Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori

BackgroundLocalization and differential expression of STAT3 and survivin in cancer cells are often related to distinct cellular functions. The involvement of survivin and STAT3 in gastric cancer has been reported in separate studies but without clear understanding of their kinetics in cancer progression.MethodsWe examined intracellular distribution of STAT3 and survivin in gastric adenocarcinoma and compared it with normal and precancer tissues using immunoblotting and immunohistochemistry.ResultsAnalysis of a total of 156 gastric samples comprising 61 histologically normal, 30 precancerous tissues (comprising intestinal metaplasia and dysplasia), and 65 adenocarcinomas, collected as endoscopic biopsies from treatment naïve study participants, revealed a significant (P < .001) increase in overall protein levels. Survivin expression was detectable in both cytoplasmic (90.8%) and nuclear (87.7%) compartments in gastric adenocarcinomas lesions. Precancerous dysplastic gastric lesions exhibited a moderate survivin expression (56.7%) localized in cytoplasmic compartment. Similarly, STAT3 and pSTAT3 expression was detected at high level in gastric cancer lesions. The levels of compartmentalized expression of survivin and STAT3/pSTAT3 correlated in precancerous and adenocarcinoma lesions. Although overexpression of these proteins was found associated with the tobacco use and alcohol consumption, their expression invariably and strongly correlated with concurrent Helicobacter pylori infection. Receiver operating characteristic analysis of nuclear survivin, STAT3, and pSTAT3 in different study groups showed acceptable positive and negative predictive values with area under the curve above 0.8 (P < .001).ConclusionOverall, our results suggest that overall increase in survivin and STAT3 and their subcellular localization are key determinants of gastric cancer progression, which can be collectively used as potential disease biomarkers and therapeutic targets for gastric cancer.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144680/1/cnr21004-Supplementary_Methods_20180313.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144680/2/cnr21004-sup-0001-F1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144680/3/cnr21004_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144680/4/cnr21004.pd

Flecainide for Conversion and Maintenance of Sinus Rhythm After Mitral Valve Replacement in Rheumatic Atrial Fibrillation

BACKGROUND: Despite successful mitral valve replacement (MVR), many patients remain in AF. Flecainide can be useful in these patients but has not been used because of underlying structural heart disease. METHODS: We assessed oral flecainide for conversion and maintenance of SR in 25 patients of chronic rheumatic AF following MVR (age 34.4 yrs, mean AF duration: 3.6 yrs). Non-converters underwent DC cardioversion at 24 h and 4 weeks. Patients received flecainide and bb/diltiazem at discharge. RESULTS: Single oral dose of Flecainide achieved SR in 6/25 (24%) while 19/25 achieved SR after DCC; at24 h 21/25 (84%) were in SR. With mean flecainide dose (93.10 ± 9.40 mg), successful maintenance of SR at 6 months was seen in 16/23 (69.5%). No significant changes in PR interval, QRS duration or QTc were noted; flecainide was well tolerated. Patients in SR had significantly better functional status, QOL scores and higher LA strain at 6 months (25.25 vs 17.43%, p \u3c .0001). Baseline LA diameter ≤ 61 mm predicted SR at 6 months (sensitivity/specificity 93.7% and 85.71%) while the values for AF duration ≤ 4 years and LA strain \u3e 21% for predicting SR were 87.5/71.43% and 100/85.71% respectively. CONCLUSION: Oral flecainide was safe and effective in post MVR rheumatic AF patients; maintenance of SR was achieved in 76% of initial converters and 64% of overall population, with better LA strain values. More studies are needed to validate these results

Overexpression of Prothymosin Alpha Predicts Poor Disease Outcome in Head and Neck Cancer

In our recent study, tissue proteomic analysis of oral pre-malignant lesions (OPLs) and normal oral mucosa led to the identification of a panel of biomarkers, including prothymosin alpha (PTMA), to distinguish OPLs from histologically normal oral tissues. This study aimed to determine the clinical significance of PTMA overexpression in oral squamous cell hyperplasia, dysplasia and head and neck squamous cell carcinoma (HNSCC).Immunohistochemistry of PTMA protein was performed in HNSCCs (n = 100), squamous cell hyperplasia (n = 116), dysplasia (n = 50) and histologically normal oral tissues (n = 100). Statistical analysis was carried out to determine the association of PTMA overexpression with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients.<0.001). Chi-square analysis showed significant association of nuclear PTMA with advanced tumor stages (III+IV). Kaplan Meier survival analysis indicated reduced disease free survival (DFS) in HNSCC patients (p<0.001; median survival 11 months). Notably, Cox-multivariate analysis revealed nuclear PTMA as an independent predictor of poor prognosis of HNSCC patients (p<0.001, Hazard's ratio, HR = 5.2, 95% CI = 2.3–11.8) in comparison with the histological grade, T-stage, nodal status and tumor stage.Nuclear PTMA may serve as prognostic marker in HNSCC to determine the subset of patients that are likely to show recurrence of the disease

