tbuckley/cabot-search huggingface dataset:
Preclinical development of ARRY-142886, a potent and selective MEK inhibitor
Authors: Eli Wallace, Tammie Yeh, Joe Lyssikatos, Jim Winkler, Patrice Lee, Allison Marlow, Brian Hurley, Vivienne Marsh, Bryan Bernat, Ron Evans, Heidi Colwell, Josh Ballard, Tony Morales, Darin Smith, Barb Brandhuber, Stefan Gross, Greg Poch, Kevin Litwiler, Gary Hingorani, Jennifer Otten, Francis Sullivan, Jim Blake, Tracy Pheneger, Michelle Goyette, Kevin Koch
Journal: Cancer Research (2004)

3890  MEK is a critical kinase in the signal transduction pathway for many growth factor receptors, including EGF-R, IGF-1R and PDGF-R, which provide growth signals to cancer cells. It is downstream of Ras and Raf proteins that are often mutated and abnormally active in cancer. The MEK inhibitor, ARRY-142886, inhibits the proliferation of several human cancer cell lines in culture, including HT29, Malme-3M, SK-MEL-28, MIA PaCa2, and SK-MEL-2. We have confirmed in vivo efficacy of ARRY-142886 in several tumor xenograft models in mice. In an HT29 human colon carcinoma model, dose-dependent inhibition of tumor growth was observed. Doses of 10 mg/kg, BID, PO resulted in greater than 50% tumor growth inhibition. Of note, in the BxPC3 human pancreatic carcinoma model, tumor regression was seen at doses of 10, 25 or 50 mg/kg, BID, PO. In these studies, tumors were excised and analyzed for ERK phosphorylation. Consistent with ARRY-142886’s mechanism of action, tumor growth inhibition correlated with decreased phospho-ERK levels in tumors. The effects of ARRY-142886 on tumor re-growth were also evaluated in a BxPC3 model. After three weeks of dosing (25 or 50 mg/kg, BID, PO), treatment was stopped for one week, during which time tumor growth resumed. Mice were then treated for an additional 3 weeks at the same doses. ARRY-142886 was effective in reducing tumor size and maintaining tumor growth inhibition of the re-established tumors, demonstrating that the tumors were still sensitive to ARRY-142886 after a dosing holiday. ARRY-142886 has shown efficacy in other xenograft models including MIA PaCa2, A549, Colon26, PANC-1, LoVo, Calu6, HCT116, MDA-MB-231, ZR-75-1 and LOX. These studies confirm that ARRY-142886 can block ERK phosphorylation in tumors and has broad anti-tumor effects in vivo.
Accidental Hypothermia
Authors: L. F. Prescott, M. C. Peard, I. R. Wallace
Journal: BMJ (1962)

Accidental hypothermia is generally thought to be uncommon in this country (Rees, 1958).It is seen most often in the elderly and infirm, in patients with myxoedema (Summers, 1953; Maiden, 1955;Macdonald, 1958), hypopituitarism (Sheehan and Summers, 1952), and in the newborn (Mann and Elliott, 1957).Recent interest in accidental hypothermia prompts this report of nine cases admitted to the general medical wards of a small hospital within a period of four months.This relatively high incidence (2.5% of acute medical admissions during that period) suggests that the condition is more prevalent than is generally believed, and that many cases pass unrecognized.In every instance the diagnosis was unsuspected before admission, although the relatives of one patient had commented, quite rightly, that she " seemed to be very cold."As impairment of consciousness is usual, it is not surprising that the diagnoses on admission included cerebrovascular accident, diabetic coma, and uraemia.In addition to the nine reported cases of hypothermia with rectal temperatures below 90' F. (32.2'C.), several other patients were seen with temperatures in the range of 92-95' F. (33.3-350C.). Clinical DetailsEight of the nine cases were women, with ages ranging from 44 to 82 years, and the rectal temperatures on admission varied from 76 to 88' F. (24.4 to 31.1'C.).Details of the cases are set out in Table I, and relevant investigations in Table II.In most instances blood count, blood, urea, blood sugar, serum electrolytes, cholesterol, protein-bound iodine (P.B.I.), amylase, and transaminase estimations were carried out.Case 4 is reported below in greater detail.Case 4 A woman aged 44 was admitted to hospital moribund, with no recordable pulse or blood-pressure.It was discovered later that she had fallen two days previously,
Controversies in Platelet Transfusion Therapy
Authors: S J Slichter
Journal: Annual Review of Medicine (1980)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Recent Membrane Research and its Implications for Clinical Medicine
Authors: V T Marchesi
Journal: Annual Review of Medicine (1978)

