other molecular characteristics remain unknown about multiple primary lung cancer (MPLC) from intrapulmonary metastatic lung cancer. Case presentation: In this study, we reported a patient with an early-stage MPLC with both adenocarcinoma in situ (AIS) subtype and minimally invasive adenocarcinoma (MIA) subtype. The patient was diagnosed with more than 10 nodules and underwent precise surgery assisted by three-dimensional (3D) reconstruction at the left upper lung lobe. Whole-exome sequencing (WES) and multiple immunohistochemistry (mIHC) were performed to reveal the genomic profiling and tumor microenvironments of multiple nodules in this patient with MPLC. Based on 3D reconstruction location information, we found that the genomic and pathological results of adjacent lymph nodes were quite different. On the other hand, PD-L1 expression and the proportion of infiltrating lymphocytes in tumor microenvironments were all at a low status and did not vary in adjacent lymph nodes. Additionally, maximum diameter and tumor mutational burden levels were found to be significantly associated with CD8+ T cell proportion (p<0.05). Besides, CD163+ macrophages and CD4+ T cell proportion were higher in MIA nodules than in AIS nodules (p<0.05). This patient reached a recurrence-free survival of 39 months. Conclusion: Generally, in addition to CT imaging and pathological results, genomic profiling and tumor microenvironments may facilitate identifying the potential molecular mechanisms and clinical outcomes in patients with early-stage MPLC.

Watershed analysis in wedge resection of pulmonary pure ground-glass nodules hardly localized by CT-guided puncture.

BACKGROUND: To investigate the feasibility and safety of watershed analysis after target pulmonary vascular occlusion for the wedge resection in patients with non-palpable and non-localizable pure ground-glass nodules during uniport thoracoscopic surgery. METHODS: A total of 30 patients with pure ground-glass nodules < 1 cm in diameter, localized in the lateral third of the lung parenchyma, were enrolled. Three-dimensional reconstruction of thin-section computed tomography (CT) data was performed using Mimics software before surgery to observe and identify the target pulmonary vessels supplying the lung tissue in the area where the pulmonary nodules were localized and to temporarily block the target pulmonary vessels during surgery. Next, the extent of the watershed was determined with the expansion-collapse method, and finally, wedge resection was performed. After wedge resection of the target lung tissue, the blocked pulmonary vessel was released, thus allowing operators to complete the procedure without damaging pulmonary vessels. RESULTS: None of the patients experienced postoperative complications. The chest CT of all patients was reviewed six months after the operation, revealing no tumor recurrence. CONCLUSIONS: Our results suggest that watershed analysis following target pulmonary vascular occlusion for wedge resection in pulmonary pure ground-glass nodules is a safe and feasible approach.

Tumor immune microenvironment predicts the pathologic response of neoadjuvant chemoimmunotherapy in non-small-cell lung cancer.

The clinical outcome of resectable non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant chemoimmunotherapy is good but varies greatly. In addition, the pathological response after neoadjuvant chemoimmunotherapy is significantly associated with survival outcomes. The aim of this retrospective study was to identify which population of patients with locally advanced and oligometastatic NSCLC has a favorable pathological response after neoadjuvant chemoimmunotherapy. NSCLC patients treated with neoadjuvant chemoimmunotherapy were enrolled between February 2018 and April 2022. Data on clinicopathological features were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment puncture specimens and surgically resected specimens. In total, 29 patients with stages III and IV locally advanced or oligometastatic NSCLC who received neoadjuvant chemoimmunotherapy and R0 resection were enrolled. The results showed that 55% (16/29) of patients had a major pathological response (MPR) and 41% (12/29) of patients had a complete pathological response (pCR). In the stroma area of the pre-treatment specimen, the higher infiltration of CD3+ PD-L1+ tumor-infiltrating lymphocytes (TILs) and the lower infiltration of CD4+ and CD4+ FOXP3+ TILs were more likely to appear in patients with pCR. However, in the tumor area, the higher infiltration of CD8+ TILs was more likely to appear in patients with non-MPR. In the post-treatment specimen, we found increased infiltration of CD3+ CD8+ , CD8+ GZMB+ , and CD8+ CD69+ TILs and decreased infiltration of PD-1+ TILs both in the stroma and tumor areas. Neoadjuvant chemoimmunotherapy achieved an MPR rate of 55% and induced greater immune infiltration. In addition, we observed that the baseline TILs and their spatial distribution correlate to the pathological response.

