tbuckley/cabot-search huggingface dataset:
Abstract 695: The generation of a mono-selective CDK7 inhibitor.
Authors: Jan E. Eickhoff, Gunther Zischinsky, Axel Choidas, Peter Habenberger, Alexander Wolf, Carsten Degenhardt, Matthias Baumann, Anke Unger, Ahmad Ghallab, Doreen Werchau, Jan Hengstler, Peter Nussbaumer, Bert M. Klebl
Journal: Cancer Research (2013)

Abstract Cyclin-depending kinase (CDK) family members that trigger passage through the cell cycle have been considered as attractive cancer targets for at least two decdes Yet, the first generation of pan-specific CDK inhibitors failed to show clinical efficacy due to their small therapeutic window. CDK family members that control processes such as transcription have caught less attention, although experimental evidence for an involvement in different pathological processes is emerging. CDK7 (or CAK) has essential roles in both the cell-division cycle and transcription, and serves as a direct link between the regulation of basal transcription and the cell cycle. In addition to its role as a transcription activator, CDK7 has been reported to act on specific transcription events by phosphorylating a series of specific transcription factors, such as the estrogen receptor and p53. These findings indicate that CDK7 is a potential target for cancer therapy, and perhaps inflammation. The detailed molecular characterization of the biological role of CDK7, as well as its therapeutic validation, is dependent on the development of highly specific and potent CDK7 inhibitors. We have developed a series of CDK7 inhibitors with picomolar potency on CDK7, more than 1000-fold selectivity over any other CDK, and single digit nM inhibition of sensitive cancer cell lines. Interestingly, a broad screen of &amp;gt;200 different tumor cell lines lead to the identification of responder and non-responder cell lines. Non-responder tumor lines, similar to primary cells are at least by a factor of 1000 less sensitive to the inhibition with the mono-selective CDK7 inhibitor. Our findings further indicate that CDK7 is neither essential for general transcription, nor for the progression through the cell cycle. It rather coordinates cell line specific biological processes. The effects of selective CDK7 inhibitors on tumor cell lines are clearly distinct from existing, nonselective pan-CDK inhibitors. The responder status for a subset of cancer cell lines can be predicted with a distinct biomarker. Chemical optimization of the selective inhibitor lead to a compound which shows dose-dependent pharmacological efficacy in mouse xenograft models after oral administration, with no signs of toxicity at the efficacious doses. Citation Format: Jan E. Eickhoff, Gunther Zischinsky, Axel Choidas, Peter Habenberger, Alexander Wolf, Carsten Degenhardt, Matthias Baumann, Anke Unger, Ahmad Ghallab, Doreen Werchau, Jan Hengstler, Peter Nussbaumer, Bert M. Klebl. The generation of a mono-selective CDK7 inhibitor. [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 695. doi:10.1158/1538-7445.AM2013-695
Duration of Nocturnal Hypoglycemia Before Seizures
Authors: Bruce Buckingham, Darrell M. Wilson, Todd Lecher, Ragnar Hanas, Kevin Kaiserman, Fergus Cameron
Journal: Diabetes Care (2008)

OBJECTIVE—Despite a high incidence of nocturnal hypoglycemia documented by the use of continuous glucose monitoring (CGM), there are no reports in the literature of nocturnal hypoglycemic seizures while a patient is wearing a CGM device. RESEARCH DESIGN AND METHODS—In this article, we describe four such cases and assess the duration of nocturnal hypoglycemia before the seizure. RESULTS—In the cases where patients had a nocturnal hypoglycemic seizure while wearing a CGM device, sensor hypoglycemia (&amp;lt;60 mg/dl) was documented on the CGM record for 2.25–4 h before seizure activity. CONCLUSIONS—Even with a subcutaneous glucose lag of 18 min when compared with blood glucose measurements, glucose sensors have time to provide clinically meaningful alarms. Current nocturnal hypoglycemic alarms need to be improved, however, since patients can sleep through the current alarm systems.
Cellular Mechanisms for Lipid Deposition in Atherosclerosis
Authors: Howard L. Bleich, Emily S. Boro, Donald M. Small
Journal: New England Journal of Medicine (1977)