Our understanding of the molecular organization of even the simplest mammalian cell membrane--that of the red blood cell--is still incomplete, yet we are reasonably sure of where and how the major components are arranged. The so-called integral membrane proteins are the most likely candidates to serve as receptors and transport sites of surface membranes, and these may be organized as macromolecular complexes with parts of their polypeptides in contact with both sides of the bilayer. These complexes may be either mobile or fixed, and if the latter, perhaps by specific interactions with other membrane proteins. The exposed segments of such glycoproteins could have recognition sites that confer cell, tissue, and/or species specificity created by oligosaccharides attached to the peptide backbone, or by specific amino acid sequences, or a combination of both.
Long term trends in prevalence of neural tube defects in Europe: population based study
Authors: Babak Khoshnood, Maria Loane, Hermien de Walle, Larraitz Arriola, Marie-Claude Addor, Ingeborg Barisic, Judit Beres, Fabrizio Bianchi, Carlos Dias, Elizabeth Draper, Ester Garne, Miriam Gatt, Martin Haeusler, Kari Klungsoyr, Anna Latos-Bielenska, Catherine Lynch, Bob McDonnell, Vera Nelen, Amanda J Neville, Mary T O’Mahony, Annette Queisser-Luft, Judith Rankin, Anke Rissmann, Annukka Ritvanen, Catherine Rounding, Antonin Sipek, David Tucker, Christine Verellen-Dumoulin, Diana Wellesley, Helen Dolk
Journal: BMJ (2015)

What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist?This was a population based, observational study using data on 11,353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends.Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10,000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD.In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification.The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.
Immunoglobulin A Targets Microbes in the Fecal Microbiota of Malawian Twins Discordant for Kwashiorkor
Authors: Andrew Kau, Joseph Planer, Sindhuja Rao, Indi Trehan, Mark Manary, Chyi-Song Hsieh, Jeffrey Gordon
Journal: Journal of Allergy and Clinical Immunology (2013)
Treatment outcomes of patients with mixed adenoneuroendocrine carcinoma (MANEC).
Authors: Leonidas Apostolidis, Frank Bergmann, Dirk Jaeger, Eva Caroline Winkler
Journal: Journal of Clinical Oncology (2015)

e15187 Background: Mixed adenoneuroendocrine carcinomas (MANEC) are considered a rare disease entity. Commonly they are treated in analogy to adenocarcinomas (AC) or neuroendocrine carcinomas (NEC) without systematic data regarding clinical course and response to therapy. The aim of this study was to analyze the treatment outcomes of MANEC patients. Methods: We performed a retrospective analysis of all patients with MANEC who presented at the National Center for Tumor Diseases between December 2011 and September 2014. Results: In the total of 30 patients identified, primary tumors were mainly located in the gastrointestinal (73.3 %) and pancreatobiliary tract (13.3 %). The neuroendocrine component was poorly differentiated in 90 % of cases, median proliferation rate (Ki67) was 80 %. Overall survival (OS) from diagnosis was 21.0 months for all patients. 23 patients in a localized stage underwent surgery. 11 of those patients developed metachronous metastases, median recurrence-free survival (RFS) was 11.7 months. 13 resected patients received perioperative multimodal treatment, including chemotherapy and/or radiotherapy. In multimodally treated patients vs. patients receiving surgery alone RFS and OS were significantly prolonged with 42.5 vs. 7.0 months (p = 0.0111) and 44.5 vs. 16.9 months (p = 0.0476) respectively. 16 patients received palliative first-line chemotherapy for metastatic disease. Partial response (PR) was observed in 37.5 % and stable disease (SD) in 18.8 % of cases. Median progression-free survival (PFS) and OS was 3.9 and 9.4 months respectively. There was no significant difference between platinum and etoposide, or oxaliplatin and 5-fluorouracil (5-FU) based regimens. 8 patients received a second-line therapy (mostly irinotecan and 5-FU), however without any documented PR or SD as best response. Conclusions: For localized MANEC, RFS seems to be prolonged in cases with multimodal treatment. For metastatic MANEC prognosis remains poor. In first-line therapy both therapeutic regimens for AC and NEC seem equally effective, our data show no benefit from second-line therapy. Further studies are needed to define the optimal treatment strategy for this rare disease entity.
Induction of CD11a/leukocyte function antigen-1 and CD54/intercellular adhesion molecule-1 on hairy cell leukemia cells is accompanied by enhanced susceptibility to T-cell but not lymphokine-activated killer- cell cytotoxicity [see comments]
Authors: JH Jansen, D van der Harst, GJ Wientjens, YM Kooy-Winkelaar, A Brand, R Willemze, HC Kluin-Nelemans
Journal: Blood (1992)
Using Technology to Create a More Humanistic Approach to Integrating Palliative Care into the Intensive Care Unit
Authors: Christopher E. Cox, J. Randall Curtis
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Section:ChooseTop of pageAbstract <<Why Is It Important to Im...What Are the Barriers to ...What Are Possible Solutio...ConclusionsReferencesCITING ARTICLES
Compliance with oral drug therapy in patients with hematologic malignancy.
Authors: A M Levine, J L Richardson, G Marks, K Chan, J Graham, J N Selser, C Kishbaugh, D R Shelton, C A Johnson
Journal: Journal of Clinical Oncology (1987)