The Association between the Risk of Esophageal Cancer and Type 2 Diabetes Mellitus: An Updated Meta-Analysis.

Background: A large amount of publications had reported the association between incidence of esophageal cancer (EC) and type 2 diabetes mellitus (T2DM) in the past decade. However, those papers' results are inconsistent on relationships between T2DM the incidence of EC. Therefore, the objective of this meta-analysis was to determine the relationship between T2DM and the risk of EC (including 2 histological types, esophageal adenocarcinoma [EADC] and esophageal squamous cell carcinoma [ESCC]). Method: We finally extracted 19 articles though Pubmed, Embased, and Cochrane library. Those identify extraction date including 14,312 cases and 24,959,067 control records and then mixed the relative risks (RRs) and corresponding 95% confidence intervals (95%CIs) through STATA. Results: We observed that there are significantly positive correlation between T2DM and EC risk (RR = 1.28, 95% CI: 1.05-1.57, P = 0.015).Also, our study showed positive correlation between T2DM and EADC (esophageal adenocarcinoma) risk (RR = 1.28, 95% CI: 1.05-1.57, P < 0.001). What's more, subgroup analysis based on ethnicity represented the Caucasian is more susceptible to EC (RR = 1.28 ,95% CI: 1.10-1.49, P = 0.001). Conclusion: Those results offer a recent epidemiological and integrated evidence to ascertain the correlations between T2DM and incidence of EC. Those results take public health implications on preventing T2DM and then depress the occurrence of EC. Our study also provides referenced information for the prevention. However, some data is still insufficient, and more research should be carried out.

Zearalenone-Induced Mechanical Damage of Intestinal Barrier via the RhoA/ROCK Signaling Pathway in IPEC-J2 Cells.

Zearalenone (ZEN) is a widespread contaminant of cereals and agricultural products which causes food safety issues. Ingesting food or feed contaminated with ZEN can disrupt the intestinal epithelial barrier function. The RhoA/ROCK signaling pathway plays a key role in regulating the epithelial barrier function, but studies on such roles have rarely focused on the intestine. The aim of this experiment was to investigate the exact mechanism of ZEN-induced intestinal barrier damage and whether the RhoA/ROCK signaling pathway is involved. The results showed that ZEN significantly induced alkaline phosphatase (AP) activity and FITC-dextran (4 kDa) passage across the epithelial barrier, which significantly reduced the transepithelial resistance (TEER). Meanwhile, ZEN could induce the significantly down-regulated mRNA expression of tight junction proteins (occludin, claudin-1, ZO-1, and claudin-3) and redistribution of ZO-1 immunofluorescence. Further studies demonstrated that ZEN exposure activated the RhoA/ROCK signaling pathway, significantly up-regulated the mRNA expression of ROCK1, the main effector of the signaling pathway, the protein expression of phosphorylated myosin light chain (MLC) and myosin light chain kinase (MLCK), and relatively increased the activity of ATP in cells, simultaneously remodeling the cytoskeleton (F-actin). Overall, our study indicated that ZEN induced intestinal barrier dysfunction by activating the RhoA/ROCK signaling pathway.

Salvianolic Acid B Suppresses Non-Small-Cell Lung Cancer Metastasis through PKM2-Independent Metabolic Reprogramming.

Objective: Salvianolic acid B (Sal B) has been demonstrated to be a potential chemoprevention agent for several cancers. Herein, we investigated the pharmacological function of Sal B on non-small-cell lung cancer (NSCLC) metastasis. Methods: Two NSCLC cell lines (NCI-H2030 and NCI-H1650) were disposed of by 200 µM Sal B or 10 µM PKM2 agonist TEPP-46. Wound healing and transwell experiments were implemented for analyzing migratory and invasive capacities. Epithelial-to-mesenchymal transition (EMT) markers ß-catenin and E-cadherin were measured via western blotting. Cellular bioenergetics were evaluated with glucose uptake, lactate production, enolase activity, cellular ATP levels, as well as seahorse-based oxygen consumption rate (OCR), extracellular acidification rate (ECAR) analysis. Metabolic reprogramming markers PKM2, LDHA, and GLUT1 were detected via western blotting and immunofluorescence. Results: The results showed that Sal B disposal weakened the migration and invasion of NCI-H2030 and NCI-H1650 cells and inactivated the EMT process according to downregulation of ß-catenin and upregulation of E-cadherin. Sal B-treated NSCLC cells displayed decreased glucose uptake, lactate production, enolase activity, cellular ATP levels, OCR, and ECAR, indicating a reduction in metabolic reprogramming. Additionally, Sal B downregulated the expression of PKM2, LDHA, and GLUT1. TEPP-46 may reverse the inhibitory effect of Sal B on metastasis as well as metabolic reprogramming. Conclusion: Our findings provide evidence that Sal B enables to weaken NSCLC metastasis through PKM2-independent metabolic reprogramming, which sheds light on the promising therapeutic usage of Sal B in treating NSCLC.

