Action of m6A-related gene signatures on the prognosis and immune microenvironment of colonic adenocarcinoma.

N6-methyladenosine (m6A) modification in human tumor cells exerts considerable influence on crucial processes like tumorigenesis, invasion, metastasis, and immune response. This study aims to comprehensively analyze the impact of m6A-related genes on the prognosis and immune microenvironment (IME) of colonic adenocarcinoma (COAD). Public data sources, predictive algorithms identified m6A-related genes and differential gene expression in COAD. Subtype analysis and assessment of immune cell infiltration patterns were performed using consensus clustering and the CIBERSORT algorithm. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis determined gene signatures. Independent prognostic factors were identified using univariate and multivariate Cox proportional hazards models. The findings indicate that 206 prognostic m6A-related DEGs contribute to the m6A regulatory network along with 8 m6A enzymes. Based on the expression levels of these genes, 438 COAD samples from The Cancer Genome Atlas (TCGA) were classified into 3 distinct subtypes, showing marked differences in survival prognosis, clinical characteristics, and immune cell infiltration profiles. Subtype 3 and 2 displayed reduced levels of infiltrating regulatory T cells and M0 macrophages, respectively. A six-gene signature, encompassing KLC3, SLC6A15, AQP7 JMJD7, HOXC6, and CLDN9, was identified and incorporated into a prognostic model. Validation across TCGA and GSE39582 datasets exhibited robust predictive specificity and sensitivity in determining the survival status of COAD patients. Additionally, independent prognostic factors were recognized, and a nomogram model was developed as a prognostic predictor for COAD. In conclusion, the six target genes governed by m6A mechanisms offer substantial potential in predicting COAD outcomes and provide insights into the unique IME profiles associated with various COAD subtypes.

Targeting MET in NSCLC: An Ever-Expanding Territory.

MET protooncogene (MET) alterations are known driver oncogenes in NSCLC. Since the identification of MET as a potential therapeutic target, extensive clinical trials have been performed. As a result, MET-targeted therapies, including MET tyrosine kinase inhibitors, monoclonal antibodies, and MET antibody-drug conjugates now play important roles in the standard treatment of MET-altered NSCLC; they have considerably improved the outcomes of patients with tumors that harbor MET oncogenic drivers. Although clinical agents are currently available and numerous other options are in development, particular challenges in the field require attention. For example, the therapeutic efficacy of each drug remains unsatisfactory, and concomitantly, the resistance mechanisms are not fully understood. Thus, there is an urgent need for optimal drug sequencing and combinations, along with a thorough understanding of treatment resistance. In this review, we describe the current landscape of pertinent clinical trials focusing on MET-targeted strategies and discuss future developmental directions in this rapidly expanding field.

Management of locally advanced non-small cell lung cancer: State of the art and future directions.

Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one-third of affected patients have locally advanced NSCLC (LA-NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA-NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA-NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA-NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA-NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA-NSCLC.

Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer.

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of ensartinib were 67% and 94% in cohort 1, and 73% and 91% in cohort 2. The median DoR was 6.8 months and median PFS was 6.1 months in the total population. Rash was the most common drug-related adverse event, and peripheral edema of any grade was reported in only 9% patients. Molecular simulations indicated favorable binding of ensartinib to c-MET. The kinase assay demonstrated an IC50 of 7.9 nM of ensartinib against METex14 protein. In vitro, Hs746T (METex14 mutation) and EBC-1 (MET amplification) cells were sensitive to ensartinib, with IC50 values of 31 and 44 nM, respectively. Ensartinib exhibited comparable inhibitory effects on cell migration as crizotinib and tepotinib in both cell types. In vivo, ensartinib suppressed the growth of Hs746T cells. Ensartinib also potently inhibited the viability of PDOs. Overall, Ensartinib exhibited substantial antitumor effects against METex14 mutant NSCLCs in preclinical and clinical trials, with relatively low peripheral edema rates.

