Negative Regulation of Transactivation Function but Not DNA Binding of NF-κB and AP-1 by IκBβ1 in Breast Cancer Cells

The transcription factor NF-κB regulates the expression of genes involved in cancer cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. In normal cells NF-κB is maintained in the cytoplasm by protein-protein interaction with inhibitor IκBs. In contrast, in cancer cells a substantial amount of NF-κB is in the nucleus and constitutively activates target genes. To understand the mechanisms of constitutive NF-κB activation, we have analyzed the function of IκBα and IκBβ in breast cancer cells. In most cases, constitutive NF-κB DNA binding correlated with reduced levels of either IκBα or IκBβ isoforms. Overexpression of IκBα but not IκBβ1 resulted in reduced constitutive DNA binding of NF-κB in MDA-MB-231 cells. Unexpectedly, IκBβ1 overexpression moderately increased 12-O-tetradecanoylphorbol-13-acetate- and interleukin-1-inducible NF-κB DNA binding. 12-O-Tetradecanoylphorbol-13-acetate- and interleukin-1-induced transactivation by NF-κB, however, was lower in IκBβ1-overexpressing cells. Mutants of IκBβ1 lacking the C-terminal casein kinase II phosphorylation sites, which form a stable complex with DNA bound NF-κB without inhibiting its transactivation in other cell types, repressed the transactivation by NF-κB in MDA-MB-231 cells. Consistent with the results of transient transfections, the expression of urokinase plasminogen activator, an NF-κB target gene, was reduced in IκBβ1-overexpressing cells. These results suggest that depending on the cell type, IκBβ1 represses the expression of NF-κB-regulated genes by inhibiting either DNA binding or transactivation function of NF-κB

Dual threshold optimization and network inference reveal convergent evidence from TF binding locations and TF perturbation responses

A high-confidence map of the direct, functional targets of each transcription factor (TF) requires convergent evidence from independent sources. Two significant sources of evidence are TF binding locations and the transcriptional responses to direct TF perturbations. Systematic data sets of both types exist for yeast and human, but they rarely converge on a common set of direct, functional targets for a TF. Even the few genes that are both bound and responsive may not be direct functional targets. Our analysis shows that when there are many nonfunctional binding sites and many indirect targets, nonfunctional sites are expected to occur in th

Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation

Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5–4.6-fold over controls (p \u3c 0.05). Patients also had increased protein levels of Nox2 subunits (p47phox, p22phox, and p67phox) and total p47phox phosphorylation, while phospho-to-total p47phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% (p \u3c 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals

EERC Center for Biomass Utilization 2006

The Center for Biomass Utilization (CBUî) 2006 project at the Energy & Environmental Research Center (EERC) consisted of three tasks related to applied fundamental research focused on converting biomass feedstocks to energy, liquid transportation fuels, and chemicals. Task 1, entitled Thermochemical Conversion of Biomass to Syngas and Chemical Feedstocks, involved three activities. Task 2, entitled Crop Oil Biorefinery Process Development, involved four activities. Task 3, entitled Management, Education, and Outreach, focused on overall project management and providing educational outreach related to biomass technologies through workshops and conferences

Potentially Heterogeneous Cross-Sectional Associations of Seafood Consumption with Diabetes and Glycemia in Urban South Asia.

Aims: In this study, we aimed to estimate cross-sectional associations of fish or shellfish consumption with diabetes and glycemia in three South Asian mega-cities. Methods: We analyzed baseline data from 2010-2011 of a cohort (n = 16,287) representing the population ≥20 years old that was neither pregnant nor on bedrest from Karachi (unweighted n = 4017), Delhi (unweighted n = 5364), and Chennai (unweighted n = 6906). Diabetes was defined as self-reported physician-diagnosed diabetes, fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), or glycated hemoglobin A1c (HbA1c) ≥6.5% (48 mmol/mol). We estimated adjusted and unadjusted odds ratios for diabetes using survey estimation logistic regression for each city, and differences in glucose and HbA1c using survey estimation linear regression for each city. Adjusted models controlled for age, gender, body mass index, waist-height ratio, sedentary lifestyle, educational attainment, tobacco use, an unhealthy diet index score, income, self-reported physician diagnosis of high blood pressure, and self-reported physician diagnosis of high cholesterol. Results: The prevalence of diabetes was 26.7% (95% confidence interval: 24.8, 28.6) in Chennai, 36.7% (32.9, 40.5) in Delhi, and 24.3% (22.0, 26.6) in Karachi. Fish and shellfish were consumed more frequently in Chennai than in the other two cities. In Chennai, the adjusted odds ratio for diabetes, comparing more than weekly vs. less than weekly fish consumption, was 0.81 (0.61, 1.08); in Delhi, it was 1.18 (0.87, 1.58), and, in Karachi, it was 1.30 (0.94, 1.80). In Chennai, the adjusted odds ratio of prevalent diabetes among persons consuming shellfish more than weekly versus less than weekly was 1.08 (95% CI: 0.90, 1.30); in Delhi, it was 1.35 (0.90, 2.01), and, in Karachi, it was 1.68 (0.98, 2.86). Conclusions: Both the direction and the magnitude of association between seafood consumption and glycemia may vary by city. Further investigation into specific locally consumed seafoods and their prospective associations with incident diabetes and related pathophysiology are warranted