Epidemiological Evidence Between Variants in Matrix Metalloproteinases-2, -7, and -9 and Cancer Risk.

Background: Matrix metalloproteinases (MMPs), a kind of proteases, have a critical function in cancer occurrence, invasion, and migration. MMP gene variants (e.g., MMP-2, MMP-7, and MMP-9) can affect the biological functions of these enzymes and lead to the occurrence and progression of cancer, which has become a hot topic in recent years, but the corresponding results are still controversial. In this context, here, the meta-analysis was conducted for assessing the relations of variants in MMP-2, MMP-7, and MMP-9 with the risk of various cancers. Methods: PubMed, Web of Science, and Medline were systemically searched, and data were extracted from all eligible studies so as to investigate the susceptibility of MMP-2, MMP-7, and MMP-9 to different types of cancers. The association between a variant in MMP and cancer susceptibility was analyzed through odds ratios (ORs) as well as 95% CIs. The Venice criteria and false-positive report probability (FPRP) were adopted to evaluate epidemiological evidence of significant associations discovered. Results: The associations between the variants of MMPs and cancer risk in 36,530 cases and 41,258 controls were found, with 12 associations (MMP-2 rs243865 with esophageal cancer and lung cancer, MMP-7 rs11568818 with bladder and cervical cancer, and MMP-9 rs3918242 with breast cancer) rated as strong associations for cancer risk and 7 and 15 as moderate and weak associations, respectively. These significant associations were mostly found in Asians. Conclusions: These findings support the relations between variants of MMP-2, MMP-7, and MMP-9 and various cancers risk, demonstrating the credibility of these relations.

Alteration of N6-Methyladenosine mRNA Methylation in a Human Stem Cell-Derived Cardiomyocyte Model of Tyrosine Kinase Inhibitor-Induced Cardiotoxicity.

Background: N6-methyladenosine (m6A) plays important roles in various cardiovascular diseases (CVDs), including cardiac hypertrophy and heart failure. Sunitinib (SUN) is a tyrosine kinase inhibitor (TKI) that is widely used in the treatment of different types of solid and blood tumors, but its efficacy is restricted by a concomitant rise in cardiotoxicities. However, the methylation modification of m6A messenger RNA (mRNA) in cardiomyocytes treated with TKI has not been investigated. Methods: The global m6A methylation level of SUN-induced cardiotoxicity was detected by m6A dot blot and colorimetric methylation assay. MeRIP-Seq (methylated RNA immunoprecipitation sequencing) and RNA-seq (RNA sequencing, input) were employed to depict the landscapes of transcriptome and epitranscriptome in TKI. Changes in major m6A-related enzymes were detected by qRT-PCR and Western blot. In addition, the effects of FTO on SUN-induced cardiotoxicity were evaluated by gain and loss of function studies. Results: In this study, we observed that the m6A methylation level was significantly elevated in SUN-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and paralleled a positively correlated cellular damage level. Through a genome-wide analysis of m6A mRNA methylation by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and input RNA sequencing (RNA-seq), we identified a total of 2,614 peaks with significant changes, of which 1,695 peaks were significantly upregulated and 919 peaks were significantly downregulated. Quantitative reverse transcription PCR (RT-qPCR), immunofluorescence, and Western blotting revealed that the RNA demethylase fat mass and obesity-associated protein (FTO) was downregulated, whereas the RNA methylases methyltransferase-like 14 (METTL14) and wilms' tumor 1-associating protein (WTAP) were upregulated. Furthermore, gain- and loss-of-function studies substantiated that FTO is cardioprotective in TKI. Conclusion: This study deciphered the methylation modification of m6A mRNA in hiPSC-CMs post-TKI treatment and determined that FTO may be a promising therapeutic target for TKI-induced cardiotoxicity.

Transcription factor NFIC functions as a tumor suppressor in lung squamous cell carcinoma progression by modulating lncRNA CASC2.