Composite Dietary Antioxidant Index and Plasma Levels of Soluble Klotho: Insights from NHANES.

Objectives: The association between dietary antioxidants and soluble Klotho (S-Klotho) levels remains unknown. We investigated to explore whether the composite dietary antioxidant index (CDAI) was associated with serum levels of S-Klotho in the middle-aged population. Methods: Eligible participants were identified from the National Health and Nutrition Examination Surveys (NHANES) from 2007 until 2016. The CDAI was calculated from the intake of six dietary antioxidants. The serum levels of S-Klotho were measured via enzyme-linked immunosorbent assay (ELISA). Generalized linear and nonlinear models were established to analyze the relationship between CDAI and S-Klotho levels. Results: Based on the S-Klotho quartiles, S-Klotho levels were higher in young women, Blacks, higher education, never smokers, lower waistlines, no medication use, and those with higher CDAI. Univariate analysis revealed that age, gender, race, smoking status, body mass index, waistline, and medication use were associated with serum levels of S-Klotho. When potential confounders were controlled, CDAI was significantly associated with S-Klotho levels. Subgroup analysis also revealed that this association remained significant in individuals who had the highest quartiles of CDAI, aged population (>60 years), male, and never smoker. A nonlinear relationship was observed between the CDAI and S-Klotho plasma concentrations. Conclusion: CDAI was positively correlated with plasma levels of S-Klotho after controlling for covariates. Further studies are needed to validate the current findings and explore the fundamental mechanisms.

SEPTIN9-SDC2-VIM methylation signature as a biomarker for the early diagnosis of colorectal cancer.

The accurate detection of colorectal cancer (CRC) at its initial stage can reduce mortality. However, the broad application of endoscopy has been limited due to the invasive procedure and patient noncompliance. Liquid biopsy with subsequent mapping of methylation in specific cell-free DNA (cfDNA) may represent an alternative approach for early diagnosis. In this study, we have developed a minimal-invasive blood-based test for detection of precancerous lesions and early-stage CRC. Using TCGA M450K methylation data, we identified candidate methylation sites with the highest Fold Change (FC) for three genes (SEPTIN9, SDC2 and VIM), which were selected from previous studies. Based on logistic regression models, we developed a 3-gene methylation signature for CRC diagnosis with high accuracy (Sensitivity =0.959, Specificity =1, AUC =0.997). Using independent public databases and data from blood samples, this model has demonstrated superior performance. The AUC was 0.919-1 and 0.905-0.916 in public tissue database for CRC and blood sample data, respectively. Thus, our proposed 3-gene methylation signature has a more reliable performance than other methods. Furthermore, signal enhancement effect of 3-gene methylation signature can improve the accuracy of early diagnosis for CRC, which demonstrates the potential for clinical application.

Influence of renal insufficiency on anticoagulant effects and safety of warfarin in Chinese patients: analysis from a randomized controlled trial.

This study aimed to analyze the influence of renal insufficiency on the anticoagulant effects and safety of warfarin in Chinese patients. Data on the creatinine levels of participants enrolled in a randomized controlled study were screened and divided into the non-renal insufficiency group, mild renal insufficiency group, and moderate renal insufficiency group, according to the creatinine clearance rate. The primary outcome measures were stable dose and average daily dose of warfarin. Secondary outcome measures were percentage of time in the therapeutic international normalized ratio (INR) (%TTR), and the first time to reach the therapeutic INR. Adverse events included bleeding events, thromboembolic events, and mortality. All participants with renal function test results and a baseline INR of less than 1.5 were included in the primary and secondary outcome analysis. The SPSS Statistics 21.0 software was used for statistical analysis. The randomized controlled trial was registered in Clinicaltrials.gov (NCT02211326). A total of 571 patients were included in this analysis. Multiple regression analysis showed that the renal function was correlated with stable dose, average daily dose, and the first time to reach therapeutic INR after adjusting for confounding factors. However, no correlation was noted between kidney function and %TTR. No significant differences were observed across the various safety parameters among the three groups. Renal function is an important consideration in patients using warfarin.

