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Showing papers by "University of Texas Medical Branch published in 2013"


Journal ArticleDOI
TL;DR: This study shows that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another.
Abstract: A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

2,438 citations



Journal ArticleDOI
TL;DR: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy and there was a significant interaction between dosing strategy and race.
Abstract: Background The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. Methods We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. Results At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There ...

656 citations


Journal ArticleDOI
TL;DR: Current knowledge of CCHFV is summarized, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range, including an extensive discussion of C CHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees.

572 citations


Journal ArticleDOI
TL;DR: H2S produced from CBS serves to maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients.
Abstract: The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target.

556 citations


Journal ArticleDOI
TL;DR: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours.
Abstract: Summary Background Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4–2·8]) than placebo (1·4 months [1·4–1·5]; hazard ratio [HR] 0·64, 90% CI 0·43–0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4–8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4–1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19–0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

512 citations


Journal ArticleDOI
24 Jan 2013-Immunity
TL;DR: The studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.

505 citations


Journal ArticleDOI
TL;DR: Remarkably, misfolded Tau can be internalized at the somatodendritic compartment, or the axon terminals and it can be transported anterogradely, retrogradely, and can enhance tauopathy in vivo.

446 citations


Journal ArticleDOI
TL;DR: The genomic landscape of sensitivity to replication stress in human cells was characterized, and >2,000 nonuniformly distributed aphidicolin-sensitive regions (ASRs) overrepresented in genes and enriched in satellite repeats were identified.
Abstract: We present a genome-wide method to map DNA double-strand breaks (DSBs) at nucleotide resolution by direct in situ breaks labeling, enrichment on streptavidin, and next-generation sequencing (BLESS). We comprehensively validated and tested BLESS using different human and mouse cells, DSBs-inducing agents, and sequencing platforms. BLESS was able to detect telomere ends, Sce endonuclease-induced DSBs, and complex genome-wide DSBs landscapes. As a proof of principle, we characterized the genomic landscape of sensitivity to replication stress in human cells, and identified over two thousand non-uniformly distributed aphidicolin-sensitive regions (ASRs) overrepresented in genes and enriched in satellite repeats. ASRs were also enriched in regions rearranged in human cancers, with many cancer-associated genes exhibiting high sensitivity to replication stress. Our method is suitable for genome-wide mapping of DSBs in various cells and experimental conditions with a specificity and resolution unachievable by current techniques.

416 citations


Journal ArticleDOI
TL;DR: On September 16, 2012, the National Lipid Association held a Consensus Conference with the goal of better defining the effect of adiposity on lipoproteins, how the pathos of excessive body fat (adiposopathy) contributes to dyslipidemia, and how therapies such as appropriate nutrition, increased physical activity, weight-management drugs, and bariatric surgery might be expected to impact dys Lipidemia.

356 citations


Journal ArticleDOI
TL;DR: PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects and multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses.

Journal ArticleDOI
TL;DR: This study examined the selectivity of commonly used pharmacological inhibitors of H2S biosynthesis towards CSE and CBS.
Abstract: Background and Purpose Hydrogen sulfide (H2S) is a signalling molecule that belongs to the gasotransmitter family. Two major sources for endogenous enzymatic production of H2S are cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). In the present study, we examined the selectivity of commonly used pharmacological inhibitors of H2S biosynthesis towards CSE and CBS. Experimental Approach To address this question, human CSE or CBS enzymes were expressed and purified from Escherichia coli as fusion proteins with GSH-S-transferase. After purification, the activity of the recombinant enzymes was tested using the methylene blue method. Key Results β-cyanoalanine (BCA) was more potent in inhibiting CSE than propargylglycine (PAG) (IC50 14 ± 0.2 μM vs. 40 ± 8 μM respectively). Similar to PAG, L-aminoethoxyvinylglycine (AVG) only inhibited CSE, but did so at much lower concentrations. On the other hand, aminooxyacetic acid (AOAA), a frequently used CBS inhibitor, was more potent in inhibiting CSE compared with BCA and PAG (IC50 1.1 ± 0.1 μM); the IC50 for AOAA for inhibiting CBS was 8.5 ± 0.7 μM. In line with our biochemical observations, relaxation to L-cysteine was blocked by AOAA in aortic rings that lacked CBS expression. Trifluoroalanine and hydroxylamine, two compounds that have also been used to block H2S biosynthesis, blocked the activity of CBS and CSE. Trifluoroalanine had a fourfold lower IC50 for CBS versus CSE, while hydroxylamine was 60-fold more selective against CSE. Conclusions and Implications In conclusion, although PAG, AVG and BCA exhibit selectivity in inhibiting CSE versus CBS, no selective pharmacological CBS inhibitor is currently available.