Nuclear factor I (NFI) family is emerging found playing oncogenic or tumor-suppressive potential in cancers. However, the function and underlying mechanisms of NFIC, in the progression of Lung Squamous Cell Carcinoma (LUSC) remain unclear. Therefore, this study aims to probe into the function of NFIC in the development of LUSC. In the present study, we reported that NFIC was low expressed in human LUSC tissues and cell lines. NFIC inhibited LUSC cell proliferation and promoted cell apoptosis in vitro and in vivo. Moreover, NFIC also inhibited LUSC cell migration and invasion. Furthermore, we found that there were binding sites between lncRNA cancer susceptibility candidate 2 (CASC2) and NFIC, whose relationship was confirmed by the luciferase reporter assay. The expression of CASC2 and the expression of NFIC were positively correlated, and the function of CASC2 overexpression is similar to that of NFIC overexpression, which suggested that CASC2 may play a key role in LUSC development. Our study provided a new perspective for NFIC acting as an antioncogene in LUSC tumorigenesis, and NFIC and CASC2 may serve as novel potential targets for the treatment of LUSC.

The Antagonistic Effect of Glutamine on Zearalenone-Induced Apoptosis via PI3K/Akt Signaling Pathway in IPEC-J2 Cells.

Zearalenone (ZEN) is a non-steroidal estrogen mycotoxin produced by Fusarium fungi, which inevitably exists in human and animal food or feed. Previous studies indicated that apoptosis seems to be a key determinant of ZEN-induced toxicity. This experiment aimed to investigate the protective effects of Glutamine (Gln) on ZEN-induced cytotoxicity in IPEC-J2 cells. The experimental results showed that Gln was able to alleviate the decline of cell viability and reduce the production of reactive oxygen species and calcium (Ca2+) induced by ZEN. Meanwhile, the mRNA expression of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, and catalase was up-regulated after Gln addition. Subsequently, Gln supplementation resulted in the nuclear fission and Bad-fluorescence distribution of apoptotic cells were weakened, and the mRNA expression and protein expression of pro-apoptotic genes and apoptotic rates were significantly reduced. Moreover, ZEN reduced the phosphorylation Akt, decreased the expression of Bcl-2, and increased the expression of Bax. Gln alleviated the above changes induced by ZEN and the antagonistic effects of Gln were disturbed by PI3K inhibitor (LY294002). To conclude, this study revealed that Gln exhibited significant protective effects on ZEN-induced apoptosis, and this effect may be attributed to the PI3K/Akt signaling pathway.

Characteristics of Oral Microbiota in Patients with Esophageal Cancer in China.

Gut microbiota dysbiosis is closely associated with intestinal carcinogenesis, but the oral microbiota of patients with esophageal squamous cell carcinoma who live in high-risk regions in China has not been fully characterized. In the current study, oral microbial diversity was investigated in 33 patients with esophageal squamous cell carcinoma and 35 healthy controls in Chongqing, China, by sequencing 16S rRNA of V3-V4 gene regions. There were statistically significant differences in oral microbiota between esophageal squamous cell carcinoma patients and controls as determined via unweighted pair-group analysis with arithmetic means. At the phylum level, in esophageal squamous cell carcinoma patients, there were comparatively greater amounts of Firmicutes (34.0% vs. 31.1%) and Bacteroidetes (25.3% vs. 24.9%) and lower amounts of Proteobacteria (17.0% vs. 20.1%). At the genus level, esophageal squamous cell carcinoma patients exhibited comparatively greater amounts of Streptococcus (17.3% vs. 14.5%) and Prevotella_7 (8.6% vs. 8.5%) and lower amounts of Neisseria (8.1% vs. 10.7%). Using a linear discriminant analysis effect size method, Planctomycetes and Verrucomicrobia were identified in the esophageal squamous cell carcinoma group. 10 genera were higher abundances identified in the healthy control group, and different 10 genera were identified in the esophageal squamous cell carcinoma group. In the present study, there were significant differences in oral microbial compositions of esophageal squamous cell carcinoma patients and healthy controls. Further longitudinal and mechanistic studies are needed to further characterize relationships between oral microbiota and esophageal squamous cell carcinoma.

Integrative Analysis of HTNV Glycoprotein Derived MHC II Epitopes by In Silico Prediction and Experimental Validation.

