tbuckley/cabot-search huggingface dataset:
The Development of a Selective Cyclin-Dependent Kinase Inhibitor That Shows Antitumor Activity
Authors: Simak Ali, Dean A. Heathcote, Sebastian H.B. Kroll, Ashutosh S. Jogalekar, Bodo Scheiper, Hetal Patel, Jan Brackow, Alekasandra Siwicka, Matthew J. Fuchter, Manikandan Periyasamy, Robert S. Tolhurst, Seshu K. Kanneganti, James P. Snyder, Dennis C. Liotta, Eric O. Aboagye, Anthony G.M. Barrett, R. Charles Coombes
Journal: Cancer Research (2009)

Abstract Normal progression through the cell cycle requires the sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4, and CDK6. Direct or indirect deregulation of CDK activity is a feature of almost all cancers and has led to the development of CDK inhibitors as anticancer agents. The CDK-activating kinase (CAK) plays a critical role in regulating cell cycle by mediating the activating phosphorylation of CDK1, CDK2, CDK4, and CDK6. As such, CDK7, which also regulates transcription as part of the TFIIH basal transcription factor, is an attractive target for the development of anticancer drugs. Computer modeling of the CDK7 structure was used to design potential potent CDK7 inhibitors. Here, we show that a pyrazolo[1,5-a]pyrimidine–derived compound, BS-181, inhibited CAK activity with an IC50 of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 μmol/L, with CDK2 being inhibited 35-fold less potently (IC50 880 nmol/L) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis to inhibit the growth of cancer cell lines, and showed antitumor effects in vivo. The drug was stable in vivo with a plasma elimination half-life in mice of 405 minutes after i.p. administration of 10 mg/kg. The same dose of drug inhibited the growth of MCF-7 human xenografts in nude mice. BS-181 therefore provides the first example of a potent and selective CDK7 inhibitor with potential as an anticancer agent. [Cancer Res 2009;69(15):6208–15]
Abstract 819: Targeted sequencing to detect somatic mutations, translocations and copy-number variation in human tumors simultaneously.
Authors: Paul Van Hummelen, Matthew Ducar, Robert T. Jones, Alina Raza, Ashwini Sunkavalli, Megan Hanna, Adri Mills, Ravali Adusumilli, Prateek Kumar, Laura Schubert, Marc Breneiser, Anna C. Cooley, Elizabeth Garcia, Lynette M. Scholl, Neal I. Lindeman, Nikhil Wagle, Levi Garraway, Kristian Cibulskis, Scott L. Carter, Michael Lawrence, Gad Getz, Matthew L. Meyerson, William C. Hahn, Laura E. MacConaill
Journal: Cancer Research (2013)

Abstract The ability to harness the power of next generation sequencing for characterizing the cancer genome would be extremely valuable to the cancer research community and ultimately improve diagnosis and individualized therapy. We present a targeted approach using massively parallel sequencing to simultaneously detect mutations, translocations and copy-number variations in archived clinical tumor specimen. Targeted sequencing was achieved by designing RNA baits to capture the exons of 504 genes with relevance to cancer. The bait set was augmented with specific intronic sequences to detect translocations often involved in cancer. The overall performance of the hybrid capture was improved by optimizing the tiling strategy of the baits. These improvements significantly shifted fragments with low or no-coverage closer to the overall mean, resulting in a more uniform coverage distribution. To validate the targeted gene panel we sequenced tumor samples harboring mutations, translocations and copy-number alterations that were previously identified by clinically approved assays. All the known alterations were confirmed with additional potentially actionable mutations. The ultimate goal of the targeted panel is to screen cancer patients quickly and economically allowing simultaneous detection of all common genomic alterations in the cancer genome. Citation Format: Paul Van Hummelen, Matthew Ducar, Robert T. Jones, Alina Raza, Ashwini Sunkavalli, Megan Hanna, Adri Mills, Ravali Adusumilli, Prateek Kumar, Laura Schubert, Marc Breneiser, Anna C. Cooley, Elizabeth Garcia, Lynette M. Scholl, Neal I. Lindeman, Nikhil Wagle, Levi Garraway, Kristian Cibulskis, Scott L. Carter, Michael Lawrence, Gad Getz, Matthew L. Meyerson, William C. Hahn, Laura E. MacConaill. Targeted sequencing to detect somatic mutations, translocations and copy-number variation in human tumors simultaneously. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 819. doi:10.1158/1538-7445.AM2013-819
Does electroconvulsive therapy cause brain damage?
Authors: Richard D. Weiner
Journal: Behavioral and Brain Sciences (1984)