(First of Two Parts*)RECENT research on the pathogenesis of atherosclerosis has focused on the physicochemical nature of the arterial wall and on the roles of smooth-muscle cells, serum lipoproteins and defects in cellular metabolism of cholesterol that lead to early atherosclerosis. Smooth-muscle-cell proliferation is widely believed to be the initial cellular event in the pathogenesis of atherosclerosis.1 A stimulus, such as an injury, a chemical or a virus, is thought to cause smooth-muscle cells to migrate into the intima, where they may transform, proliferate, produce connective tissue and lipid and thus initiate the early lesion. Cellular isoenzyme typing . . .
Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection
Authors: Christophe Hézode, Nicole Forestier, Geoffrey Dusheiko, Peter Ferenci, Stanislas Pol, Tobias Goeser, Jean-Pierre Bronowicki, Marc Bourlière, Shahin Gharakhanian, Leif Bengtsson, Lindsay McNair, Shelley George, Tara Kieffer, Ann Kwong, Robert S. Kauffman, John Alam, Jean-Michel Pawlotsky, Stefan Zeuzem
Journal: New England Journal of Medicine (2009)

In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)
Long-Term Neuroprotection Achieved with Latency-Associated Promoter-Driven Herpes Simplex Virus Gene Transfer to the Peripheral Nervous System
Authors: Munmun Chattopadhyay, Darren Wolfe, Marina Mata, Shaohua Huang, Joseph C. Glorioso, David J. Fink
Journal: Molecular Therapy (2005)

We examined the ability of the herpes simplex virus (HSV) latency-associated promoter (LAP2) to drive biologically relevant prolonged transgene expression in the peripheral nervous system. Rat dorsal root ganglia were transduced in vivo by subcutaneous inoculation of replication-incompetent HSV-based vectors containing nerve growth factor (NGF) or neurotrophin-3 (NT-3) under the control of LAP2 (vectors SLN and QLNT3, respectively) and vector SHN expressing NGF under the control of the human cytomegalovirus immediate early promoter. Twenty-four weeks later a pure sensory neuropathy was induced by overdose of pyridoxine (PDX), and the animals were assessed 6 months after inoculation. Inoculation of SLN, but not SHN, attenuated the nerve damage caused by PDX and protected foot sensory amplitude, H-wave amplitude, and behavioral measures of proprioceptive function. QLNT3 was more effective than SLN in preserving the largest myelinated fibers from degeneration. These results indicate that expression of NGF or NT-3 driven by LAP2 is sufficient to prevent the development of neuropathy 6 months after vector inoculation in rats.
Calcium Metabolism in Acromegaly
Authors: A. Nadarajah, M. Hartog, B. Redfern, N. Thalassinos, A. D. Wright, G. F. Joplin, T. R. Fraser
Journal: BMJ (1968)

A total of 78 acromegalic patients were studied before and after treatment by yttrium-90 needle implantation.Among the untreated patients 16% had a borderline or raised serum calcium. In half of these patients the serum calcium fell to normal after remission of their acromegaly. In the others the hypercalcaemia was due to associated proved or probable hyperparathyroidism. A downward trend of the serum calcium was noted even in the normocalcaemic patients with remission of their disease.Only 20% of untreated patients had a raised serum phosphate, and follow-up showed this measurement to be a poor index of disease activity.Net calcium absorption and calcium balances in five patients in this series and 12 others from the literature were essentially normal for their given level of calcium intake. No patient showed definite radiological evidence of osteoporosis and vertebral fractures.Bone uptake rate of calcium-47 and stable strontium was raised in the untreated state in all nine patients studied. The 24-hour strontium space was raised in 73% of untreated patients and fell to normal after treatment in all the retested patients in whom it was high initially.
Topiramate as Treatment for Alcohol Dependence—Reply
Authors: Bankole A. Johnson, Nassima Ait-Daoud, Raymond F. Anton, Domenic A. Ciraulo, Henry R. Kranzler, Karl Mann, Stephanie S. O’Malley, Robert M. Swift
Journal: JAMA (2008)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Dose Reduction/Discontinuation for First-Episode Psychosis
Authors: Wieteke S. Elzinga, Peter F. J. Schulte
Journal: JAMA Psychiatry (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Physician–Industry Relations. Part 2: Organizational Issues
Authors: Susan L. Coyle
Journal: Annals of Internal Medicine (2002)

