Analysis Of Gene Alterations Research Articles

Identification and Validation of a Novel Tertiary Lymphoid Structures-Related Prognostic Gene Signature in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs, are closely connected to chronic inflammation and tumorigenesis. However, the detailed relationship between TLS and HCC prognosis remained unclear. In this study, we aimed to construct a TLS-related gene signature for predicting the prognosis of HCC patients. The Cancer Genome Atlas (TCGA) clinical data from 369 HCC tissues and 50 normal liver tissues were utilized to examine the differential expression of TLS-related genes. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the prognostic model was constructed using the TCGA cohort and validated in the GSE14520 cohort and International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Furthermore, Cox regression analysis was applied to identify whether the TLS score could be employed as an independent prognosis factor. A nomogram was developed to predict the survival probability of HCC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for TLS-related genes. Genetic mutation analysis, the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA) were used to assess the tumor mutation landscape and immune infiltration. Finally, the role of the TLS score in HCC therapy was investigated. Six genes were included in the construction of our prognostic model (CETP, DNASE1L3, PLAC8, SKAP1, C7, and VNN2), and we validated its accuracy. Survival analysis showed that patients in the high-TLS score group had a significantly better overall survival than those in the low-TLS score group. Univariate, multivariate Cox regression analysis and the establishment of a nomogram indicated that the TLS score could independently function as a potential prognostic marker. A significant association between TLS score and immunity was revealed by an analysis of gene alterations and immune cell infiltration. In addition, two subtypes of the TLS score could accurately predict the effectiveness of sorafenib, transcatheter arterial chemoembolization (TACE), and immunotherapy in HCC patients. In this research, we conducted and validated a prognostic model associated with TLS that may be helpful for predicting clinical outcomes and treatment responsiveness for HCC patients.

Abstract 7612: Genetic predictors of anti-PD(L)-1 therapy response in hepatocellular carcinoma

Abstract Introduction: Immunotherapy targeting PD-1/PD-L1 shows promise in treating hepatocellular carcinoma (HCC), but standard predictors like PD-L1 expression are unreliable for gauging treatment response. RNA sequencing has identified a BMS 4-gene inflammatory signature that could more accurately forecast clinical outcomes. However, genomic alterations and tumor mutational burden (TMB) haven't consistently predicted anti-PD(L)-1 therapy response in HCC. Therefore, the aim of this research is to identify potential genetic alternation that could serve as predictive marker for anti-PD(L)-1 therapy responses in advanced HCC. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 38 HCC patients were analyzed using targeted next-generation sequencing with the ACTOncoTM panel before anti-PD(L)-1 therapy. This analysis identified somatic variants across 440 genes and calculated TMB. In silico tools like NetMHC and IEDB predicted neo-peptide-HLA class I binding affinity. Additionally, peripheral blood mononuclear cells provided germline data for paired TMB calculations, with tumor responses assessed by RECIST criteria. Results: Within a cohort of 167 patients with HCC undergoing ICI therapy, 35 (20.9%) responded to treatment, while 132 (79.1%) did not. Available formalin-fixed paraffin-embedded (FFPE) samples from this population included those from 14 responders and 30 non-responders. After conducting quality control measures, which assessed tumor purity, DNA quantity and integrity, as well as sequencing quality, 13 samples from responders and 25 from non-responders qualified for further analysis. Gene alteration analysis identified mutations in TP53 (47%), MUC16 (34%), CTNNB1 (32%), USH2A (16%), ARID1A (13%), NOTCH3 (13%), and ADAMTS16 (11%) of the cases. A TP53 mutation was linked to poor overall survival, whereas mutations in CTNNB1 and the RTK/RAS/RAF pathway did not correlate with clinical outcomes. The median TMB, predicted at 3.2 ± 4.3 mutations per megabase (muts/Mb), was nominally higher in patients who achieved disease control compared to non-responders (4.6 vs. 3.7 muts/Mb, p=0.53). Utilizing paired TMB analysis, those with disease control exhibited a higher TMB trend than non-responders (6.0 vs. 2.2 muts/Mb, p=0.06). Notably, the 13 cases with MUC16 mutations were associated with a significantly higher predicted TMB (10.0 vs. 3.3 muts/Mb, p=0.0015). Conclusions: This study suggests that certain genetic alterations, especially TP53 mutations, may have predictive value for the response to anti-PD(L)-1 therapy in HCC. Moreover, an elevated TMB, particularly when associated with MUC16 mutations, seems to be correlated with improved disease control. Citation Format: San-Chi Chen, Nai-Jung Chiang, MingHuang Chen, Muh-Hwa Yang. Genetic predictors of anti-PD(L)-1 therapy response in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7612.