Journal ArticleDOI
07 Mar 2013-Nature
TL;DR: It is shown that, unlike most genes in Neurospora, frq exhibits non-optimal codon usage across its entire open reading frame, and optimization of frqcodon usage abolishes both overt and molecular circadian rhythms.
Abstract: Codon-usage bias has been observed in almost all genomes and is thought to result from selection for efficient and accurate translation of highly expressed genes. Codon usage is also implicated in the control of transcription, splicing and RNA structure. Many genes exhibit little codon-usage bias, which is thought to reflect a lack of selection for messenger RNA translation. Alternatively, however, non-optimal codon usage may be of biological importance. The rhythmic expression and the proper function of the Neurospora FREQUENCY (FRQ) protein are essential for circadian clock function. Here we show that, unlike most genes in Neurospora, frq exhibits non-optimal codon usage across its entire open reading frame. Optimization of frq codon usage abolishes both overt and molecular circadian rhythms. Codon optimization not only increases FRQ levels but, unexpectedly, also results in conformational changes in FRQ protein, altered FRQ phosphorylation profile and stability, and impaired functions in the circadian feedback loops. These results indicate that non-optimal codon usage of frq is essential for its circadian clock function. Our study provides an example of how non-optimal codon usage functions to regulate protein expression and to achieve optimal protein structure and function.

Journal ArticleDOI
TL;DR: New research and novel research methodologies are necessary to establish the protein needs and optimal patterns of protein intake for older persons.
Abstract: Background. Protein is a macronutrient essential for growth, muscle function, immunity and overall tissue homeostasis. Suboptimal protein intake can significantly impact physical function and overall health in older adults.

Journal ArticleDOI
TL;DR: Data from Clinformatics DataMart, one of the nation's largest commercial health insurance populations, was used to examine androgen prescribing patterns in the United States over the past decade.
Abstract: Although commercial sales of androgen replacement therapy (ART) have increased substantially in recent years,1,2 to our knowledge, no national population-based studies of this treatment have been reported. In view of the conflicting evidence on the risks and benefits of ART,3-7 understanding androgen prescribing patterns in the United States is important from both a clinical and a public health perspective. We used data from Clinformatics DataMart (CDM), one of the nation's largest commercial health insurance populations, to examine androgen prescribing patterns in the United States over the past decade.

Journal ArticleDOI
TL;DR: Therapeutic lifestyle change continues to be the most important intervention in clinical practice to improve adipose tissue function and avoid development of insulin resistance and related cardio-metabolic complications.
Abstract: The burden of obesity has increased globally over the last few decades and its association with insulin resistance and related cardio-metabolic problems have adversely affected our ability to reduce population morbidity and mortality. Traditionally, adipose tissue in the visceral fat depot has been considered a major culprit in the development of insulin resistance. However, there is a growing body of evidence supporting the role of subcutaneous truncal/abdominal adipose tissue in the development of insulin resistance. There are significant differences in the functional characteristics of subcutaneous abdominal/truncal vs. intraabdominal vs. gluteo-femoral fat depots. More recently, mounting evidence has been supporting the role of adipose tissue function in the development of metabolic complications independent of adipose tissue volume or distribution. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger a vicious cycle of inflammation leading to subcutaneous adipose tissue dysfunction and ectopic fat deposition. Therapeutic lifestyle change continues to be the most important intervention in clinical practice to improve adipose tissue function and avoid development of insulin resistance and related cardio-metabolic complications.

Journal ArticleDOI
TL;DR: The surgery-induced stress response is largely similar to that triggered by traumatic injuries; the duration of the stress response, however, varies according to the severity of injury (surgical or traumatic).
Abstract: The stress response to surgery, critical illness, trauma, and burns encompasses derangements of metabolic and physiological processes that induce perturbations in the inflammatory, acute phase, hormonal, and genomic responses. Hypermetabolism and hypercatabolism result, leading to muscle wasting, impaired immune function and wound healing, organ failure, and death. The surgery-induced stress response is largely similar to that triggered by traumatic injuries; the duration of the stress response, however, varies according to the severity of injury (surgical or traumatic). This spectrum of injuries and insults ranges from small lacerations to severe insults such as large poly-traumatic and burn injuries. Burn injuries provide an extreme model of trauma induced stress responses that can be used to study the long-term effects of a prolonged stress response. Although the stress response to acute trauma evolved to confer improved chances of survival following injury, in modern surgical practice the stress respo...