Nine Genes Mediate the Therapeutic Effects of Iodine-131 Radiotherapy in Thyroid Carcinoma Patients.

BACKGROUND: Thyroid carcinoma (THCA) is one of the most common malignancies of the endocrine system, which is usually treated by surgery combined with iodine-131 (I131) radiotherapy. AIMS: This study is aimed at exploring the potential targets of I131 radiotherapy in THCA. METHODS: The RNA-sequencing data of THCA in The Cancer Genome Atlas database (including 568 THCA samples) was downloaded. The differentially expressed genes (DEGs) between the tumour samples whether or not subjected to I131 radiotherapy were identified using edgeR package. Using the WGCNA package, the module that was relevant with I131 radiotherapy was selected. The intersection genes of the hub module nodes and the DEGs were obtained as hub genes, followed by the function and pathway enrichment analyses using the clusterProfiler package. Moreover, the protein-protein interaction (PPI) network for the hub genes was constructed using Cytoscape software. In addition, more important hub genes were analysed with function mining using the GenCLiP2 online tool. The qPCR analysis was used to verify the mRNA expression of more important hub genes in THCA tissues. RESULTS: There were 500 DEGs (167 upregulated and 333 downregulated) between the two groups. WGCNA analysis showed that the green module (428 nodes) exhibited the most significant correlation with I131 radiotherapy. A PPI network was built after the identification of 53 hub genes. In the PPI network, CDH5, KDR, CD34, FLT4, EMCN, FLT1, ROBO4, PTPRB, and CD93 exhibited higher degrees, which were mainly implicated in the vascular function. The relative expression of nine mRNAs in the THCA tissues treated with I131 was lower. CONCLUSION: I131 radiotherapy might exert therapeutic effects by targeting CDH5, KDR, CD34, FLT4, EMCN, FLT1, ROBO4, PTPRB, and CD93 in THCA patients.

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

BACKGROUND: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. METHODS: We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. RESULTS: A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. CONCLUSIONS: The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.

Can small nucleolar RNA be a novel molecular target for hepatocellular carcinoma?

BACKGROUND: Globally, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Recently, many studies have demonstrated that small nucleolar RNA (snoRNA) was closely related to HCC. OBJECTIVE: To explore whether snoRNA can be used as a molecular target for HCC. METHODS: The PubMed, Embase, and Cochrane databases were searched for the published literatures related to snoRNA and HCC until August 12, 2019. After identification, screening, and verification, this study finally included 26 studies correlating small nucleolar RNA host gene (SNHG) and HCC, and 8 studies correlating snoRNA and HCC. Based on the collation of the relevant literature, the correlation network diagram between snoRNAs and HCC was constructed. RESULTS: The SNHGs, such as SNHG1, SNHG6, SNHG16, and SNHG20 can play varied roles in HCC through different regulatory mechanisms. These SNHGs can promote and inhibit tumorigenesis. SNORD76 can promote the proliferation of tumor tissues and cells in vitro through different pathways. SnoU2_19 and SNORD76 can function through the same pathway. SNHG3, SNHG20, SNHG6, SNORD76, and snoRA47 can modulate epithelial-mesenchymal transition (EMT) to regulate the development of HCC cell or tissue. SNHG16, SNORD76, and SnoU2_19 can regulate the development of HCC through Wnt/ß-catenin signaling pathway. CONCLUSION: snoRNA can regulate the occurrence of HCC by modulating multiple molecular signaling pathways. Hence, snoRNA can be a potential molecular target for HCC.

Protective effect of the "food-microorganism-SCFAs" axis on colorectal cancer: from basic research to practical application.

