tbuckley/cabot-search huggingface dataset:
Abstract P193: Nuclear Localization of the α1B-Adrenergic Receptor Subtype Is Required for Hypertrophic Signaling in Cardiac Myocytes
Authors: Steven C Wu, Andrew L Cypher, Chastity L Healy, Casey D Wright, Yuan Huang, Timothy D O'Connell
Journal: Circulation Research (2011)

We previously demonstrated that α1-adrenergic receptors (α1-ARs) in the heart are required for physiologic hypertrophy during development and prevent a maladaptive response to pathologic stress. We have also shown that the major subtypes, α1A and α1B, both localize to the nucleus in adult cardiac myocytes. Importantly, we have defined a nuclear α1A-ERK survival and an α1A-PKCδ-cTnI inotropic signaling pathway that both originate at the nucleus and are transduced to cytosolic targets, suggesting that the α1A is required for cardiac myocyte survival and contractility. However, less is known about the molecular function of the α1B. In the current study, we examined the role of the α1B-subtype in hypertrophic signaling. First, we identified a bi-partite nuclear localization sequence (NLS) in the carboxy-terminal tail of the receptor. Mutation of the NLS (α1B-NLSmut) disrupted its localization to the nucleus when expressed in adult cardiac myocytes. We then compared hypertrophic signaling of the wild-type α1B- to the mutated receptor by reconstitution in cardiac myocytes lacking endogenous α1B (α1BKO) receptors. Activation of the wild-type receptor by the α1-agonist phenylephrine in α1BKO myocytes restored hypertrophic signaling, as we observed increased phosphorylation of protein kinase C (PKC) isoforms δ and ε, and histone deacetylases (HDAC) 4 and 5. We also observed increased expression of the hypertrophic gene marker, atrial natriuretic factor (ANF). Expression of the α1B-NLSmut failed to activate hypertrophic signaling in α1BKO cardiac myocytes despite phenylephrine stimulation. Together, our data show that nuclear localization of the α1B-subtype is required for hypertrophic signaling and overall further suggest that α1-adrenergic receptors are functional only at the nucleus in cardiac myocytes.
Cholangioscopy-directed lithotripsy for a large bile duct stone: the “donut technique”
Authors: Noor Bekkali, Sham Direkze, George Webster
Journal: Endoscopy (2017)

Conventionally, choledocholithiasis is managed by endoscopic retrograde cholangiopancreatography (ERCP), and it accounts for at least 50 % of the approximately 52 000 ERCPs performed in the UK each year [1] [2] [3] [4] [5]. Bile duct stone clearance traditionally involves the performance of ERCP with biliary sphincterotomy (or sphincteroplasty), followed by the removal of stones from the biliary tree using an extraction balloon, with or without the use of a basket or mechanical lithotripter. Stones may be difficult to remove at ERCP owing to a range of factors, including size (e. g. stones > 15 mm), number, location (e. g. intrahepatic or within the cystic duct), and other anatomical factors (e. g. stones above strictures).
Screening for antineoplastic ionic liquids by targeting RLIP76.
Authors: Muhammad Saad Khan, Fred L. Hardwicke, Henry Palangdao Igid, Hassan Kaleem, Sanjay Awasthi, Daniel Armstrong
Journal: Journal of Clinical Oncology (2017)

