tbuckley/cabot-search huggingface dataset:
Selective and Total Shunts in the Treatment of Bleeding Varices
Authors: John T. Galambos, W. Dean Warren, Daniel Rudman, Robert B. Smith, Atef A. Salam
Journal: New England Journal of Medicine (1976)

Two types of surgical therapy of bleeding esophageal varices were evaluated in 48 patients by a randomized controlled trial: 24 were randomized for a total shunt and 24 for the selective shunt. In two of the latter, a total shunt had to be performed for technical reasons. The fatality rates (six in the 24 total, and six in 22 selective [performed], and seven in 24 selective [randomized]), the frequency of shunt occlusion (two in each group), and of recurrent gastronintestinal bleeding (three in each group) were similar. Encephalopathy developed more often after a total shunt -- 10 of 24, or one per 58 patient-months -- than after selective (performed) -- one of 22, or one per 593 patient-months (P less than 0.005). Total shunts consistently diverted the hepatopetal mesenteric-portal flow from the liver. Deterioration of hepatic function (maximum rate of urea synthesis) was greater after total than selective shunt (P less than 0.05).
Clinical Study of Daunomycin and Prednisone for Induction of Remission in Children with Advanced Leukemia
Authors: Charlene P. Holton, Teresa J. Vietti, Audrey H. Nora, M. H. Donaldson, W. J. Stuckey, W. Lorraine Watkins, D. M. Lane
Journal: New England Journal of Medicine (1969)

Sixty-seven children with acute leukemia and with one or more previous relapses were treated with Daunomycin and prednisone to determine the effectiveness of this combination for inducing clinical and hematologic remissions. Sixty had acute lymphocytic, and seven acute myelocytic leukemia. Of the former, 39 attained complete, and 10 partial, bone-marrow remission. Of the latter, one had complete, and one partial remission. Median time to onset of remission marrow in the 51 children was 27 days. Maintenance of remission by Daunomycin was not studied. Limiting toxicity included leukopenia, thrombocytopenia, oral ulcerations, Cushingoid appearance and chemical cellulitis at the injection site. Daunomycin and prednisone are a highly effective drug combination for induction of remissions in children with leukemia refractory to conventional antileukemic drugs.
Loss of somatostatin receptor 2 expression and lung cancer growth.
Authors: Jonathan Lehman, Megan Hoeksema, Heidi Chen, Chanjuan Shi, Rosana Eisenberg, Pierre P. Massion
Journal: Journal of Clinical Oncology (2015)

7569 Background: Small cell lung cancer (SCLC) is a neuroendocrine cancer of the lung responsible for up to 25% of lung cancer deaths. Targeted therapies for SCLC are sorely needed. Somatostatin receptors (SSTR) are G protein-coupled receptors with effects on cell cycling, angiogenesis, and apoptosis which signal by inhibition of adenylate cyclase, Ca influx, and act through multiple kinases. SSTR2 is highly expressed in SCLCs and we hypothesize that its signaling supports cancer growth. Methods: Tumor microarrays containing 98 SCLCs were scored based on SSTR2 staining intensity and % tumor staining. Tumors were categorized as SSTR2 expressing (score > 0) which comprised 48% of the samples, or non expressing, and analyzed by Cox proportional hazard model including: age, smoking hx, stage, and SSTR2 expression. These results led to evaluation of SSTR2 expression and immunoblotting of multiple cell lines and tumors. We established SSTR2 shRNA knockdown lines including bronchial carcinoid, squamous cell carcinoma (SCC), and SCLC lines. We evaluated these lines with proliferation, flow cytometry, clonogenic assays, and a SCC cell line in vivo with mouse xenografts. Results: Non SSTR2 expressing SCLCs had a median survival by Kaplan Meier in limited stage (LS) disease of 36 compared to 12 months in SSTR2 expressing SCLCs suggesting SSTR2 expression has clinical relevance (p = 0.001). The 95% confidence interval for the hazard ratio was 0.23-0.87 for LS disease. There was no significant difference in survival in extensive stage disease. Most SCLC and a subset of SCC lines expressed SSTR2. Knockdown led to up to 3 fold decreases in cell viability in vitro in multiple lines and constructs. Xenograft experiments showed dramatically reduced ki67 staining and reduced tumor weight and growth curves in an SSTR2 shRNA H520 line. Phospho-protein array and immunoblots suggest dysregulation of pAKT and AMPK signaling with SSTR2 knockdown. Conclusions: SSTR2 expression in SCLC is associated with worse outcomes suggesting a role in cancer progression. Our data support this hypothesis and suggest downstream changes in pAKT and AMPK contribute to this phenotype. Overall, this suggests SSTR2 antagonism or downstream mediators may be future targets in lung carcinoma.
Abstract 13040: Alpha-Adrenergic Coronary Vasoconstriction and Myocardial Function in Humans
Authors: Zhaohui Gao, Samson Spilk, Afsana Momen, Cheryl Blaha, Jessica Mast, Urs A Leuenberger, Lawrence I Sinoway
Journal: Circulation (2010)