Abstract Although the use of ECT has declined dramatically from its inception, this decrease has recently shown signs of leveling out because of ECT's powerful therapeutic effect in severely ill depressed individuals who either do not respond to pharmacologic alternatives or are too ill to tolerate a relatively lengthy drug trial. Notwithstanding its therapeutic benefits, ECT has also remained a controversial treatment modality, particularly in the eye of the public. Given the unsavory qualities associated with the word “electroconvulsive,” claims of possible, probable, or even certain brain damage with ECT have easily found listeners. A careful, nonselective assessment of data covering the areas of pathology, radiology, electrophysiology, biochemistry, and neuropsychology leads both to certain conclusions and to certain unanswered questions. ECT is not the devastating purveyor of wholesale brain damage that some of its detractors claim. For the typical individual receiving ECT, no detectable correlates of irreversible brain damage appear to occur. Still, there remains the possibility that either subtle, objectively undetectable persistent deficits, particularly in the area of autobiographic memory function, occur, or that a rarely occurring syndrome of more pervasive persistent deficits related to ECT use may be present. Clearly, more research directed toward answering these questions needs to be carried out so that the role of ECT can be more rigorously defined. While such research is pending, however, we cannot expect that the conditions that predispose to clinical referrals for ECT will disappear. Given the misery, anguish, and risk of death by suicide, starvation, or debilitation associated with severe depressive illness, for example, it still appears that ECT, at least for the present, must continue to be available.
Endocardial and Epicardial Epithelial to Mesenchymal Transitions in Heart Development and Disease
Authors: Alexander von Gise, William T. Pu
Journal: Circulation Research (2012)

Epithelial to mesenchymal transition (EMT) converts epithelial cells to mobile and developmentally plastic mesenchymal cells. All cells in the heart arise from one or more EMTs. Endocardial and epicardial EMTs produce most of the noncardiomyocyte lineages of the mature heart. Endocardial EMT generates valve progenitor cells and is necessary for formation of the cardiac valves and for complete cardiac septation. Epicardial EMT is required for myocardial growth and coronary vessel formation, and it generates cardiac fibroblasts, vascular smooth muscle cells, a subset of coronary endothelial cells, and possibly a subset of cardiomyocytes. Emerging studies suggest that these developmental mechanisms are redeployed in adult heart valve disease, in cardiac fibrosis, and in myocardial responses to ischemic injury. Redirection and amplification of disease-related EMTs offer potential new therapeutic strategies and approaches for treatment of heart disease. Here, we review the role and molecular regulation of endocardial and epicardial EMT in fetal heart development, and we summarize key literature implicating reactivation of endocardial and epicardial EMT in adult heart disease.
Feed-forward and the evolution of social behavior
Authors: C. N. Slobodchikoff
Journal: Behavioral and Brain Sciences (2000)

Feed-forward Pavlovian conditioning can serve as a proximate mechanism for the evolution of social behavior. Feed-forward can provide the impetus for animals to associate other individuals' presence, and cooperation with them, with the acquisition of resources, whether or not the animals are genetically related. Other social behaviors such as play and grooming may develop as conditioned stimuli in feed-forward social systems.
MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor–Dependent Fashion to Suppress Carcinoma Growth
Authors: Yu-Wen Zhang, Ben Staal, Curt Essenburg, Yanli Su, Liang Kang, Rich West, Dafna Kaufman, Tom DeKoning, Bryn Eagleson, Sean G. Buchanan, George F. Vande Woude
Journal: Cancer Research (2010)