This is part 2 of a 2-part paper on ethics and physician-industry relationships. Part 1 offers advice to individual physicians; part 2 gives recommendations to medical education providers and medical professional societies. Industry often sponsors programs for graduate and continuing medical education, as well as major events of medical professional societies. Industry is an abundant source of advances in medicine and technology and plays a crucial role in disseminating up-to-date medical information. Although industry information fills an important need, studies suggest that it is often biased. Providers of graduate and continuing medical education have a duty to present objective and balanced information to their participants; thus, they should not accept any funds that are contingent on a sponsor's ability to shape programming. Medical educators need to evaluate and control the planning, content, and delivery of education provided under their auspices. They should disclose industry sponsorship to students, faculty, and continuing medical education participants and should adopt explicit organizational policies about acceptable and unacceptable interactions with industry. Medical professional societies have a duty to promote the independent judgment and professionalism of their members. Organizers of industry-sponsored meetings should clearly separate product promotion from impartial medical education. Adopting specific policies for dealing with industry sponsorship can also help professional societies guard against outside influence. The American College of Physicians--American Society of Internal Medicine's core ethical principles for external funding and relationships serve as an example.
A study of etretinate alopecia
Authors: J. BERTH-JONES, D. SHUTTLEWORTH, P.E. HUTCHINSON
Journal: British Journal of Dermatology (1990)

Twenty-two patients receiving etretinate were studied in an attempt to clarify the changes in hair cycle dynamics responsible for etretinate alopecia. Shed hair counts and telogen counts on samples of plucked hair were performed prior to therapy and after 6 and 12 weeks' treatment with etretinate. No evidence of anagen effluvium was found. In two individuals there were findings compatible with a classical telogen effluvium, but these had atypical features. The main finding in the study was an increase in the plucked telogen count, maximal at 12 weeks. As an arrest in the onset of anagen could produce only a comparatively small telogen increase, the predominant cause of this increase was a decrease in the duration of anagen. In two subjects there was also evidence of a telogen anchorage defect.
Alterations of cytochrome P450-dependent monooxygenase activities in Eriocheir japonicus in response to water pollution.
Authors: M Ishizuka, H Hoshi, N Minamoto, M Masuda, A Kazusaka, S Fujita
Journal: Environmental Health Perspectives (1996)

Eriocheir japonicus, fresh-water crabs inhabiting rivers and estuaries in Japan, were investigated for cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activities to see if these activities reflect the river pollution gradient. From the laboratory dose-response experiments, we found that the polycyclic aromatic hydrocarbon (PAH) 3-methylcholanthrene induced total CYP contents, ethoxycoumarin O-deethylase activity, and bunitrolol 4-hydroxylase activity in crab hepatopancreas. In the field studies, crabs collected from the river with the highest concentration of PAHs exhibited the highest levels of CYP, the highest activities of benzo[a]pyrene 3-hydroxylase, imipramine 2-hydroxylase, bunitrolol 4-hydroxylase, ethoxycoumarin O-deethylase, and the ability to metabolically activate benzo[a]pyrene, but erythromycin N-demethylase activity was not induced. The correlation between PAH levels and drug-metabolizing enzyme activities in female crabs were not as marked as in male crabs. The levels and activities of CYP did not appear to reflect the concentrations of organochlorines and polychlorinated biphenyl congeners (PCBs) studied in the fat of crab hepatopancreas.
EXPERIMENTAL STUDIES OF THE NASOPHARYNGEAL SECRETIONS FROM INFLUENZA PATIENTS
Authors: Peter K. Olitsky, Frederick L. Gates
Journal: The Journal of Experimental Medicine (1922)