Sympathetically mediated coronary vasoconstriction is regulated by stimulation of alpha-adrenergic receptors. This process may be protective in animals since it evokes blood flow redistribution to ...
Thrombin and fibrinogen γ′ impact clot structure by marked effects on intrafibrillar structure and protofibril packing
Authors: Marco M. Domingues, Fraser L. Macrae, Cédric Duval, Helen R. McPherson, Katherine I. Bridge, Ramzi A. Ajjan, Victoria C. Ridger, Simon D. Connell, Helen Philippou, Robert A. S. Ariëns
Journal: Blood (2015)
Randomized trial of 1‐week versus 2‐week intervals for endoscopic ligation in the treatment of patients with esophageal variceal bleeding
Authors: Sarah Sheibani, Saro Khemichian, John J. Kim, Linda Hou, Arthur W. Yan, James Buxbaum, Lily Dara, Loren Laine
Journal: Hepatology (2016)

The appropriate interval between ligation sessions for treatment of esophageal variceal bleeding is uncertain. The optimal interval would provide variceal eradication as rapidly as possible to lessen early rebleeding while minimizing ligation‐induced adverse events. We randomly assigned patients hospitalized with acute esophageal variceal bleeding who had successful ligation at presentation to repeat ligation at 1‐week or 2‐week intervals. Beta‐blocker therapy was also prescribed. Ligation was performed at the assigned interval until varices were eradicated and then at 3 and 9 months after eradication. The primary endpoint was the proportion of patients with variceal eradication at 4 weeks. Four‐week variceal eradication occurred more often in the 1‐week than in the 2‐week group: 37/45 (82%) versus 23/45 (51%); difference = 31%, 95% confidence interval 12%‐48%. Eradication occurred more rapidly in the 1‐week group (18.1 versus 30.8 days, difference = −12.7 days, 95% confidence interval −20.0 to −5.4 days). The mean number of endoscopies to achieve eradication or to the last endoscopy in those not achieving eradication was comparable in the 1‐week and 2‐week groups (2.3 versus 2.1), with the mean number of postponed ligation sessions 0.3 versus 0.1 (difference = 0.2, 95% confidence interval −0.02 to 0.4). Rebleeding at 4 weeks (4% versus 4%) and 8 weeks (11% versus 9%), dysphagia/odynophagia/chest pain (9% versus 2%), strictures (0% versus 0%), and mortality (7% versus 7%) were similar with 1‐week and 2‐week intervals. Conclusion: One‐week ligation intervals led to more rapid eradication than 2‐week intervals without an increase in complications or number of endoscopies and without a reduction in rebleeding or other clinical outcomes; the decision regarding ligation intervals may be individualized based on patient and physician preferences and local logistics and resources. (H epatology 2016;64:549‐555)
Relapse and rebound following discontinuation of benzodiazepine treatment of panic attacks: alprazolam versus diazepam
Authors: P P Roy-Byrne, S R Dager, D S Cowley, P Vitaliano, D L Dunner
Journal: American Journal of Psychiatry (1989)

The authors assessed the effects of partial tapering followed by abrupt discontinuation of alprazolam, diazepam, and placebo in 40 patients with panic attacks. The anxiety scores and frequency of panic attacks of the three groups did not differ at the end of the initial 2-week taper, but 1 week after abrupt discontinuation of the remaining medication, patients formerly taking alprazolam had greater increases in anxiety but no more panic attacks than did the other patients. Because of low statistical power, differences in benzodiazepine half-lives, absence of multiple ratings, and imbalances between groups in clinical characteristics, these findings must be viewed as preliminary.
Abstract B29: MDM4 is a major p53 regulator in hepatoblastoma
Authors: Yan Shi, Roma Patel, Emporia Hollingsworth, Stephen Sarabia, Jingling Jin, Dolores Lopez-Terrada, Sanjeev Vasudevan
Journal: Cancer Research (2016)