Nuclear S100A7 Is Associated with Poor Prognosis in Head and Neck Cancer

Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC.Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (p(trend)<0.001). Significant increase in nuclear S100A7 was observed in HNSCC as compared to dysplastic lesions (p = 0.005) and associated with well differentiated squamous cell carcinoma (p = 0.031). Notably, nuclear accumulation of S100A7 also emerged as an independent predictor of reduced disease free survival (p = 0.006, Hazard ratio (HR = 7.6), 95% CI = 1.3-5.1) in multivariate analysis underscoring its relevance as a poor prognosticator of HNSCC patients.Our study demonstrated nuclear accumulation of S100A7 may serve as predictor of poor prognosis in HNSCC patients. Further, increased nuclear accumulation of S100A7 in HNSCC as compared to dysplastic lesions warrants a large-scale longitudinal study of patients with dysplasia to evaluate its potential as a determinant of increased risk of transformation of oral premalignant lesions

The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer

Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-&gamma; (IFN-&gamma;). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers

Promoter hypermethylation in Indian primary oral squamous cell carcinoma

We evaluated promoter hypermethylation of a panel of tumor suppressor genes as a means to detect epigenetic alterations in oral squamous cell carcinomas (OSCC) of Indian-origin and compare with North-American head and neck squamous cell carcinomas (HNSCC). Quantitative-methylation-specific PCR was used to investigate the promoter methylation status of DCC, EDNRB, p16(INK4a) and KIF1A in 92 OSCC, and compared to 48 paired normal tissues and 30 saliva and sera samples from healthy control subjects. Aberrant methylation of at-least one of these genes was detected in 74/92 (80.4%) OSCC; 72.8% at EDNRB, 71.7% at KIF1A, 47.8% at p16(INK4a) and 58.7% at DCC; and in 5 of 48 (10.4%) normal oral tissues. None of the saliva and sera samples from controls exhibited DNA methylation in these four target genes. Thirty-two of 72 node positive cases harbored p16(INK4a) and DCC hypermethylation (p = 0.005). Thus, promoter hypermethylation in genes analyzed herein is a common event in Indian OSCC and may represent promising markers for the molecular staging of OSCC patients. We found higher frequency of p16(INK4a) methylation (47.8%) in this Indian cohort in comparison with a North-American cohort (37.5%). In conclusion, aberrant methylation of EDNRB, KIF1A, DCC and p16(INK4a) genes is a common event in Indian OSCC, suggesting that epigenetic alterations of these genes warrant validation in larger studies for their potential use as biomarkers

Flecainide for conversion and maintenance of sinus rhythm after mitral valve replacement in rheumatic atrial fibrillationWhat is Already Known?What this Study Adds

Background: Despite successful mitral valve replacement (MVR), many patients remain in AF. Flecainide can be useful in these patients but has not been used because of underlying structural heart disease. Methods: We assessed oral flecainide for conversion and maintenance of SR in 25 patients of chronic rheumatic AF following MVR (age 34.4 yrs, mean AF duration: 3.6 yrs). Non-converters underwent DC cardioversion at 24 h and 4 weeks. Patients received flecainide and bb/diltiazem at discharge. Results: Single oral dose of Flecainide achieved SR in 6/25 (24%) while 19/25 achieved SR after DCC; at 24 h 21/25 (84%) were in SR. With mean flecainide dose (93.10 ± 9.40 mg), successful maintenance of SR at 6 months was seen in 16/23 (69.5%). No significant changes in PR interval, QRS duration or QTc were noted; flecainide was well tolerated. Patients in SR had significantly better functional status, QOL scores and higher LA strain at 6 months (25.25 vs 17.43%, p  21% for predicting SR were 87.5/71.43% and 100/85.71% respectively. Conclusion: Oral flecainide was safe and effective in post MVR rheumatic AF patients; maintenance of SR was achieved in 76% of initial converters and 64% of overall population, with better LA strain values. More studies are needed to validate these results

Discovery and Verification of Head-and-neck Cancer Biomarkers by Differential Protein Expression Analysis Using iTRAQ Labeling, Multidimensional Liquid Chromatography, and Tandem Mass Spectrometry*S⃞