Progression of follicular lymphoma and related entities: Report from the 2021 SH/EAHP Workshop.

The 2021 Society for Hematopathology and European Association for Haematopathology Workshop addressed the molecular and cytogenetic underpinnings of transformation and transdifferentiation in lymphoid neoplasms. Session 4, "Transformations of Follicular Lymphoma," and session 5, "Transformations of Other B-Cell Lymphomas," included 45 cases. Gene alteration analysis and expression profiling were performed on cases with submitted formalin-fixed, paraffin embedded tissue. The findings from session 4 suggest that "diffuse large B-cell lymphoma/high-grade B-cell lymphoma with rearrangements of MYC and BCL2" is a distinct category arising from the constraints of a preexisting BCL2 translocation. TdT expression in aggressive B-cell lymphomas is associated with MYC rearrangements, immunophenotypic immaturity, and a dismal prognosis but must be differentiated from lymphoblastic -lymphoma. Cases in session 5 illustrated unusual morphologic and immunophenotypic patterns of transformation. Additionally, the findings support the role of cytogenetic abnormalities-specifically, MYC and NOTCH1 rearrangements-as well as single gene alterations, including TP53, in transformation. Together, these unique cases and their accompanying molecular and cytogenetic data suggest potential mechanisms for and unusual patterns of transformation in B-cell lymphomas and indicate numerous opportunities for further study.

Expression of MCMs in Endometrial Cancer and its Biological Correlation Analysis.

Minichromosome maintenance (MCM) has been demonstrated to be involved in tumorigenesis and pathogenesis of many cancer types. However, the role of MCMs in endometrial cancer (EC) has not been elucidated. We first employed GEPIA, cBioPortal, and R software to perform the differential expression analysis, survival analysis, and gene alteration analysis of the MCMs family. Then, GSE17025 and GSE63678 datasets and CTPAC were used to verify the mRNA and protein expression levels of MCM4. In addition, the internal mechanism of the MCM4 was investigated by comparing MCM4 expression-correlated differentially expressed genes (DEGs) from GEPIA and MCM4-interacted genes from STRING. Last, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify MCM4-related biological processes. Compared with normal tissues, only MCM2 and MCM4 expression were significantly upregulated in EC tissues. High expression of MCM4 was related to worse clinicopathological features and poor prognosis in EC cohorts. Additionally, a certain degree of gene alterations in the MCM2-7 gene was observed. By comparing MCM4 expression-correlated DEGs and MCM4- interacted genes, six genes were obtained: SSRP1, ORC1, GINS1, CDK2, DBF4 and GINS3. Functional enrichment analysis suggested that MCM4 may be involved in regulating the biological processes of DNA replication and the p53 signaling pathway. This was the first comprehensive study to disclose the biological effects of MCMs in EC, indicating that MCM4 could be used as a new prognostic biomarker and potential therapeutic target for EC.

Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303)

BackgroundPI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC.MethodsBKM120 (100 mg/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay.ResultsOf 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1–67.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8–3.2) and 9.0 (95% CI 6.5–11.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response.ConclusionsBKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.

MDM2 is a Potential Target Gene of Glycyrrhizic Acid for Circumventing Breast Cancer Resistance to Tamoxifen: Integrative Bioinformatics Analysis.

Tamoxifen is the drug of choice for treating breast cancer, particularly the estrogen receptor-positive luminal A subtype. However, the increased occurrence of Tamoxifen resistance highlights the need to develop an agent to enhance the effectiveness of this drug. Although glycyrrhizic acid (GA) is known to exhibit cytotoxic effects on Michigan Cancer Foundation-7 cells, the specific gene targets and pathways it employs to overcome Tamoxifen resistance are incompletely understood. Therefore, the goal of the present research is to discover the potential targets and pathways of GA by using a bioinformatics approach. Differentially expressed genes (DEGs) were identified in the Gene Expression Omnibus NCBI database using microarray data from GSE67916 and GSE85871. Further analyses were performed on these DEGs by using DAVID v6.8, STRING-DB v11.0, and Cytoscape v3.8.0. Analysis of gene alterations was performed using cBioPortal for target validation, and the relevant interaction process was examined via the molecular docking method. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses identified the PI3K-AKT signaling as the potential target mechanism. Construction of the protein-protein interaction network and analysis of hub genes identified the top 25 hub genes. Genetic alterations were observed in six potential target genes, such as CDK2, MDM2, NF1, SMAD3, PTPN11, and CALM1. Molecular docking analysis demonstrated that the docking score of GA is lower than that of the native ligand of p53. More importantly, 3n the PI3K-AKT signaling pathway is a potential target for overcoming Tamoxifen resistance in breast cancer. MDM2 may be a potential gene target of GA and the PI3K-AKT signaling may be a prospective mechanism for overcoming Tamoxifen resistance in breast cancer cells. Additional research is required to validate the findings of this study.