Hantaan virus (HTNV), the causative pathogen of hemorrhagic fever with renal syndrome (HFRS), is a negative RNA virus belonging to the Orthohantaviridae family. HTNV envelope glycoprotein (GP), encoded by the genomic medium segment, is immunogenic and is therefore a promising vaccine candidate. Major histocompatibility complex class I (MHC-I) epitopes derived from HTNV has been extensively studied, but little is known of MHC-II epitopes. In silico predictions based on four databases indicated that the full-length HTNV GP has 1121 15-mer epitopes, of which 289 had a high score for binding to the human and murine MHC-II superfamily. It found that epitope ILTVLKFIANIFHTS could potentially bind most MHC-II molecules covering human and murine haplotypes. Dominant epitopes were validated by enzyme-linked immunospot assay of splenocytes from immunized mice; 6 of 10 epitopes supported the predictions including TATYSIVGPANAKVP, TKTLVIGQCIYTITS, FSLLPGVAHSIAVEL, CETYKELKAHGVSCP, CGLYLDRLKPVGSAY, and NLGENPCKIGLQTSS. Conservation analysis of dominant epitopes revealed host-virus interactions without geographic stratification, thus meeting the requirements of candidate vaccines for large-population prophylaxis. These findings provide insight into hantavirus antigenicity and suggest that vaccines targeting MHC-II could provide immune protection in large population to complement symptomatic therapies for the treatment of HFRS.

Durable Response to Immunotherapy With Antiangiogenic Drug in Large-Cell Lung Carcinoma With Multiple Fulminant Postoperative Metastases: A Case Report.

Immunotherapy alone or chemo-immunotherapy has recently been recommended for treating advanced lung carcinoma in patients without driver mutations. However, the efficacy of immunotherapy and molecular mechanism in large-cell lung cancer (LCLC) remains unclear. Here, we reported a rare case of multiple fulminant postoperative body and mouth metastases in LCLC treating with combination immunotherapy. Initially, the patient was diagnosed as early stage LCLC and underwent a radical resection of the right lower lobe. Just one month later, multiple fulminant body and mouth lesions appeared in the right upper arm, right elbow, right waist, and tongue root. Meanwhile, serum neuron specific enolase (NSE) concentration dramatically increased from 12.12 to 30.14 ng/ml. Immumohistochemistry findings demonstrated moderate PD-L1 expressions with tumor proportion score (TPS), while next-generation sequencing indicated moderate tumor mutational burden (TMB) levels and gene mutations in PBRM1 L1230P and TP53 L194R of both foci. Besides, loss of heterozygosity (LOH) at human leukocyte antigen (HLA) class I (HLA-A*02:03, HLA-B*55:02 and HLA-C*12:03) were detected in the right upper arm metastasis, which may facilitate malignant postoperative metastases in this case. Notably, this patient received combination therapy with anti-PD-1 antibody sintilimab plus anlotinib, and achieved a partial response for at least 12 months. Using an integrated computational method, the mutant peptide TEIPENDIPL derived from PBRM1 L1230P was predicted to be a specific neoantigen and could still be presented by HLA-B*40:01. This case suggests that immunotherapy plus antiangiogenic drug may provide an alternative therapeutic option for advanced LCLC patients without common gene mutations.

Rupture of contralateral mainstem bronchus during uniportal video-assisted thoracoscopy surgery lobectomy and 3 successful cases of repair.

BACKGROUND: Our goal was to discuss the treatment for rupture of contralateral mainstem bronchus during uniportal video-assisted thoracoscopy surgery (uniportal VATS) lobectomy. CASE PRESENTATION: We analyzed clinical data of 3 cases of rupture of contralateral mainstem bronchus during uniportal VATS. Surgical repair was performed immediately under an uniportal VATS during operation, as a result, 3 cases of bronchial rupture all were repaired successfully, and we continued to complete lobectomy and systemic lymph node dissection. Reexamination was performed after 1 week, and no fistula was found in trachea and bronchi through a fiberoptic bronchoscopy. The time range for indwelling the chest tube is 6-9 days, and the hospital stay is 8-10 days. No abnormality was observed on chest radiography when the 3 patients returned to the hospital 1 month after the operation for the second reexamination. CONCLUSIONS: Instant surgical repair is recommended to the treatment of bronchial rupture in thoracic surgery. It is safe and feasible to repair bronchial tear with uniportal VATS.

Prognostic value of long noncoding RNA urothelial carcinoma-associated 1 in esophageal carcinoma: A protocol for meta-analysis, TCGA data and bioinformatics analysis.