BACKGROUND: Recent studies have shown that the short-chain fatty acids (SCFAs) produced by the gut microbiota play a positive role in the development of colorectal cancer (CRC). AIMS: This study aims to elucidate the "food-microorganism-SCFAs" axis and to provide guidance for prevention and intervention in CRC. METHODS: The PubMed, Embase and Cochrane databases were searched from their inceptions to August 2018, and 75 articles and 25 conference abstracts were included and analysed after identification and screening. RESULTS: The concentrations of SCFAs in CRC patients and individuals with a high risk of CRC were higher than those in healthy individuals. The protective mechanism of SCFAs against CRC has been described in three aspects: epigenetics, immunology and molecular signalling pathways. Many food and plant extracts that were fermented by microorganisms produced SCFAs that play positive roles with preventive and therapeutic effects on CRC. The "food-microorganism-SCFAs" axis was constructed by summarizing the pertinent literature. CONCLUSIONS: This study provides insight into the basic research and practical application of SCFAs by assessing the protective effect of SCFAs on CRC.

Gut microbiome associated with chemotherapy-induced diarrhea from the CapeOX regimen as adjuvant chemotherapy in resected stage III colorectal cancer.

BACKGROUND: Chemotherapy induced diarrhea (CID) is a common side effect in patients receiving chemotherapy for cancer. The aim of our study was to explore the association between gut microorganisms and CID from the CapeOX regimen in resected stage III colorectal cancer (CRC) patients. RESULTS: After screening and identification, 17 stool samples were collected from resected stage III CRC patients undergoing the CapeOX regimen. Bacterial 16S ribosomal RNA genes was sequenced, and a bioinformatics analysis was executed to screen for the distinctive gut microbiome and the functional metabolism associated with CID due to the CapeOX regimen. The gut microbial community richness and community diversity were lower in CID (p < 0.05 vs control group). Klebsiella pneumoniae was the most predominant species (31.22%) among the gut microbiome in CRC patients with CID. There were 75 microorganisms with statistically significant differences at the species level between the CRC patients with and without CID (LDA, linear discriminant analysis score > 2), and there were 23 pathways that the differential microorganisms might be involved in. CONCLUSIONS: The gut microbial community structure and diversity have changed in CRC patients with CID. It may provide novel insights into the prevention and treatment of CID.

Relationship between intestinal microorganisms and T lymphocytes in colorectal cancer.

Colorectal cancer (CRC) is a common type of malignant cancer worldwide. Recent studies have identified the gut microbiota as the origin of CRC, and T lymphocyte-mediated immune functions have been shown to play an important role in this disease. By summarizing previous literature, we found that Fusobacterium nucleatum may protect CRC from immune cell attack by inhibiting T cells and influencing the production of many chemokines and cytokines. Some bacterial metabolites and probiotics have been shown to participate in the regulation of CRC through T cell-mediated molecular pathways. To visualize the relevant data, an association network of intestinal microorganisms and T lymphocytes associated with CRC was constructed. This work may provide direction for - and insight into - further research on the relationship between intestinal microorganisms and T lymphocytes in CRC.

Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressive Effects of Mycophenolate Mofetil and Hepatitis B Virus Infection.

The purpose of this study is to investigate whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) affect the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. Hepatic NK cells were isolated from C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice treated with MMF in the presence or absence of IL-15. After incubation of isolated hepatic NK cells in the presence or absence of MPA, reverse transcription polymerase chain reaction and immunolabeling were used to assess the expression of NK receptors Ly49A, NKG2A and NKG2D. In addition, cytokine enzyme-linked immunosorbent assay and [H]-TdR-release assay were carried out to assess NK cell activation and cytotoxic capacity. After treatment with MMF in the presence or absence of IL-15, HBsAg titers were measured in C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice. Treatment with either MPA or MMF resulted in reduced NK cell cytotoxicity, downregulated NKG2D and Ly49A expression and upregulated NKG2A. Interestingly, NKG2D downregulation was ameliorated by IL-15. In HBV-transgenic mice, MMF treatment impaired NK cell activity but did not affect virus replication, whereas IL-15 treatment reduced HBsAg titers. MPA and MMF mediate NKG2D downregulation both in vitro and in vivo, reducing the cytotoxic capacity of NK cells. These findings indicate that NKG2D regulation may be important in the immunosuppressive effect NK cells and involved in HBV infection.