Multidimensional LC-MS/MS has been used for the analysis of biological samples labeled with isobaric mass tags for relative and absolute quantitation (iTRAQ) to identify proteins that are differentially expressed in human head-and-neck squamous cell carcinomas (HNSCCs) in relation to non-cancerous head-and-neck tissues (controls) for cancer biomarker discovery. Fifteen individual samples (cancer and non-cancerous tissues) were compared against a pooled non-cancerous control (prepared by pooling equal amounts of proteins from six non-cancerous tissues) in five sets by on-line and off-line separation. We identified 811 non-redundant proteins in HNSCCs, including structural proteins, signaling components, enzymes, receptors, transcription factors, and chaperones. A panel of proteins showing consistent differential expression in HNSCC relative to the non-cancerous controls was discovered. Some of the proteins include stratifin (14-3-3σ); YWHAZ (14-3-3ζ); three calcium-binding proteins of the S100 family, S100-A2, S100-A7 (psoriasin), and S100-A11 (calgizarrin); prothymosin α (PTHA); l-lactate dehydrogenase A chain; glutathione S-transferase Pi; APC-binding protein EB1; and fascin. Peroxiredoxin2, carbonic anhydrase I, flavin reductase, histone H3, and polybromo-1D (BAF180) were underexpressed in HNSCCs. A panel of the three best performing biomarkers, YWHAZ, stratifin, and S100-A7, achieved a sensitivity of 0.92 and a specificity of 0.91 in discriminating cancerous from non-cancerous head-and-neck tissues. Verification of differential expression of YWHAZ, stratifin, and S100-A7 proteins in clinical samples of HNSCCs and paired and non-paired non-cancerous tissues by immunohistochemistry, immunoblotting, and RT-PCR confirmed their overexpression in head-and-neck cancer. Verification of YWHAZ, stratifin, and S100-A7 in an independent set of HNSCCs achieved a sensitivity of 0.92 and a specificity of 0.87 in discriminating cancerous from non-cancerous head-and-neck tissues, thereby confirming their overexpressions and utility as credible cancer biomarkers

Modification of Graphite Sheet Anode with Iron (II, III) Oxide-Carbon Dots for Enhancing the Performance of Microbial Fuel Cell

The present study explores the use of carbon dots coated with Iron (II, III) oxide (Fe3O4) for its application as an anode in microbial fuel cells (MFC). Fe3O4@PSA-C was synthesized using a hydrothermal-assisted probe sonication method. Nanoparticles were characterized with XRD, SEM, FTIR, and RAMAN Spectroscopy. Different concentrations of Fe3O4- carbon dots (0.25, 0.5, 0.75, and 1 mg/cm2) were coated onto the graphite sheets (Fe3O4@PSA-C), and their performance in MFC was evaluated. Cyclic voltammetry (CV) of Fe3O4@PSA-C (1 mg/cm2) modified anode indicated oxidation peaks at &minus;0.26 mV and +0.16 mV, respectively, with peak currents of 7.7 mA and 8.1 mA. The fluxes of these anodes were much higher than those of other low-concentration Fe3O4@PSA-C modified anodes and the bare graphite sheet anode. The maximum power density (Pmax) was observed in MFC with a 1 mg/cm2 concentration of Fe3O4@PSA-C was 440.01 mW/m2, 1.54 times higher than MFCs using bare graphite sheet anode (285.01 mW/m2). The elevated interaction area of carbon dots permits pervasive Fe3O4 crystallization providing enhanced cell attachment capability of the anode, boosting the biocompatibility of Fe3O4@PSA-C. This significantly improved the performance of the MFC, making Fe3O4@PSA-C modified graphite sheets a good choice as an anode for its application in MFC

Modification of Graphite Sheet Anode with Iron (II, III) Oxide-Carbon Dots for Enhancing the Performance of Microbial Fuel Cell

The present study explores the use of carbon dots coated with Iron (II, III) oxide (Fe3O4) for its application as an anode in microbial fuel cells (MFC). Fe3O4@PSA-C was synthesized using a hydrothermal-assisted probe sonication method. Nanoparticles were characterized with XRD, SEM, FTIR, and RAMAN Spectroscopy. Different concentrations of Fe3O4- carbon dots (0.25, 0.5, 0.75, and 1 mg/cm2) were coated onto the graphite sheets (Fe3O4@PSA-C), and their performance in MFC was evaluated. Cyclic voltammetry (CV) of Fe3O4@PSA-C (1 mg/cm2) modified anode indicated oxidation peaks at −0.26 mV and +0.16 mV, respectively, with peak currents of 7.7 mA and 8.1 mA. The fluxes of these anodes were much higher than those of other low-concentration Fe3O4@PSA-C modified anodes and the bare graphite sheet anode. The maximum power density (Pmax) was observed in MFC with a 1 mg/cm2 concentration of Fe3O4@PSA-C was 440.01 mW/m2, 1.54 times higher than MFCs using bare graphite sheet anode (285.01 mW/m2). The elevated interaction area of carbon dots permits pervasive Fe3O4 crystallization providing enhanced cell attachment capability of the anode, boosting the biocompatibility of Fe3O4@PSA-C. This significantly improved the performance of the MFC, making Fe3O4@PSA-C modified graphite sheets a good choice as an anode for its application in MFC