Compliance with oral self-administered allopurinol (daily medication) and prednisone (intermittent medication) as well as compliance with monthly scheduled clinic appointments, were examined in 108 patients with newly diagnosed hematologic malignancy. Baseline levels of compliance (control group) were compared to results obtained after implementation of three intervention packages, whose aim was to increase compliance. The packages included combinations of education, home psychologic support and restructuring, and training in pill taking. A 24-hour profile of the two drugs and their metabolites was first determined. Serum samples were then obtained monthly over 6 months and analyzed for presence of the drugs. Control patients were fully compliant with allopurinol only 16.8% of the time. This rate increased significantly (44% to 48% of the time) for those who received any one of the intervention programs. With respect to prednisone, control patients were compliant 26.8% of the time, with no real improvement after interventions. Finally, self reports overestimated compliance by a factor of two when compared to drug analysis. The results indicated that full compliance with oral medications was remarkably low among our patients who have treatable and in some cases curable hematologic malignancy. However, compliance can be significantly improved by the use of various intervention packages.
Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858–1867
Authors: David P. Sonne, Filip K. Knop
Journal: Diabetes Care (2015)

In the task of alluding to the mode of action of metformin, Xu et al. (1) examined 131 fasting serum metabolites in three independent cross-sectional cohort studies. The authors found decreased concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) in patients with type 2 diabetes treated with metformin compared with control groups not using glucose-lowering oral medication. The reduction of these metabolites was associated with lower plasma concentrations of LDL cholesterol, which was partially mediated by the three PCs. Statistical analyses suggested that the reduced PC concentrations were explained by metformin’s effect on AMPK in …
Abstract 15882: Gene-Panel Based Next Generation Sequencing (NGS) Greatly Improves Clinical Genetic Diagnostics in Inherited Cardiomyopathies
Authors: Jan D Jongbloed, Anna Pósafalvi, Renée C Niessen, Yvonne M Hoedemaekers, Paul A van der Zwaag, Daniela Q Barge-Schaapveld, Sebastiaan R Piers, Jasper J van der Smagt, Folkert W Asselbergs, Rudolf A de Boer, Maarten P van den Berg, Rowida Almomani, Richard J Sinke, J. P van Tintelen
Journal: Circulation (2014)