From the nasopharyngeal secretions of patients in the early hours of uncomplicated epidemic influenza during the recurrence in New York City in January and February, 1922, we have again obtained an active agent, pathogenic for rabbits, and have identified this active agent as Bacterium pneumosintes. Four new strains of this micro-organism have been isolated in pure culture and identified with the 1918-19 and 1920 strains on morphological, cultural, and serological grounds. All of the significant characteristics of the old strains, including their effect upon the resistance of the lungs of rabbits to secondary invasion with other bacteria, have been noted in the new strains, which thus have served to confirm and extend our original observations.
Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs.
Authors: H Kohrogi, J A Nadel, B Malfroy, C Gorman, R Bridenbaugh, J S Patton, D B Borson
Journal: Journal of Clinical Investigation (1989)

To determine whether recombinant enkephalinase (neutral endopeptidase, EC 3.4.24.11) prevents cough induced by exogenously applied and endogenously released neuropeptides, we measured cough responses to aerosolized solutions of substance P or of capsaicin for 2 min in random-source guinea pigs before or after exposing them to aerosolized recombinant human enkephalinase. Substance P (10(-16) M) increased coughing compared with its vehicle. Enkephalinase (120 micrograms) inhibited cough induced by subsequent exposure to substance P compared with the response to substance P alone, but after further exposure to the enkephalinase inhibitor leucine-thiorphan (10(-5) M), substance P increased cough significantly. Similar results were obtained for capsaicin-induced cough. In pathogen-free guinea pigs, after they inhaled inactive recombinant enkephalinase (33 micrograms), capsaicin (10(-13) M) increased cough significantly. In contrast, after they inhaled active recombinant enkephalinase (33 micrograms), capsaicin increased cough only slightly. These results suggest that aerosolized enkephalinase reaches the sites of release or actions of endogenous neuropeptides and, by degrading them, prevents cough induced by their release. Furthermore, these studies suggest that recombinant enkephalinase might be useful in the treatment of cough and other symptoms of diseases involving peptides cleaved by this enzyme.
Claude Bernard and Animal Chemistry: The Emergence of a Scientist
Authors: Lester S. King
Journal: JAMA (1975)

"Animal chemistry" refers to what we now call biochemistry. In this discipline the second quarter of the 19th century was particularly important, for the chemists were slowly applying their new experimental methods to the living body. Particularly challenging were the problems of nutrition— the way that ingested food became part of the living tissue. Professor Holmes concentrates on the years 1842 to 1848, crucial for the development of biochemistry and crucial in the career of Claude Bernard. The first third of the book takes up chiefly the conceptual background of the second quarter of the 19th century, the chemical and biological theories, the experimental bases on which they rested, and the men involved in the personal and national rivalries. The remainder deals more intimately with Claude Bernard. Bernard, who devoted himself entirely to physiology, received his medical degree in 1843, at the age of 30. His dissertation dealt with the
Acute cancer services should be provided in emergency care, says government advisory group
Authors: H. Mooney
Journal: BMJ (2009)

All hospitals with emergency departments should provide acute cancer services in a bid to improve the quality and safety of chemotherapy for patients with cancer, says a report from a government advisory group.

The report from the National Chemotherapy Advisory Group is a response to the November 2008 review of the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) ( BMJ 2008;237:a2498, doi:10.1136/bmj.a2498).

The NCEPOD review raised serious concerns about the safety and quality of chemotherapy services in England. Its analysis of the care of patients who …
The production and costs of health service across four African countries: Ghana, Kenya, Uganda, and Zambia
Authors: Michael Hanlon, Jane Achan, Roy Burstein, Anirban Chatterjee, Ruben Conner, Emily Dansereau, Brendan DeCenso, Herbert Duber, Anne Gasasira, Bertha Garshong, Annie Haakenstad, Gloria Ikilezi, Emmanuel Kwakye Kontor, Caroline Kisia, Santosh Kumar, Felix Masiye, Samuel Masters, Kelsey Moore, Chrispin Mphuka, Jane Mwangi, Pamela Njuguna, Thomas Odeny, Emelda Okiro, Ivy Osei, Emmanuela Gakidou, Christopher JL Murray
Journal: The Lancet (2013)