P35-7 Analysis of BRCA1/2 mutations for metastatic castration resistant prostate cancer in clinical practice

Olaparib can be used for patients with metastatic castration resistant prostate cancer (mCRPC) who have altered BRCA1 or BRCA2. For the analysis of gene alterations, Foundation One CDx and BRACAnalysis are available in Japan. All patients with mCRPC who become resistant to 1st line androgen receptor axis targeted therapy are advised to receive the analysis. However, it is still unclear how these two analyses are recommended. In this study, we report the current status of BRCA1/2 analysis and examined the optimal strategy for detecting BRCA1/2 alterations in patients with mCRPC.

Multi-Omics Analysis of Molecular Characteristics and Carcinogenic Effect of NFE2L3 in Pan-Cancer.

NFE2L3, also known as NFE2L3, is a nuclear transcription factor associated with the pathogenesis and progression of human tumors. To systematically and comprehensively investigate the role of NFE2L3 in tumors, a pan-cancer analysis was performed using multi-omics data, including gene expression analysis, diagnostic and prognostic analysis, epigenetic methylation analysis, gene alteration analysis, immune feature analysis, functional enrichment analysis, and tumor cell functional status analysis. Furthermore, the molecular mechanism of NFE2L3 in liver hepatocellular carcinoma (LIHC) was explored. The relationship between NFE2L3 expression and survival prognosis of patients with LIHC was analyzed and a nomogram prediction model was constructed. Our study showed that NFE2L3 expression was upregulated in most cancers, suggesting that NFE2L3 may play an important role in promoting cancer progression. NFE2L3 expression is closely related to DNA methylation, genetic alteration, immune signature, and tumor cell functional status in pan-cancers. Furthermore, NFE2L3 was demonstrated to be an independent risk factor for LIHC, and the nomogram model based on NFE2L3 expression had good prediction efficiency for the overall survival of patients with LIHC. In summary, our study indicated that NFE2L3 may be an important molecular biomarker for the diagnosis and prognosis of pan-cancer. NFE2L3 is expected to be a potential molecular target for the treatment of tumors.

Non-invasive cell-free DNA monitoring for predicting the response to neoadjuvant immunotherapy in locally advanced esophageal squamous cell carcinoma.

e16040 Background: The combined modality therapy including neoadjuvant chemoradiotherapy has been selected as the standard care for locally advanced Esophageal squamous cell carcinoma (ESCC). However, the conclusive evidences to support the effectiveness of neoadjuvant immunotherapy for ESCC are rarely discussed. This study aims to investigate the molecular features of cell-free DNA (cfDNA) and the impact of their dynamic changes on the response to neoadjuvant immunotherapy in locally advanced ESCC patients. Methods: Twenty-four eligible locally advanced ESCC patients with received neoadjuvant immunotherapy were enrolled in this study. 7 patients achieved pathological complete regression (pCR) and the other 17 patients had non-pCR. The baseline, second and third blood samples (before neoadjuvant immunotherapy, at one month and two months after neoadjuvant immunotherapy, respectively) were collected from Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Both cfDNA fragments and genomic DNA were extracted for enrichment of a customized panel covering exon regions of 599 genes. The dynamic analysis of gene alterations, which allows the monitoring of the response to neoadjuvant immunotherapy in locally advanced ESCC patients, were conducted based on multiple blood sampling strategy. Results: The most frequently mutated genes among all cases were TP53, KMT2D, CREBBP and KMT2B. MSI scores of both second and third blood samples were remarkablely higher than those in baseline blood samples (p = 0.002, 0.04). On the contrary, the TMB values and mean variant allele frequency (VAF) of second and third blood samples were significantly decreased compared with the baseline blood (TMB, p = 0.04, 0.03; mean VAF, p = 0.01, 0.02). Moreover, a decreasing trend of mean VAF was observed at the time-series blood samples from ESCC patients with pCR, while the mean VAF of ESCC patients with non-pCR declined in the blood samples from the second time point then increased in the blood samples from the thrid time point. Conclusions: The detection of dynamic changes of mean VAF could distinguish the pCR and non-pCR ESCC patients with neoadjuvant immunotherapy. These findings warrant further expanded prospective cohorts to validate.

Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p<0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p<0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]

Comprehensive Analysis of Centromere Protein Family Member Genes in Lung Adenocarcinoma

Centromere protein family member genes (CENPx genes) have been reported to be exceptionally expressed in various cancers. However, the systematic analysis of their roles in lung adenocarcinoma (LUAD) is still lacking. The aim of this study is to comprehensively analyze the expression and survival value of CENPx genes in LUAD and to perform immune analysis and related mechanistic investigations. We confirmed that CENPA, CENPF, CENPI, CENPK, CENPM, CENPN, CENPU and CENPW were highly expressed in LUAD, and their high expression were associated with poor prognosis (P < 0.05). Methylation results showed that methylation of one CpG site on promotor of CENPF, one of CENPU and two CENPMs were relevant to overall survival in LUAD. The gene alteration analysis demonstrated that the altered group of CENPF were correlated with poor overall survival. Microsatellite instability analysis concluded that the expression of CENPF and microsatellite instability scores were correlated positively with statistical significance. In addition, the expression changes of these eight genes were significantly associated with immune cell infiltration and the expression of immunoinhibitors, immunostimulators, and major histocompatibility complex (MHC) molecules. Functional enrichment analysis indicated that directly related genes were mainly involved in MRNA splicing, via spliceosome, Poly(A) RNA binding and Spliceosome. Moreover, we established a risk model based on LASSO regression. The expression changes of these eight genes in the Gene Expression Omnibus were also highly expressed in LUAD-compared with normal tissues, which confirmed the analysis in the Gene Expression Profiling Interactive Analysis (GEPIA) database. To sum up, we aimed to provide new biomarkers.

Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study

BackgroundThe genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS).MethodsWe retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status.ResultsThe most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p < 0.01).ConclusionsTP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

The role of proteomics in the multiplexed analysis of gene alterations in human cancer

ABSTRACT Introduction Proteomics has played a pivotal role in identifying proteins perturbed in disease conditions when compared with healthy samples. Study of dysregulated proteins aids in identifying diagnostic markers and potential therapeutic targets. Cancer is an outcome of interplay of several such disarrayed proteins and molecular pathways which perturb cellular homeostasis, resulting in transformation. In this review, we discuss various facets of proteomic approaches, including tools and technological advancements, aiding in understanding differentially expressed molecules and signaling mechanisms. Areas covered In this review, we have taken the approach of documenting the different methods of proteomic studies, ranging from labeling techniques, data analysis methods, and the nature of molecule detected. We summarize each technique and provide a glimpse of cancer research carried out using them, highlighting the advantages and drawbacks in comparison with others. Literature search using online resources, such as PubMed and Google Scholar were carried out for this approach. Expert opinion Technological advancements in proteomics studies have come a long way from the study of two-dimensional mapping of proteins separated on gels in the early 1970s. Higher precision in molecular identification and quantification (high throughput), and greater number of samples analyzed have been the focus of researchers.

Integrated analysis of gene expression, alteration and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer.

Even though cell-cell adhesion molecule carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is extensively studied since the discovery, the role of CEACAM1 in different cancers is not completely clarified. In the present study, we examined CEACAM1 expression and its association with patient survival in various cancers by analysis of multiple databases. Oncomine database analysis revealed that CEACAM1 expression was upregulated in lung and pancreatic cancers, but downregulated in colorectal and head and neck cancers. PrognoScan and Kaplan‑Meier analyses showed that colorectal cancer patients as well as head and neck cancer patients with high CEACAM1 expression exhibited a higher overall survival rate. STRING analysis identified CEACAM3, CEACAM8, FN1, etc. as CEACAM1 interactors. Gene alteration analysis showed that CEACAM1 mutation predominantly occurred in the N-terminal. Coexpression analysis demonstrated that CEACAM1 had distinct coexpressed genes in different cancers, but KRT protein was consistently coexpressed with CEACAM1 in diverse cancer types. All the observations supported that CEACAM1 can serve as a diagnostic marker for some cancers, such as pancreatic cancer. And high CEACAM1 expression provides a better prognosis for some cancers, such as colorectal and head and neck cancers.