Journal ArticleDOI
TL;DR: The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV; the proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009.
Abstract: Background In the background of availability of better treatments for specific liver diseases and listing of nonalcoholic steatohepatitis (NASH) as an etiology for liver transplantation (LT), data are unclear on the impact of disease etiology on the frequency of LT and liver posttransplantation outcomes. Methods The United Network for Organ Sharing database (1994-2009) was queried for adults receiving first LT for primary biliary cirrhosis (PBC; n=3052), primary sclerosing cholangitis (PSC; n=3854), hepatitis C virus (HCV; n=15,147), alcoholic cirrhosis (AC; n=8940), HCV+alcohol (n=6066), NASH (n=1368), cryptogenic cirrhosis (CC; n=5856), hepatitis B virus (HBV; n=1816), and hepatocellular carcinoma (HCC; n=8588). Graft and patient survival were compared and Cox models were built to determine independent prediction of outcomes by disease etiology. Results The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV. The proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009. Compared with PBC, 5-year graft and patient survival were (a) similar for PSC, NASH, and HBV (80-85%), (b) poorer for AC and CC (hazard ratio, 1-1.5), and (c) worst for HCV, HCV+alcohol, and HCC (hazard ratio, 1.5-2.4). Five-year outcomes for HCV-associated HCC were poorer compared with HCC due to other etiologies. Conclusions LT performed for NASH and HCC are increasing. Potent treatment options resulted in a decrease in number of transplants for HBV, HCV, and PBC. Better treatment modalities for HCV are expected to further reduce the number of LT for HCV. Excellent posttransplantation outcomes for NASH and AC are encouraging, resulting in wider acceptance of transplants for these etiologies.

Journal ArticleDOI
TL;DR: Overexpression of FKBP51 in a tau transgenic mouse model revealed that FK BP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain.
Abstract: Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5–/– mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer’s disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

Journal ArticleDOI
TL;DR: It is concluded that an endogenous intramitochondrial H2S‐producing pathway, governed by 3‐MST, complements and balances the bioenergetic role of Krebs cycle‐derived electron donors.
Abstract: It is well established that exposure of mammalian cells to hydrogen sulfide (H(2)S) suppresses mitochondrial function by inhibiting cytochrome-c oxidase (CcOX; complex IV). However, recent experimental data show that administration of H(2)S to mammalian cells can serve as an electron donor and inorganic source of energy. The aim of our study was to investigate the role of endogenously produced H(2)S in the regulation of mitochondrial electron transport and oxidative phosphorylation in isolated liver mitochondria and in the cultured murine hepatoma cell line Hepa1c1c7. Low concentrations of H(2)S (0.1-1 μM) elicited a significant increase in mitochondrial function, while higher concentrations of H(2)S (3-30 μM) were inhibitory. The positive bioenergetic effect of H(2)S required a basal activity of the Krebs cycle and was most pronounced at intermediate concentrations of succinate. 3-mercaptopyruvate (3-MP), the substrate of the mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) stimulated mitochondrial H(2)S production and enhanced mitochondrial electron transport and cellular bioenergetics at low concentrations (10-100 nM), while at higher concentrations, it inhibited cellular bioenergetics. SiRNA silencing of 3-MST reduced basal bioenergetic parameters and prevented the stimulating effect of 3-MP on mitochondrial bioenergetics. Silencing of sulfide quinone oxidoreductase (SQR) also reduced basal and 3-MP-stimulated bioenergetic parameters. We conclude that an endogenous intramitochondrial H(2)S-producing pathway, governed by 3-MST, complements and balances the bioenergetic role of Krebs cycle-derived electron donors. This pathway may serve a physiological role in the maintenance of mitochondrial electron transport and cellular bioenergetics.

Journal ArticleDOI
TL;DR: This study presents novel information on the induction of a functional tRF by viral infection by applying deep sequencing to cells infected with human respiratory syncytial virus, the most common cause of bronchiolitis and pneumonia in babies.

Journal ArticleDOI
TL;DR: Although ineffective immunity and high viral loads are characteristic of several viral hemorrhagic fevers, severe plasma leakage occurs at the time of viral clearance and defervescence in dengue hemorrhagic fever.
Abstract: Four families of enveloped RNA viruses, filoviruses, flaviviruses, arenaviruses, and bunyaviruses, cause hemorrhagic fevers. These viruses are maintained in specific natural cycles involving nonhuman primates, bats, rodents, domestic ruminants, humans, mosquitoes, and ticks. Vascular instability varies from mild to fatal shock, and hemorrhage ranges from none to life threatening. The pathogenic mechanisms are extremely diverse and include deficiency of hepatic synthesis of coagulation factors owing to hepatocellular necrosis, cytokine storm, increased permeability by vascular endothelial growth factor, complement activation, and disseminated intravascular coagulation in one or more hemorrhagic fevers. The severity of disease caused by these agents varies tremendously; there are extremely high fatality rates in Ebola and Marburg hemorrhagic fevers, and asymptomatic infection predominates in yellow fever and dengue viral infections. Although ineffective immunity and high viral loads are characteristic of several viral hemorrhagic fevers, severe plasma leakage occurs at the time of viral clearance and defervescence in dengue hemorrhagic fever.