Abstract The hepatocyte growth factor (HGF)-MET pathway supports several hallmark cancer traits, and it is frequently activated in a broad spectrum of human cancers (http://www.vai.org/met/). With the development of many cancer drugs targeting this pathway, there is a need for relevant in vivo model systems for preclinical evaluation of drug efficacy. Here, we show that production of the human HGF ligand in transgenic severe combined immunodeficient mice (hHGFtg-SCID mice) enhances the growth of many MET-expressing human carcinoma xenografts, including those derived from lung, breast, kidney, colon, stomach, and pancreas. In this model, the MET-specific small-molecule kinase inhibitor SGX523 partially inhibits the HGF-dependent growth of lung, breast, and pancreatic tumors. However, much greater growth suppression is achieved by combinatorial inhibition with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. Together, these results validate the hHGFtg-SCID mouse model for in vivo determination of MET sensitivity to drug inhibition. Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated. Cancer Res; 70(17); 6880–90. ©2010 AACR.
Structure-function relationship of follicle-stimulating hormone and its receptor
Authors: A Ulloa-Aguirre
Journal: Human Reproduction Update (1998)

Follicle stimulating hormone (FSH) is one of the two pituitary gonadotrophins involved in the regulation of gonadal function. Structurally, this gonadotrophin is a heterodimer composed of two non-covalently associated subunits containing several heterogenous oligosaccharide residues which play an important role in both the in-vivo and in-vitro bioactivity of the hormone. Its cognate receptor, which belongs to the superfamily of the G protein-linked cell surface receptors, also displays a high degree of functional and molecular complexity. Studies employing monoclonal antibodies, synthetic peptides and/or site directed mutagenesis, have unveiled some of the multiple structural determinants involved in FSH and FSH receptor function and interaction. Despite their structural complexity, both molecules exhibit a high degree of plasticity and diversity that allows formation of distinct ligand-receptor complexes capable of selectively activating or deactivating a variety of signalling pathways. Knowledge and mapping of the structural determinants and functional epitopes for intra- and extracellular hormone action are of paramount importance not only for a better and more detailed understanding of the molecular basis of FSH action and FSH receptor function but also for the rational design of analogues with predicted properties and effects.
Shortening Medical Training by 30%
Authors: Ezekiel J. Emanuel, Victor R. Fuchs
Journal: JAMA (2012)

EXPERTS AGREE THAT THERE IS SUBSTANTIAL WASTE IN THE UShealthcaresystem.Thiswastedrivesupcosts,threatensthegovernment’slong-termfiscalstability,suppresses incomes,andreducesresourcesforpubliceducationand other essential services. Similarly, there is substantial waste in the education and training of US physicians. Years of training have been added without evidence that they enhance clinical skillsor thequalityofcare.Thiswasteadds to the financialburden of young physicians and increases health care costs. The average length of medical training could be reduced by about 30% without compromising physician competence or quality of care. The Obsolete Image of the Ideal Physician
A patient with apparent idiopathic A‐megakaryocytic thrombocytopenia
Authors: Hyoung D. Kim, Dane R. Boggs
Journal: American Journal of Hematology (1980)

Abstract A 71‐year‐old woman developed life‐threatening thrombocytopenia which resolved (probably spontaneously), recurred, and then again resolved. The thrombocytopenia was characterized by selective aplasia of megakaryocytes, near‐normal platelet survival, and very slow recovery. No underlying disorder nor any drug could be incriminated, so we must assume this patient suffered from an idiopathic and very rare form of thrombocytopenia.
Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.
Authors: K Egashira, Y Hirooka, H Kai, M Sugimachi, S Suzuki, T Inou, A Takeshita
Journal: Circulation (1994)