Abstract Purpose: Unresectable or metastatic hepatoblastoma generally confers a poor survival. MDM4 and MDM2 are the major negative regulators of p53, which has a predominantly wild type status in hepatoblastoma. Having previously shown that MDM4 has copy gain/amplification associated with the 1q32.1 amplicon in hepatoblastoma, we hypothesize that MDM4 is the predominant negative regulator of p53 function in hepatoblastoma and that blocking MDM4 will cause tumor cell death due to uninhibited p53 tumor suppressor activity. Methods: An MTT assay was used to measure NSC207895 (MDM4 inhibitor) and Nutlin-3a (MDM2 inhibitor) cytotoxicity on hepatoblastoma cell lines (HepG2, HepT1, and Huh-6) as well as a patient-derived hepatoblastoma cell line (PDCL-1). CCK-8 was used to assess effects of low dose NSC207895 on HB cell line proliferation. Soft agar was used to assess the effect of NSC207895 on hepatoblastoma colony formation. Immunoblotting and quantitative RT-PCR was used to measure expression of p53 downstream targets in hepatoblastoma after treatment with NSC207895. P53 knockdowns were created to assess the effect of NSC207895 in hepatoblastoma in the absence of p53. Cell cycle analysis was performed using BRDU. Results: Huh-6, HepG2, and HepT1 were all tested with Nutlin-3a and did not show significant cell death (IC50 &amp;gt;10μΜ) inhibition with NSC207895 caused significant cell death in Huh-6 (IC50=1.27μΜ), HepG2 (1.62μΜ), and HepT1 (2.05μΜ). A decrease in cell proliferation was noted with concentrations of NSC207895 as low as 0.05μΜ, 0.1μΜ and 0.3μΜ in HepG2, HepT1, and Huh-6 respectively. An increase in IC50 was seen in the p53 knockdowns compared to each respective control (HepG2: 12.6μΜ vs 3.38μΜ; HepT1: &amp;gt;50μΜ vs 1.45μΜ; Huh-6: 20.2μΜ vs 7.52μΜ). Increased PARP cleavage products and decreased MDM4 expression were seen on immunoblotting after treatment with NSC207895. By both immunoblotting and qPCR, the p53 downstream transcriptional targets, p21, BAX and PUMA, were increased after exposure to NSC207895 in all three cell lines. Cell cycle analysis showed an increased percentage of cells in G1/G0-phase and decreased percentage of actively replicating S-phase cells in HepG2 with NSC207895 treatment. Conclusion: Our data supports the hypothesis that in hepatoblastoma, MDM4 may be a dominant inhibitor of p53 and inhibition of MDM4 causes p53-mediated cell death and growth inhibition. Therefore, inhibition of MDM4 may be a viable drug target for treating hepatoblastoma. Citation Format: Yan Shi, Roma Patel, Emporia Hollingsworth, Stephen Sarabia, Jingling Jin, Dolores Lopez-Terrada, Sanjeev Vasudevan. MDM4 is a major p53 regulator in hepatoblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B29.
Molecular Pathology -- Detection of Neoplasia
Authors: Stephen P. Naber
Journal: New England Journal of Medicine (1994)

Modern concepts of neoplasia rely on the evidence that a tumor arises from the clonal progeny of a single transformed cell. This ancestral cell of the neoplasm has multiple sites of acquired, and sometimes inherited, DNA damage that all its progeny share. During the early steps of carcinogenesis, there may be genetic alterations that lead to an intrinsic genetic instability, allowing additional mutations to accumulate. These genetic changes confer selective advantages on the clone of tumor cells by disrupting the regulation of cell proliferation. This mechanism permits the evolution of tumor-cell subclones and favors neoplastic progression. The analysis of tumors . . .
Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression
Authors: Xiaoxu Zhou, Xiujuan Zang, Murugavel Ponnusamy, Monica V. Masucci, Evelyn Tolbert, Rujun Gong, Ting C. Zhao, Na Liu, George Bayliss, Lance D. Dworkin, Shougang Zhuang
Journal: Journal of the American Society of Nephrology (2015)

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNA-mediated silencing of EZH2 inhibited serum- and TGF β 1-induced activation of renal interstitial fibroblasts in vitro , and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of α -smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGF β receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGF β receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum–stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.
Effect of Uracil Mustard and Several Antitumor Drugs on the Primary Antibody Response in Rats and Mice
Authors: Harold H. Buskirk, John A. Crim, Harold G. Petering, Katharine Merritt, Arthur G. Johnson
Journal: JNCI Journal of the National Cancer Institute (1965)