e13033 Background: RLIP76 is a stress-responsive multispecific transporter which functions as an anti-apoptotic protein in cancer cells. The targeting of RLIP76 by antibodies, antisense, or siRNA modalities causes complete regression of cancers such as melanoma, colon cancer and lung cancer. We carried out studies to determine whether the ATPase activity of purified recombinant human RLIP76 protein (encoded by RALBP1, chromosome 18p11.22) can be used to screen for novel ionic liquid compounds with antineoplastic activity. Methods: A series of ionic liquid compounds were tested for their ability to inhibit or activate the ATPase activity and doxorubicin transport activity of purified recombinant human RLIP76. The growth inhibitory effects of these compounds were monitored in human non-small cell lung cancer cell line NCI H358, with human aorta vascular smooth muscle cells serving as non-malignant controls. Results: ATPase activation correlated with doxorubicin transport inhibition. More importantly, the antineoplastic activity towards lung cancer cells was also correlated with degree of ATPase activation or transport inhibition. Cytotoxicity towards the non-neoplastic cell line was 1-2 orders of magnitude less than observed for the lung cancer cells, a characteristic of other agents that target RLIP76. The predicted antineoplastic effect was confirmed in H358 xenografts in nude mice. Conclusions: These studies indicate the potential utility of screening for antineoplastic agents using recombinant RLIP76 and also demonstrate antineoplastic activity of a novel ionic liquid compound.
Endoscopic submucosal dissection of early colorectal neoplasms with a monopolar scissor-type knife: short- to long-term outcomes
Authors: Toshio Kuwai, Toshiki Yamaguchi, Hiroki Imagawa, Yuki Sumida, Takeshi Takasago, Yuki Miyasako, Tomoyuki Nishimura, Sumio Iio, Atsushi Yamaguchi, Hirotaka Kouno, Hiroshi Kohno, Sauid Ishaq
Journal: Endoscopy (2017)

Abstract Background and study aims Endoscopic submucosal dissection (ESD) for colorectal neoplasms remains challenging because of technical issues imposed by the complex anatomical features of the large intestine. We evaluated the feasibility, and the short- and long-term clinical outcomes of ESD for early colorectal neoplasms performed using the Stag-beetle Knife Jr. (SB Knife Jr.) Patients and methods We retrospectively assessed 228 patients who underwent ESD for 247 colorectal lesions with the SB Knife Jr. Clinicopathological characteristics of the neoplasms, complications, and various short- and long-term outcomes were evaluated. Results Mean tumor size was 34.3 mm and median procedure time was 76 minutes. The SB Knife Jr. achieved 98.4 % en bloc resection, 93.9 % complete resection, and 85.4 % curative resection. No perforations occurred during the procedure, and a delayed bleeding rate of 2.4 % was observed. Long-term outcomes were favorable with no distant recurrence, 1.1 % local recurrence, a 5-year overall survival rate of 94.1 % and 5-year tumor-specific survival rate of 98.6 % in patients with cancer. Conclusions ESD using the SB Knife Jr. is technically efficient and safe in treating early colorectal neoplasms and is associated with favorable short- and long-term outcomes.
PTH-125 Opiate analgesia and surgical interventions are associated with adverse outcomes in chronic continuous abdominal pain: a tertiary clinic experience
Authors: E Kilgallon, DH Vasant, PL Shields, S Hamdy, S Lal, PA Paine
Journal: Gut (2017)

Introduction  Centrally mediated disorders are characterised by chronic continuous or near continuous abdominal pain (CCAP)1. Due to lack of cohort-specific evidence, their management remains challenging. We examined impacts of opiate use, surgery and anti-neuropathic (antiNP) analgesia on clinical outcome in a cohort of CCAP patients.  Method  Consecutive tertiary referrals with CCAP to a neurogastroenterology clinic between 2009–2016 were included. Other primary functional gut disorders and anterior cutaneous nerve entrapment were excluded. Medical, surgical and drug histories; interventions and outcomes were collected retrospectively. Clinical outcomes were compared (categorical: Chi Square/Fisher; continuous: one way ANOVA) by neuropathic pain (NP)2 diagnosis and opiate use.  Results  104 patients (mean age 40 years, 86% female) were included. 92/104 (88%) had been diagnosed clinically with NP and 12/104 (12%) with narcotic bowel syndrome (NBS).  Opiate use was associated with poor symptom response in most patients (50/73, 68% NP and 11/12, 92% NBS). Short-acting oral morphine (p=0.02) and use of ≥4 opiates (p=0.01) were associated with NBS. Weaker opiates were inversely associated with NBS (p=0.03). Current (p=0.01) and previous opiate use (p=0.004) were associated with constipation.  44/104 (42%) patients had ≥1 diagnostic or therapeutic surgical procedure for their pain. Surgery did not resolve symptoms in any patient and 13/44 (35%) patients, reported pain worsened after surgery. Opiate use (p=0.03) and NBS (p=0.03) were associated with increased number of surgeries performed for pain.  96/104 (92%) received antiNP drugs with clinical outcomes in 51/96 (response 34/51, 67%; non-response 10/51, 19%; intolerant 7/51, 14%). Sub-analyses (n=7 excluded as unknown prescribing sequence) showed combination therapy (>1 antiNP (86% response, n=14), or antiNP + linaclotide (100% response, n=11) was superior to antiNP monotherapy (47% response, n=19), p=0.002. Duloxetine was the single most effective antiNP (p=0.05). Opiate use and NBS were associated with more tertiary appointments and service use (p=0.02).  Conclusion  This is the largest cohort-specific study of centrally mediated abdominal pain management to date. Opiate use, exploratory and therapeutic surgical procedures for CCAP are associated with worse clinical outcomes. Combinations of antiNP agents and linaclotide appear efficacious but optimum regimes need further exploration.  References  . Keefer, et al. Gastro2016.  . Searle, et al. Br J Anaes2012.  Disclosure of Interest  None Declared
A Single Factor Underlies the Metabolic Syndrome: A Confirmatory Factor Analysis
Authors: Manel Pladevall, Bonita Singal, L. Keoki Williams, Carlos Brotons, Heidi Guyer, Josep Sadurni, Carles Falces, Manuel Serrano-Rios, Rafael Gabriel, Jonathan E. Shaw, Paul Z. Zimmet, Steven Haffner
Journal: Diabetes Care (2006)