INTRODUCTION: NGS techniques can be successfully applied to find mutations underlying genetic cardiomyopathies. However, Exome Sequencing (ES) shows incomplete representation and coverage of exons, leading to clinically relevant mutations being missed. Thus, ES will, at least for now, coexist in clinical genetic diagnostics with other NGS-based strategies, such as gene-panel based resequencing. Therefore, we aimed at evaluating the yield of gene-panel based resequencing of 55 genes in cardiomyopathy patients referred to our department. METHODS: We constructed an enrichment kit targeting 55 cardiomyopathy genes and implemented this into routine diagnostics. We evaluated our first 162 patients: 47 fulfilled generally accepted clinical criteria for hypertrophic cardiomyopathy (HCM), 72 fulfilled the Mestroni criteria for dilated cardiomyopathy (DCM) and 3 were diagnosed with arrhythmogenic cardiomyopathy (ACM). In addition, 23, 11 and 6 cases showed signs of DCM, HCM and ACM, yet did not fulfill the formal criteria. Additional cosegregation analyses were performed to further support pathogenicity of potentially causal mutations. RESULTS: In the DCM cohort 40 pathogenic or likely pathogenic mutations were identified (55%; 40/72). Mutations in TTN were found in 14% of DCM patients (10/72). The yield in criteria positive HCM and ACM patients was 40% (17/43) and 33% (1/3). In patients not fully fulfilling criteria for DCM, HCM and ACM the yield was 52% (12/23), 36% (4/11) and 83% (5/6). In 13 % (21/162) of cases two or more (potentially) pathogenic mutations were identified. Results of cosegregation analyses supported pathogenicity of potentially causal mutations in 42 families. In 6 results argued against pathogenicity. CONCLUSIONS: Gene-panel based NGS results in a substantial increase in diagnostic yield for DCM patients compared to previous results of Sanger sequencing most prevalent genes (55% vs 20-25%). TTN mutations are most prevalent in DCM patients (14%). Higher diagnostic yields are achieved for patients fulfilling DCM and HCM criteria. Cosegregation analyses further support pathogenicity of potentially causal mutations. Together, our gene-panel based approach greatly improved genetic diagnostics in cardiomyopathies.
JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse
Authors: Jamee M. Berg, Changhoon Lee, Leslie Chen, Laurie Galvan, Carlos Cepeda, Jane Y. Chen, Olga Peñagarikano, Jason L. Stein, Alvin Li, Asami Oguro-Ando, Jeremy A. Miller, Ajay A. Vashisht, Mary E. Starks, Elyse P. Kite, Eric Tam, Amos Gdalyahu, Noor B. Al-Sharif, Zachary D. Burkett, Stephanie A. White, Scott C. Fears, Michael S. Levine, James A. Wohlschlegel, Daniel H. Geschwind
Journal: Neuron (2015)
Graft-Versus-Host Disease: Pathophysiological and Clinical Aspects
Authors: H J Deeg, R Storb
Journal: Annual Review of Medicine (1984)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Abstract 259: Ibrutinib enhances the anti-tumor efficacy of CTLA-4 blockade in lymphoma and colon cancer models
Authors: Patrick Ng, Daniel Lu, Betty Chang
Journal: Cancer Research (2015)

Abstract The anti-CTLA-4 antibody ipilimumab was the first immune checkpoint blockade antibody to show significant clinical efficacy. However, only a subset of the treated melanoma patients had long-term survival benefits (Schadendorf, D., et al. ECCO 2013). Combining ipilimumab with an agent that modulates immunity by a different mechanism may improve efficacy. Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (Btk), an essential enzyme in the B-cell receptor signaling pathway. Ibrutinib also inhibits the interleukin-2-inducible Tec kinase (Itk) that is required for the activation/survival of Th2 T cells. This activity is consistent with preclinical studies that demonstrated ibrutinib could potentiate Th1 immunity (Dubovsky, JA., et al. Blood 2013). We investigated whether ibrutinib could enhance the anti-tumor effect of CTLA-4 blockade using the A20 B-cell lymphoma and the CT26 colon carcinoma mouse models. BALB/c mice (9-11/group) were implanted with tumor cells subcutaneously on the hind flanks. Animals bearing 80-100 mm3 (D x d2 x 0.4) tumors were dosed daily with oral ibrutinib (24 mg/kg) with or without the anti-mouse CTLA-4 antibody 9D9 (100 μg/mouse) given every 2 days by intraperitoneal injections. Animals in the lymphoma and colon cancer models were treated for 13 and 37 days, respectively. Tumor volume was measured and survival recorded for up to 2 months after tumor inoculation. Neither the A20 tumors, which express Btk, nor the CT26 tumors were inhibited by ibrutinib. In the A20 model, although 9D9 alone resulted in complete tumor regression in 7 of 9 treated animals, tumors in 2 of the 7 mice relapsed after treatment had ended. In contrast, 9D9 in combination with ibrutinib led to rapid, complete, and durable responses in 7 of 9 treated animals that lasted until the end of the study. In the CT26 model, treatment with 9D9 alone had minimal effects on tumor growth, but the addition of ibrutinib led to complete tumor regression in 6 of 10 treated animals. Thus, ibrutinib enhanced the anti-tumor efficacy of an anti-CTLA-4 antibody in B-cell lymphoma and colon carcinoma mouse models. The mechanism of tumor eradication by the combination therapy is under investigation and will be discussed at presentation. Citation Format: Patrick Ng, Daniel Lu, Betty Chang. Ibrutinib enhances the anti-tumor efficacy of CTLA-4 blockade in lymphoma and colon cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 259. doi:10.1158/1538-7445.AM2015-259
The Brain Fights Back: New Approaches to Mitigating Cognitive Decline
Authors: Bridget M. Kuehn
Journal: JAMA (2015)

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Molecular Immunobiology of Complement Biosynthesis: A Model of Single-Cell Control of Effector-Inhibitor Balance
Authors: D H Perlmutter, H R Colten
Journal: Annual Review of Immunology (1986)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More