BACKGROUND This study aimed to determine if cholesterol-lowering therapy improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. METHODS AND RESULTS Nine patients with hypercholesterolemia were studied before and after cholesterol-lowering therapy with pravastatin (an inhibitor of HMG-CoA reductase) for 6 +/- 3 months, which lowered serum cholesterol from 272 +/- 8 to 187 +/- 16 mg/dL (P &lt; .01). Control patients with serum cholesterol of 218 +/- 23 mg/dL also were studied twice in a similar interval (8 +/- 2 months) with no cholesterol-lowering drugs. Acetylcholine (the endothelium-dependent vasodilator) and papaverine and nitrate (endothelium-independent vasodilators) were infused into the study coronary artery. Changes in the diameter of the epicardial coronary artery and coronary blood flow were assessed by quantitative coronary arteriography and an intracoronary Doppler catheter. In patients with hypercholesterolemia, acetylcholine-induced vasoconstriction of the epicardial artery was less (P &lt; .05) and the acetylcholine-induced increases in coronary blood flow were greater (P &lt; .001) after than before pravastatin. In control patients, responses of the epicardial coronary artery and coronary blood flow to acetylcholine did not change over the follow-up period. The vasomotor responses to papaverine or nitrate were similar between the two groups, and no interval changes in their responses were noted in either group. CONCLUSIONS These results suggest that cholesterol-lowering therapy with pravastatin may improve endothelium-dependent coronary vasomotion, which may possibly contribute to the improvement of myocardial perfusion as well as the regression of coronary atherosclerosis.
Relation of Abdominal Fat Depots to Systemic Markers of Inflammation in Type 2 Diabetes
Authors: Susan Sam, Steven Haffner, Michael H. Davidson, Ralph B. D'Agostino, Steven Feinstein, George Kondos, Alfonso Perez, Theodore Mazzone
Journal: Diabetes Care (2009)

OBJECTIVE Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C. RESULTS VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P &amp;lt; 0.01), PAI-1 (P &amp;lt; 0.0001), ICAM-1 (P &amp;lt; 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P &amp;lt; 0.0001) and IL-6 (P &amp;lt; 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI. CONCLUSIONS In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.
High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets
Authors: V. Fallet, R. Saffroy, N. Girard, J. Mazieres, S. Lantuejoul, T. Vieira, I. Rouquette, F. Thivolet-Bejui, M. Ung, V. Poulot, L. Schlick, D. Moro-Sibilot, M. Antoine, J. Cadranel, A. Lemoine, M. Wislez
Journal: Annals of Oncology (2015)
Evolution of Saxitoxin Synthesis in Cyanobacteria and Dinoflagellates
Authors: Jeremiah D. Hackett, Jennifer H. Wisecaver, Michael L. Brosnahan, David M. Kulis, Donald M. Anderson, Debashish Bhattacharya, F. Gerald Plumley, Deana L. Erdner
Journal: Molecular Biology and Evolution (2012)

Dinoflagellates produce a variety of toxic secondary metabolites that have a significant impact on marine ecosystems and fisheries. Saxitoxin (STX), the cause of paralytic shellfish poisoning, is produced by three marine dinoflagellate genera and is also made by some freshwater cyanobacteria. Genes involved in STX synthesis have been identified in cyanobacteria but are yet to be reported in the massive genomes of dinoflagellates. We have assembled comprehensive transcriptome data sets for several STX-producing dinoflagellates and a related non-toxic species and have identified 265 putative homologs of 13 cyanobacterial STX synthesis genes, including all of the genes directly involved in toxin synthesis. Putative homologs of four proteins group closely in phylogenies with cyanobacteria and are likely the functional homologs of sxtA, sxtG, and sxtB in dinoflagellates. However, the phylogenies do not support the transfer of these genes directly between toxic cyanobacteria and dinoflagellates. SxtA is split into two proteins in the dinoflagellates corresponding to the N-terminal portion containing the methyltransferase and acyl carrier protein domains and a C-terminal portion with the aminotransferase domain. Homologs of sxtB and N-terminal sxtA are present in non-toxic strains, suggesting their functions may not be limited to saxitoxin production. Only homologs of the C-terminus of sxtA and sxtG were found exclusively in toxic strains. A more thorough survey of STX+ dinoflagellates will be needed to determine if these two genes may be specific to SXT production in dinoflagellates. The A. tamarense transcriptome does not contain homologs for the remaining STX genes. Nevertheless, we identified candidate genes with similar predicted biochemical activities that account for the missing functions. These results suggest that the STX synthesis pathway was likely assembled independently in the distantly related cyanobacteria and dinoflagellates, although using some evolutionarily related proteins. The biological role of STX is not well understood in either cyanobacteria or dinoflagellates. However, STX production in these two ecologically distinct groups of organisms suggests that this toxin confers a benefit to producers that we do not yet fully understand.
AUTONOMY: The First Randomized Trial Comparing Two Patient-Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes
Authors: Steve V. Edelman, Rong Liu, Jennal Johnson, Leonard C. Glass
Journal: Diabetes Care (2014)