We thank McCaffery et al. (1) for their comments on our study (2). In their first report (3), they used confirmatory factor analysis to analyze the metabolic syndrome structure and to expose the limitations of exploratory factor analysis (EFA). We agree that their results support the concept of a common factor underlying the different components of the metabolic syndrome.

What, therefore, are the differences between our studies? The one-factor model in our study was based …
The in vitro metabolism of estrogens by human fecal bacteria; a comparison of equol-producers and non-producers
Authors: Charlotte Atkinson, Sheryl Berman, Wendy K. Thomas, Johanna W. Lampe
Journal: Cancer Research (2005)

1581  Hormonal exposure is associated with risk of breast cancer and determinants of circulating levels of estrogens and of estrogen metabolism are among the primary risk factors for breast cancer. Steroid hormone metabolism in humans involves numerous steps including intestinal bacterial metabolism. Thus, inter-individual differences in intestinal bacterial populations may contribute to variation in disease susceptibility through effects on metabolism and subsequent exposure to estrogens. One-third to one-half of the population harbors the yet-to-be-identified bacteria that metabolize daidzein, a soy isoflavone, to equol. Studies suggest that equol production may be associated with reduced breast cancer risk, but mechanisms for this relationship are unknown. Our aim was to determine whether fecal bacterial metabolism of estrogens differs according to equol-producer phenotype. Previously frozen fecal samples from 34 women were available for this study. According to previously analyzed urine samples (collected after soy consumption) 20 were equol-producers (EP), 12 were equol non-producers (ENP), and 2 had trace amounts of equol in their urine. Fecal samples were thawed, and added to brain heart infusion (BHI) media. Aliquots of this slurry were incubated in BHI media under anaerobic conditions for 5 days at 37°C with daidzein or the following estrogens: estrone, estradiol, estriol, 2-hydroxyestrone, 16α-hydroxyestrone, and 2-methoxyestrone. Each estrogen was assayed in triplicate, and daidzein in duplicate. After incubation, estrogens and isoflavones were extracted from the BHI media using ethyl acetate and quantified by gas chromatography-mass spectrometry. Fecal bacteria from 1 known EP did not metabolize daidzein to equol in vitro; their data were not included in statistical analyses. Fecal bacteria from the remaining EP (n=19), and 1 individual with trace equol in their urine, metabolized daidzein to equol. Fecal bacteria from the 12 ENP, and 1 individual with trace equol in their urine, did not metabolize daidzein to equol. EP, compared to ENP, metabolized significantly more estrone to estradiol, and 16α-hydroxyestrone to estriol (p≤0.05). Although differences between EP and ENP in the amount of 2-hydroxyestrone metabolized to 2-hydroxyestradiol were not significant, EP were more likely than ENP to show metabolism of 2-hydroxyestrone to 2-hydroxyestradiol (χ2=4.1, p=0.04). All other differences between EP and ENP were not statistically significant. These preliminary findings suggest that differences in fecal bacterial estrogen metabolism may exist between equol-producers and non-producers. This work was supported by a Department of Defense Breast Cancer Research Program Concept Award (DAMD17-03-1-0604), and Fred Hutchinson Cancer Research Center.
PTH-035 Assessment of gastric emptying and antral motility in different types of abdominal pain related functional gastrointestinal diseases: a paediatric study: Abstract PTH-035
Authors: N M Devanarayana, S Rajindrajith
Journal: Gut (2010)