When 5-bis(2-chloroethyl)aminouracil (Uracil Mustard) was given 1 to 5 hours before antigen (sheep red blood cells) as a single dose of about 0.5 LD50, either orally or intraperitoneally, it did not suppress the antibody synthesis in rats. At oral doses effective for tumor therapy in rats, 0.2 mg per kg daily for 5 days or 1.0 mg per Kg twice weekly for 3 weeks, there was also no indication of suppression of antibody production. The time of administration of Uracil Mustard in relation to the antigen, in order to achieve a depression of antibody synthesis in rats, was 24 and 48 hours after antigen. The depression observed was only at the 4th day and serum titers from the 7th through the 42d day were in the normal range. In contrast, cyclophosphamide, 25 or 50 mg per kg, and 6-mercaptopurine, 80 mg per kg, which are doses with antitumor activity, caused prolonged suppression of antibody production when given 48 hours after antigen. 2-Keto-3-ethoxybutyraldehyde bis(thiosemicarbazone) showed no indication of antibody suppression in the rat at levels of 25, 50, or 100 mg per kg given orally daily for 7 days, beginning 4 days before antigen. Daily oral doses of 25 mg per kg caused regression of established Walker 256 tumors in rats. One intraperitoneal dose of Uracil Mustard at 0.3 LD50 given to BALB mice 1 hour before the injection of human γ-globulin or bovine γ-globulin caused an increase in circulating antibody, as did endotoxin, 5-fluoro-2-deoxyuridine, and cyclophosphamide. Highly toxic doses of Uracil Mustard (40, 60, and 80 µg/mouse) caused depression of antibody synthesis. This was also true of daily doses of 20 μg per mouse. 1-β-D-Arabinofuranosyl-cytosine hydrochloride (Cytarabine hydrochloride) at 0.5 or 1 mg per mouse for 12 daily doses suppressed antibody production. These levels (equivalent to 20–40 mg/kg) are in the dose range used in tumor therapy. One 8 mg per mouse dose of Cytarabine did not suppress antibody formation and in some cases caused enhancement.
Nonmelanoma Cancers of the Skin
Authors: Diana S. Preston, Robert S. Stern
Journal: New England Journal of Medicine (1992)

BASAL-CELL and squamous-cell cancers of the skin are the most frequent malignant conditions in the white population. About 600,000 new cases are detected each year in the United States.1 Fortunately, only a small proportion lead to death. Nonmelanoma cancers are associated with substantial morbidity, including loss of function and disfigurement, and their treatment is costly. Early detection can reduce morbidity and cost.We will review the epidemiology, recognition, treatment, and prevention of basal-cell and squamous-cell carcinomas, which together account for most nonmelanoma skin cancers (we exclude tumors of the mucous membranes). We shall emphasize risk factors for the development of . . .
Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels
Authors: Jeanne S. Teitelbaum, Robert J. Zatorre, Stirling Carpenter, Daniel Gendron, Alan C. Evans, Albert Gjedde, Neil R. Cashman
Journal: New England Journal of Medicine (1990)

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.
Gender Analysis of Icatibant-Treatment Outcomes of Acute Angioedema Attacks in Patients with Hereditary Angioedema Type I and II: Results from the Icatibant Outcome Survey
Authors: Teresa Caballero, Laurence Bouillet, Hilary J. Longhurst, Werner Aberer, Marcus Maurer, Andrea Zanichelli, Amandine Perrin, Irmgard Andresen
Journal: Journal of Allergy and Clinical Immunology (2016)
GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo
Authors: Caroline Pabst, Anne Bergeron, Vincent-Philippe Lavallée, Jonathan Yeh, Patrick Gendron, Gudmundur L. Norddahl, Jana Krosl, Isabel Boivin, Eric Deneault, Jessica Simard, Suzan Imren, Geneviève Boucher, Kolja Eppert, Tobias Herold, Stefan K. Bohlander, Keith Humphries, Sébastien Lemieux, Josée Hébert, Guy Sauvageau, Frédéric Barabé
Journal: Blood (2016)
Surgical Management of Neoplastic Pulmonary Metastases
Authors: John W. Strieder
Journal: New England Journal of Medicine (1956)

THE increasing age of the population with the associated increased incidence of cancer, the increasing number of patients successfully operated upon for neoplastic disease and the larger number of routine chest survey roentgenograms are facts that tend to emphasize the importance of the growing problem of pulmonary metastatic disease.The present state of perfection of the technics for the resection of pulmonary tissue, or the excision of tumors growing in the lung, no longer permits a defeatist attitude when the physician is faced with the problem of metastatic neoplastic deposits in the lungs. There is no gainsaying the fact that . . .
2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis
Authors: Angelo Ravelli, Francesca Minoia, Sergio Davì, AnnaCarin Horne, Francesca Bovis, Angela Pistorio, Maurizio Aricò, Tadej Avcin, Edward M Behrens, Fabrizio De Benedetti, Lisa Filipovic, Alexei A Grom, Jan-Inge Henter, Norman T Ilowite, Michael B Jordan, Raju Khubchandani, Toshiyuki Kitoh, Kai Lehmberg, Daniel J Lovell, Paivi Miettunen, Kim E Nichols, Seza Ozen, Jana Pachlopnik Schmid, Athimalaipet V Ramanan, Ricardo Russo, Rayfel Schneider, Gary Sterba, Yosef Uziel, Carol Wallace, Carine Wouters, Nico Wulffraat, Erkan Demirkaya, Hermine I Brunner, Alberto Martini, Nicolino Ruperto, Randy Q Cron
Journal: Annals of the Rheumatic Diseases (2016)

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA—associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.