Integrative analysis of gene alterations and immunoexpression profiles of cell cycle checkpoints in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) represents 95% of all cancers of the head and neck region. The five-year survival rate of OSCC patients is about 60% and has not gone throw significant improvements despite recent advances in molecular biology, or the identification of key pathways in its pathophysiology such as cell cycle. 1) to analyse the inmunoexpression of cell cycle checkpoints (CPs) in an OSCC institutional cohort and to relate it to clinicopathological features and survival, and 2) to study CPs-related genes in the OSCC subset of the TCGA database. Immunohistochemistry (IHC) for p16INK4a, p21CIP1, cyclin D1 and p27KIP1 protein expression was quantified by tissue microarray analysis in 68 samples from OSCC patients. In order to analyse its correlation with genetic information, a cohort belonging to The Cancer Genome Atlas (TCGA) database was analysed. Of 68 patients, 34 (50%) developed recurrence, and 36 (52.09%) died as a result of disease progression (mean survival 34.09 months). IHC staining for nuclear cyclin D1 was associated with worse staging and tobacco use. p16INK4a, p21CIP1, cyclin D1, and p27KIP1 expression was unrelated to overall survival. No statistically significant correlation linked the CPs-related genes mutations to OSCC overall survival in the TCGA database. CPs variations at a phenotype and genotype level seem not to affect significantly clinicopathological features and survival in the studied OSCC cohorts.

Effects of oral florfenicol on intestinal structure, function and microbiota in mice.

Many kinds of antibiotics have effects on intestinal structure and function. In the current experimental study, we evaluate the effect of oral florfenicol on intestinal barrier in mice. Thirty adult male mice were randomly divided into two groups, the group none (N) and the group florfenicol (F), the mice in group F were orally administered florfenicol 100mg/kg body weight (BW) for 7days. At day 8, mice were euthanized and sampled for the analysis of alterations in genes and proteins from jejunum, jejunum morphology and microbiota analysis. Administration of florfenicol caused higher liver index (P < 0.05). In the jejunum, mucosa injury and villus rupture, compared with the group N, the villus length and V/C (villus length/crypt depth) in group F were marked decrease (P < 0.01). The transcription level of Muc2 and occludin in group F were significantly lower than those in group N (P < 0.01 or P < 0.05). The expression of APRIL, IL-17, IL-22, BAFF and sIgA on protein level were significantly down-regulated (P < 0.01 or P < 0.05), while the expression of IL-10, TGF-β, IL-6, IL-4 were significantly up-regulated (P < 0.01) in group F. The abundances of bacteria in Firmicutes and Lactobacillus decreased significantly (P < 0.01) in group F. Our results indicated that oral administration of florfenicol might have a negative impact on functions of intestinal mucosal barrier, immune system and the intestinal microbiota.

Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing

Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes andwith decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

ALA-induced fluorescence detection with photoresist-based microfluidic cell sorter for bladder cancer diagnosis

We present a photoresist-based microfluidic fluorescence-activated cell sorter (μFACS) for bladder cancer diagnosis and assess its potential for clinical application. In the developed μFACS system, bladder cancer cells in urine sediment are detected using aminolevulinic acid (ALA)-based fluorescence detection, and then sorted at the Y-junction of the microchannel using an off-chip pinch valve. Once cancer cells are collected, they can be analyzed using polymerase chain reaction (PCR) for detailed gene alteration analysis. Generally, time and cost-effective advantages of negative photoresist material and fabrication technologies have been widely pronounced; however, autofluorescence is a significant drawback when negative photoresist is used as a structural material for μFACS applications. To achieve sensitive fluorescence detection, autofluorescence in the detection area is minimized by thinning the photoresist cover layer of the microchannel and inclining the optical angle of the detection system. Through system calibrations and clinical tests using urine sediments, our experimental results demonstrate a combination of ALA-based photodynamic diagnostic tests using μFACS systems and subsequent PCR analysis is a promising diagnostic approach for bladder cancer.

Photoresist-based Microfluidic Cell Sorter for Photodynamic Urine Diagnosis

We report a photoresist-based microfluidic cell sorting system for genitourinary cancer based on photodynamic analysis of urine and its potential for a clinical application. In the system, genitourinary cancer cells in urine are detected using 5-aminolevulinic acid (ALA)-induced fluorescence, and then sorted and concentrated for the gene alteration analysis. In order to achieve sensitive fluorescence detection, autofluorescence in detection area was minimized by thinning photoresist membrane of the microchannel and inclining the optical angle of detection system. Our experimental results demonstrate that the ALA-based fluorescence detection assay using the proposed device is promising tool for early diagnosis of genitourinary cancers.