Foreign body retained in liver long after gauze packing.

This case report describes a foreign body retained in the liver long after perihepatic gauze packing. A 64-year-old female patient had suffered a rib fracture and liver rupture during a traffic accident in 1973. She discovered a mass in her right hypochondrium. Her hepatic ultrasonography showed a round mass (20.3 cm × 17.3 cm × 16.0 cm in size) with fluid echogenicity in the right lobe of her liver, and a hepatic cystic-solid mass (19.7 cm × 18.5 cm × 15.6 cm in size) was identified in an abdominal computerized tomography scan. Several pieces of gauze were extracted, and brown pus from the hepatic mass was suctioned during her exploratory laparotomy. Histology documented gauze remnants with necrotic material inclusions and fibrotic capsules. To our knowledge, this patient's case represents the longest time for which a foreign body has been retained in the liver. In addition, we conducted a comprehensive literature review of foreign bodies retained in the liver. Foreign bodies may be introduced into the liver via penetrating trauma, surgical procedures or the ingestion of foreign bodies (which then migrate from the gut). Thus, they can be classified into the following three categories: penetrating, medical and migrated foreign bodies. The details of the case are thoroughly described.

When the lowest energy does not induce native structures: parallel minimization of multi-energy values by hybridizing searching intelligences.

BACKGROUND: Protein structure prediction (PSP), which is usually modeled as a computational optimization problem, remains one of the biggest challenges in computational biology. PSP encounters two difficult obstacles: the inaccurate energy function problem and the searching problem. Even if the lowest energy has been luckily found by the searching procedure, the correct protein structures are not guaranteed to obtain. RESULTS: A general parallel metaheuristic approach is presented to tackle the above two problems. Multi-energy functions are employed to simultaneously guide the parallel searching threads. Searching trajectories are in fact controlled by the parameters of heuristic algorithms. The parallel approach allows the parameters to be perturbed during the searching threads are running in parallel, while each thread is searching the lowest energy value determined by an individual energy function. By hybridizing the intelligences of parallel ant colonies and Monte Carlo Metropolis search, this paper demonstrates an implementation of our parallel approach for PSP. 16 classical instances were tested to show that the parallel approach is competitive for solving PSP problem. CONCLUSIONS: This parallel approach combines various sources of both searching intelligences and energy functions, and thus predicts protein conformations with good quality jointly determined by all the parallel searching threads and energy functions. It provides a framework to combine different searching intelligence embedded in heuristic algorithms. It also constructs a container to hybridize different not-so-accurate objective functions which are usually derived from the domain expertise.

[Analysis of prognostic factors and treatment of pulmonary metastasis from colorectal cancer].

OBJECTIVE: To investigate effect of the treatments and prognostic factors of patients with pulmonary metastasis from colorectal cancer. METHODS: Clinical data of 79 patients who suffered from lung metastatic diseases from colorectal cancer in 1990 - 2010 were retrospectively analyzed. The number of patients who had received lung operation was 22, and non-operated group contained 57 patients. Compared the prognosis of operated group and non-operated group and analyzed the prognostic factors. RESULTS: The median survival time after the pulmonary resections was 34.5 months; the overall survival of 1-, 3- and 5-year survival rates were 90.9%, 45.4% and 4.5%, and the overall of 1-, 3-, and 5-year survival rate in non-operated group were 59.6%, 14.0% and 0. The surgery (RR = 4.805, 95% CI: 1.864 - 12.384, P = 0.001) and the number of metastasis (RR = 2.177, 95% CI: 1.431 - 3.314, P = 0.010) were the factors that could influence the patients prognosis. CONCLUSION: The surgery for pulmonary metastases from colorectal cancer is effective.