Journal ArticleDOI
05 Apr 2013-PLOS ONE
TL;DR: The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.
Abstract: Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency.

Journal ArticleDOI
TL;DR: An immigrant advantage relative to non-Hispanic whites in hypertension and, to a lesser extent, obesity is found and it is illustrated that although ignoring return migrants when testing for the HHP and its mechanisms, exaggerates these associations, they are not fully driven by return migration-related attrition.
Abstract: In this article, we test for four potential explanations of the Hispanic Health Paradox (HHP): the “salmon bias,” emigration selection, and sociocultural protection originating in either destination or sending country. To reduce biases related to attrition by return migration typical of most U.S.-based surveys, we combine data from the Mexican Health and Aging Study in Mexico and the U.S. National Health Interview Survey to compare self-reported diabetes, hypertension, current smoking, obesity, and self-rated health among Mexican-born men ages 50 and older according to their previous U.S. migration experience, and U.S.-born Mexican Americans and non-Hispanic whites. We also use height, a measure of health during childhood, to bolster some of our tests. We find an immigrant advantage relative to non-Hispanic whites in hypertension and, to a lesser extent, obesity. We find evidence consistent with emigration selection and the salmon bias in height, hypertension, and self-rated health among immigrants with less than 15 years of experience in the United States; we do not find conclusive evidence consistent with sociocultural protection mechanisms. Finally, we illustrate that although ignoring return migrants when testing for the HHP and its mechanisms, as well as for the association between U.S. experience and health, exaggerates these associations, they are not fully driven by return migration-related attrition.

Journal ArticleDOI
TL;DR: The studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for Pancreatic cancer.
Abstract: Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer.

Journal ArticleDOI
TL;DR: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.
Abstract: Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. Objective: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)– and c-Jun-N-terminal kinase (JNK)–specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. Results: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10–15 to 10–7 M). When combined with 10–9 M E2, the physiologic estrogen’s ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release. Conclusion: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.

Journal ArticleDOI
TL;DR: Findings reported in the literature demonstrating the accuracy of EGG in recording gastric slow waves and gastric dysrhythmia are reviewed and discussed and the correlation of the electrogastrogram with gastric contraction is carefully discussed.
Abstract: Electrogastrography (EGG) is a non-invasive method for the measurement of gastric myoelectrical activity. It was first discovered in 1921 and popularized in 1990s. EGG is attractive because it is non-invasive. However, due to its non-invasive nature, there have also been controversies regarding validity and applications of EGG. The aim of this review is to discuss the methodologies, validation and applications of EGG. Pros and cons of EGG will also be discussed in detail. First, the gastric slow wave and its correlation with gastric motility are presented. The association between gastric dysrhythmia and impaired gastric motility is reviewed. Secondly the method for recording the electrogastrogram is presented in detail and pitfalls in the recording and analysis of EGG are discussed. Thirdly, findings reported in the literature demonstrating the accuracy of EGG in recording gastric slow waves and gastric dysrhythmia are reviewed and discussed. The correlation of the electrogastrogram with gastric contraction is carefully discussed. Finally, applications of EGG in a few major areas are reviewed.

Journal ArticleDOI
TL;DR: These results identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth and provide a pivotal molecular target for disrupting neural signaling in the tumor microenvironment.
Abstract: The neurotransmitter noradrenaline can regulate cellular processes that contribute to cancer progression, but the underlying mechanisms remain largely unknown. Here the authors identify Src as a key mediator of noradrenaline signalling networks in tumour metastasis.

Journal ArticleDOI
TL;DR: Urban emergences of dengue, chikungunya, and yellow fever viruses and potential strategies for their prevention and control are reviewed.

Journal ArticleDOI
01 Oct 2013-Glia
TL;DR: What are the mechanisms underlying the neuronal soma and SGC communication in sensory ganglia and “how do tissue or nerve injuries affect the communication?” are the main questions addressed in this review.
Abstract: Studies of the structural organization and functions of the cell body of a neuron (soma) and its surrounding satellite glial cells (SGCs) in sensory ganglia have led to the realization that SGCs actively participate in the information processing of sensory signals from afferent terminals to the spinal cord. SGCs use a variety ways to communicate with each other and with their enwrapped soma. Changes in this communication under injurious conditions often lead to abnormal pain conditions. "What are the mechanisms underlying the neuronal soma and SGC communication in sensory ganglia?" and "how do tissue or nerve injuries affect the communication?" are the main questions addressed in this review.