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study

BACKGROUND: Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE). METHODS AND RESULTS: The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium. CONCLUSIONS: Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future

Giant hepatic hydatid cyst with sub-fascial extension treated by open minimally invasive surgery: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatic hydatid disease can be successfully treated by a variety of modalities.</p> <p>Case Presentation</p> <p>We report a case of a 60 year old male with giant hepatic hydatid disease who presented with a huge cystic mass in the upper abdomen. Diagnosis was confirmed by serology, ultrasonography and CT scan. The patient was treated successfully by open minimally invasive surgery with minimum breaching of the peritoneal cavity using a laparoscopic trocar to evacuate the cyst.</p> <p>Conclusion</p> <p>The use of a laparoscopic trocar through a small abdominal incision in selected patients with hepatic hydatid disease with subfascial extension can be a safe, minimally-invasive option of treatment</p

Association between full service and fast food restaurant density, dietary intake and overweight/obesity among adults in Delhi, India

Abstract Background The food environment has been implicated as an underlying contributor to the global obesity epidemic. However, few studies have evaluated the relationship between the food environment, dietary intake, and overweight/obesity in low- and middle-income countries (LMICs). The aim of this study was to assess the association of full service and fast food restaurant density with dietary intake and overweight/obesity in Delhi, India. Methods Data are from a cross-sectional, population-based study conducted in Delhi. Using multilevel cluster random sampling, 5364 participants were selected from 134 census enumeration blocks (CEBs). Geographic information system data were available for 131 CEBs (n = 5264) from a field survey conducted using hand-held global positioning system devices. The number of full service and fast food restaurants within a 1-km buffer of CEBs was recorded by trained staff using ArcGIS software, and participants were assigned to tertiles of full service and fast food restaurant density based on their resident CEB. Height and weight were measured using standardized procedures and overweight/obesity was defined as a BMI ≥25 kg/m2. Results The most common full service and fast food restaurants were Indian savory restaurants (57.2%) and Indian sweet shops (25.8%). Only 14.1% of full service and fast food restaurants were Western style. After adjustment for age, household income, education, and tobacco and alcohol use, participants in the highest tertile of full service and fast food restaurant density were less likely to consume fruit and more likely to consume refined grains compared to participants in the lowest tertile (both p < 0.05). In unadjusted logistic regression models, participants in the highest versus lowest tertile of full service and fast food restaurant density were significantly more likely to be overweight/obese: odds ratio (95% confidence interval), 1.44 (1.24, 1.67). After adjustment for age, household income, and education, the effect was attenuated: 1.08 (0.92, 1.26). Results were consistent with further adjustment for tobacco and alcohol use, moderate physical activity, and owning a bicycle or motorized vehicle. Conclusions Most full service and fast food restaurants were Indian, suggesting that the nutrition transition in this megacity may be better characterized by the large number of unhealthy Indian food outlets rather than the Western food outlets. Full service and fast food restaurant density in the residence area of adults in Delhi, India, was associated with poor dietary intake. It was also positively associated with overweight/obesity, but this was largely explained by socioeconomic status. Further research is needed exploring these associations prospectively and in other LMICs

Identification of Single- and Multiple-Class Specific Signature Genes from Gene Expression Profiles by Group Marker Index

Informative genes from microarray data can be used to construct prediction model and investigate biological mechanisms. Differentially expressed genes, the main targets of most gene selection methods, can be classified as single- and multiple-class specific signature genes. Here, we present a novel gene selection algorithm based on a Group Marker Index (GMI), which is intuitive, of low-computational complexity, and efficient in identification of both types of genes. Most gene selection methods identify only single-class specific signature genes and cannot identify multiple-class specific signature genes easily. Our algorithm can detect de novo certain conditions of multiple-class specificity of a gene and makes use of a novel non-parametric indicator to assess the discrimination ability between classes. Our method is effective even when the sample size is small as well as when the class sizes are significantly different. To compare the effectiveness and robustness we formulate an intuitive template-based method and use four well-known datasets. We demonstrate that our algorithm outperforms the template-based method in difficult cases with unbalanced distribution. Moreover, the multiple-class specific genes are good biomarkers and play important roles in biological pathways. Our literature survey supports that the proposed method identifies unique multiple-class specific marker genes (not reported earlier to be related to cancer) in the Central Nervous System data. It also discovers unique biomarkers indicating the intrinsic difference between subtypes of lung cancer. We also associate the pathway information with the multiple-class specific signature genes and cross-reference to published studies. We find that the identified genes participate in the pathways directly involved in cancer development in leukemia data. Our method gives a promising way to find genes that can involve in pathways of multiple diseases and hence opens up the possibility of using an existing drug on other diseases as well as designing a single drug for multiple diseases