<h3>Introduction</h3> Functional gastrointestinal disorders (FGD) are common among paediatric population. Abdominal pain related FGD are the most common subgroup found, of which irritable bowel syndrome is the most common. The exact mechanism of pain remains unclear in FGD. Visceral hypersensitivity and altered gastrointestinal motility are considered possible causes for abdominal pain and discomfort found in these children. <h3>Methods</h3> The main aim of this study was to evaluate the gastric emptying and antral motility in children and adolescents with abdominal pain related FGD. Hundred and fifty-five children referred to the Gastroenterology Research Laboratory who fulfilled Rome III criteria for abdominal pain related FGD (60 (38.5%) males, 4–14 years, mean 8.1 years, SD 2.6 years) and 20 healthy children without gastrointestinal symptoms (8 (40%) males, 4–15 years, mean 8.9 years, SD 2.7 years) were recruited. None had clinical or laboratory evidence of organic diseases. All subjects underwent ultrasonographic assessment of liquid gastric emptying rate (GE) and antral motility, using a previously reported method. <h3>Results</h3> Gastric motility parameters of children with FGD and controls are presented in the table. GE negatively correlated with the scores obtained for severity of symptoms in functional dyspepsia (FD) (r=−0.67, p&lt;0.001) and functional abdominal pain (FAP) (r=−0.38, p&lt;0.001), but not in irritable bowel syndrome (IBS) (r=−0.16, p=0.29) (Abstract 035). <h3>Conclusion</h3> GE and antral motility parameters were significantly impaired in children with all types of abdominal pain related FGD. GE negatively correlated with symptoms in FD and FAP. Motility parameters were not significantly different between subtypes of IBS.
KEYNOTE-185: a randomized, open-label phase 3 study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM).
Authors: Antonio Palumbo, María-Victoria Mateos, Jesus San Miguel, Jatin Shah, Seth Thompson, Patricia Maria Marinello, Sundar Jagannath
Journal: Journal of Clinical Oncology (2016)

TPS8069 Background: Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, leading to antitumor immune response. In the phase 1 KEYNOTE-023 trial of pembrolizumab + lenalidomide and low-dose dexamethasone, the treatment combination had an acceptable safety profile and promising preliminary efficacy in patients with relapsed/refractory MM, supporting further evaluation of pembrolizumab for patients with MM. The randomized, open-label, multicenter, phase 3 KEYNOTE-185 study (NCT02579863) was designed to compare the efficacy and safety of lenalidomide and low-dose dexamethasone (standard of care) with or without pembrolizumab in patients with newly diagnosed and treatment-naive MM. Methods: Eligible patients must be aged ≥ 18 years, have newly diagnosed, treatment-naive active MM with measurable disease and be ineligible for autologous stem cell transplant. Patients are to be randomized 1:1 to receive lenalidomide 25 mg daily on days 1-21 and low-dose dexamethasone 40 mg daily on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without pembrolizumab 200 mg every 3 weeks. Stratification is to be based on age ( < 75 vs ≥ 75 years old) and International Staging System stage (ISS I or II vs ISS III). Treatment is to continue until progressive disease or unacceptable toxicity. Response is to be assessed every 28 days by Clinical Adjudication Committee blinded central review and by investigator review based on International Myeloma Working Group (IMWG) response criteria. Adverse events (AEs) are to be assessed throughout treatment and for 30 days thereafter (90 days for events of clinical interest) and graded per NCI CTCAE v4.0. Primary end point is to be progression-free survival as assessed by central review according to IMWG criteria; secondary end points are to include overall survival, overall response rate, and safety and tolerability. Enrollment in KEYNOTE-185 is ongoing; ~640 patients are to be enrolled. Clinical trial information: NCT02579863.
MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor–Initiating Cells
Authors: Xiuxing Wang, Zhi Huang, Qiulian Wu, Briana C. Prager, Stephen C. Mack, Kailin Yang, Leo J.Y. Kim, Ryan C. Gimple, Yu Shi, Sisi Lai, Qi Xie, Tyler E. Miller, Christopher G. Hubert, Anne Song, Zhen Dong, Wenchao Zhou, Xiaoguang Fang, Zhe Zhu, Vaidehi Mahadev, Shideng Bao, Jeremy N. Rich
Journal: Cancer Research (2017)

Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor-initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting.
MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer
Authors: Venugopal Gunda, Joshua Souchek, Jaime Abrego, Surendra K. Shukla, Gennifer D. Goode, Enza Vernucci, Aneesha Dasgupta, Nina V. Chaika, Ryan J. King, Sicong Li, Shuo Wang, Fang Yu, Tadayoshi Bessho, Chi Lin, Pankaj K. Singh
Journal: Clinical Cancer Research (2017)

Purpose:MUC1, an oncogene overexpressed in multiple solid tumors, including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth-promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models.Experimental Design: We used MUC1-knockdown and -overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response, and metabolomic evaluations. We also investigated whether inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance by using in vitro and in vivo models.Results: MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pretreatment with the glycolysis inhibitor 3-bromopyruvate abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pretreatment with nucleoside pools.Conclusions: MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation resistance in pancreatic cancer and targeted effectively through glycolytic inhibition. Clin Cancer Res; 23(19); 5881-91. ©2017 AACR.
IND-directed, five-day repeat dose toxicity study of NLCQ-1 (NSC 709257) administered with or without Taxol® in Sprague Dawley rats.
Authors: Maria V. Papadopoulou, William D. Bloomer, Vincent R. Torti, John G. Page
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

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4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) is a weak DNA-intercalating, hypoxia-selective cytotoxin with a promising profile as an adjuvant to radio/chemotherapy in preclinical studies. NCLQ-1 is about to enter Phase I Clinical Trials. The present investigation was undertaken to further evaluate potential systemic toxicity induced by i.v. doses of NLCQ-1 alone or in combination with Taxol® in Sprague-Dawley Rats, in support of an IND-application. Doses of NLCQ-1 were based on previous range-finding studies in which deaths occurred at i.v. doses as low as 14 mg/kg (male rats) and 20 mg/kg (female rats). NLCQ-1 was administered either alone, at 0, 6, 9 or12 mg/kg/dose to male rats and 8, 12 or16 mg/kg/dose to female rats or, at 9 (male rats) and 12 (female rats) mg/kg/dose, in combination with Taxol®, on a qdx5 schedule. Taxol® was administered i.v. at 3.5 mg/kg/dose one hour before NLCQ-1. Observations were recorded for mortality/moribundity, clinical signs of toxicity, body weights, food consumption, hematology, clinical chemistry, gross lesions at necropsy, and histopathology. On Day 8, ten animals from each dose group had blood samples taken, and on Day 33, ten animals from each dose group had blood samples taken prior to scheduled sacrifice. Administration of i.v. doses of NLCQ-1 once each day for five consecutive days resulted in no signs of toxicity over the 33 day study. Taxol®-induced toxicity included minimal decreases in the group mean RBC, HGB, and HCT values, minimal increases in group mean reticulocyte counts (females), marked decreases in group mean neutrophil counts and minimal decreases in group mean monocyte and eosinophil counts. Lymphoid atrophy of thymus, atrophy of bone marrow, and atrophy of the germinal epithelium of testis was also associated with the administration of Taxol®. There was no additional toxicity associated with the co-administration of NLCQ-1 and Taxol®. In the present study, the NOAEL for NLCQ-1 is > 12 and > 16 mg/kg/dose in male and female rats, respectively, when administered on a qdx5 schedule. Daily administration of 9 (male rats) or 12 (female rats) mg/kg of NLCQ-1 one hour after iv administration of Taxol® (3.5 mg/kg) had no effect on Taxol®-induced toxicity.