OBJECTIVE To compare two self-titration algorithms for initiating and escalating prandial insulin lispro in patients with type 2 diabetes inadequately controlled on basal insulin. RESEARCH DESIGN AND METHODS The trial was designed as two independent, multinational, parallel, open-label studies (A and B), identical in design, to provide substantial evidence of efficacy and safety in endocrine and generalist settings. Subjects were 18–85 years old (study A: N = 528; study B: N = 578), on basal insulin plus oral antidiabetic drugs for ≥3 months, and had an HbA1c 7.0% to ≤12.0% (&amp;gt;53.0 to ≤107.7 mmol/mol). Once optimized on insulin glargine, subjects were randomized to one of two self-titration algorithm groups adjusting lispro either every day (Q1D) or every 3 days (Q3D) for 24 weeks. The primary outcome was the change in HbA1c from baseline. The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old. RESULTS Baseline HbA1c was similar (study A: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.453; study B: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.162). Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D –0.96% [–10.49 mmol/mol], Q1D –1.00% [–10.93 mmol/mol], Q3D–Q1D 0.04% [0.44 mmol/mol] [95% CI –0.15 to 0.22 (–1.64 to 2.40)]; study B: Q3D –0.92% [–10.06 mmol/mol], Q1D –0.98% [–10.71 mmol/mol], Q3D–Q1D 0.06% [0.66 mmol/mol] [95% CI –0.12 to 0.24 (–1.31 to 2.62)]). The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. In general, no clinically relevant differences were found between the two algorithms in subjects ≥65 years old in either study. CONCLUSIONS Prandial insulin lispro can effectively and safely be initiated, by either of two self-titrated algorithms, in a variety of practice settings.
Nonbilayer phase of lipoplex–membrane mixture determines endosomal escape of genetic cargo and transfection efficiency
Authors: Inge S. Zuhorn, Udo Bakowsky, Evgeny Polushkin, Willy H. Visser, Marc C.A. Stuart, Jan B.F.N. Engberts, Dick Hoekstra
Journal: Molecular Therapy (2005)

Cationic lipids are widely used for gene delivery, and inclusion of dioleoylphosphatidylethanolamine (DOPE) as a helper lipid in cationic lipid-DNA formulations often promotes transfection efficacy. To investigate the significance of DOPE's preference to adopt a hexagonal phase in the mechanism of transfection, the properties and transfection efficiencies of SAINT-2/DOPE lipoplexes were compared to those of lipoplexes containing lamellar-phase-forming dipalmitoylphosphatidylethanolamine (DPPE). After interaction with anionic vesicles, to simulate lipoplex-endosomal membrane interaction, SAINT-2/DOPE lipoplexes show a perfect hexagonal phase, whereas SAINT-2/DPPE lipoplexes form a mixed lamellar-hexagonal phase. The transition to the hexagonal phase is crucial for dissociation of DNA or oligonucleotides (ODN) from the lipoplexes. However, while the efficiencies of nucleic acid release from either complex were similar, SAINT-2/DOPE lipoplexes displayed a two- to threefold higher transfection efficiency or nuclear ODN delivery. Interestingly, rupture of endosomes following a cellular incubation with ODN-containing SAINT-2/DPPE complexes dramatically improved nuclear ODN delivery to a level that was similar to that observed for SAINT-2/DOPE complexes. Our data demonstrate that although hexagonal phase formation in lipoplexes is a prerequisite for nucleic acid release from the complex, it appears highly critical for accomplishing efficient translocation of nucleic acids across the endosomal membrane into the cytosol for transport to the nucleus.