BACKGROUND: Currently, an increasing number of long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human carcinomas and play a vital role in tumourigenesis. Some studies have been carried out to investigate the influence of the expression of LncRNA human urothelial carcinoma associated 1 (UCA1) on prognosis and clinical significance in patients with esophageal cancer, but the results are contradictory and uncertain. A meta-analysis and was conducted with controversial data to accurately assess the issue. We collected relevant TCGA data to further testify the result. In addition, bioinformatics analysis was conducted to investigate the mechanism and related pathways of LncRNA UCA1 in esophageal carcinoma. METHODS: Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science were thoroughly searched for relevant information. Two reviewers independently performed data extraction and literature quality evaluation. Odd ratio and its 95% confidence intervals were applied to evaluate the relationship between LncRNA UCA1 and clinicopathological characteristics of esophageal carcinoma patients. Hazard ratios and its 95% confidence intervals were adopted to assess the prognostic effects of LncRNA UCA1 on overall survival and disease-free survival. Meta-analysis was performed with Stata 14.0 software. To further assess the function of LncRNA UCA1 in esophageal carcinoma, relevant data from The Cancer Genome Atlas (TCGA) database was collected. Three databases, miRWalk, TargetScan, and miRDB, were used for prediction of target genes. Genes present in these 3 databases were considered as predicted target genes of LncRNA UCA1. Venny 2.1 were used for intersection analysis. Subsequently, GO, KEGG, and PPI network analysis were conducted based on the overlapping target genes of LncRNA UCA1 to explore the possible molecular mechanism in esophageal carcinoma. RESULTS: This study provides a high-quality medical evidence for the correlation between LncRNA UCA1 expression and overall survival, and between disease-free survival and clinicopathological features. Based on bioinformatics analysis, this study enhanced the understanding of the mechanism and related pathways of LncRNA UCA1 in esophageal carcinoma. CONCLUSION: The study provides updated evidence to evaluate whether the expression of LncRNA UCA1 is in association with poor prognosis in patients with esophageal carcinoma. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/8MCHW.

Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.

BACKGROUND: Neoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC. METHODS: This study was conducted in a total of 2 hospitals in the Chinese cities of Xi'an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA-IIIB NSCLC. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (3-4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle. RESULTS: Twenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%). CONCLUSIONS: Our results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.

A multicenter single-arm trial of sintilimab in combination with chemotherapy for neoadjuvant treatment of resectable esophageal cancer (SIN-ICE study).

BACKGROUND: Preoperative chemotherapy or chemoradiotherapy is the standard treatment for resectable esophageal cancer (EC); however, it is associated with increased postoperative complications and mortality. Recently, Immune Checkpoint inhibitors have been incorporated in the treatment of advanced EC. Its role in the preoperative setting has not been established yet. In this multicenter, single-arm study, we evaluated the efficacy and safety of neoadjuvant therapy with sintilimab in combination with chemotherapy in treating EC. METHODS: Patients received neoadjuvant therapy with 3 cycles of sintilimab 200 mg Q3W in combination with platinum-based chemotherapy. Surgery was performed within 4-6 weeks after neoadjuvant therapy. The primary endpoints of the trial were pathological complete response (pCR) and safety. RESULTS: A total of 23 patients (21 men and 2 women) were enrolled. Surgery was completed in 17 participants, with 16 achieving R0 resection and 1 had R1 resection, 5 participants refused surgery. One patient progressed prior to surgery. Twenty one patients (91%) had significant improvement in their dysphagia following treatment as assessed by Stooler's criteria. The majority of patients who underwent resection have a good pathological response and downstaging rate was 76.5% (13/17). A pCR was achieved in 6 cases (6/17, 35.3%) and major pathological response (MPR) in 9 cases (9/17, 52.9%). The main preoperative adverse events (AEs) were vomiting (13/23, 56.5%), leukopenia (12/23, 52.2%), neutropenia (9/23, 39.1%), and malaise (8/23, 34.8%). Immune-related AEs were mild and included hypothyroidism (2/23, 8.7%) and rash (4/23, 17.4%). The incidence of ≥ grade 3 treatment related AEs was 30.4% (7/23). There were no ≥ grade 4 AEs. CONCLUSIONS: Sintilimab in combination with chemotherapy in the neoadjuvant treatment of EC is safe and lead to a high pCR. Therefore, further testing is warranted.