tbuckley/cabot-search huggingface dataset:
Abstract 1322: Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal breast cancer
Authors: Patrick J. Roberts, David B. Darr, John E. Bisi, Jay C. Strum
Journal: Cancer Research (2014)

Abstract Introduction: Selective CDK4/6 inhibitors have emerged as attractive antineoplastic agents due to the importance of CDK4/6 activity in regulating cell proliferation. We have identified a series of orally available, potent and selective dual CDK4/6 inhibitors (G1T100182, G1T100183, G1T101551). Preclinical characterization of these compounds indicates that they inhibit CDK4 and CDK6 with an IC50 of 0.7-1.0 nM and 5-6 nM, respectively. In Rb competent tumor cells, these compounds potently inhibit Rb phosphorylation resulting in a G1 arrest. Here we assess the in vivo efficacy of these compounds in a genetically engineered mouse model of luminal breast cancer. Methods: MMTV-Neu mice were housed and therapeutic response assessed in the UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U). Compounds were supplied by G1 Therapeutics, Inc. Tumors were serially assessed weekly using caliper measurements. Therapeutic intervention began once tumors reached 40-64mm3 and continued for 28 consecutive days. Tumor volume was calculated using the formula ((Width2) x Length)/2). All compounds were administered orally via medicated diets. RECIST criteria were used to assess objective response rates. Results: Significant objective responses were noted in mice treated with G1T100182, G1T100183, G1T101551. Treatments produced modest reversible myelosuppression, but where otherwise well tolerated with no other clinical signs of toxicity or deaths associated with toxicity. A linear regression t-test was used to determine statistical significance of tumor volume changes over time. All treatment cohorts demonstrated statistically significant improvement when compared to un-treated mice; G1T100182, p&amp;lt;0.0001; G1T100183, p=0.0001; G1T101551, p&amp;lt;0.0001. Conclusions: In summary, we have identified a series of orally active, potent, and selective small molecule inhibitors of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein. Complete ResponsePartial ResponseStable DiseaseProgressive DiseaseORR % (CR+PR+SD/PD)Mean % Change in Tumor VolNo Treatment00090 (0/9)500G1T1001821510100 (7/0)-70G1T100183141185 (6/1)-67G1T1015511250100 (8/0)-40 Citation Format: Patrick J. Roberts, David B. Darr, John E. Bisi, Jay C. Strum. Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2014-1322
Drugs Five Years Later
Authors: MARY LEE VANCE
Journal: Annals of Internal Medicine (1984)

Bromocriptine, a specific dopamine receptor agonist, has been used for the treatment of various hyperprolactinemic conditions and as adjunctive therapy for acromegaly (with or without concomitant hyperprolactinemia) and Parkinson's disease. Bromocriptine is extremely effective in suppressing prolactin secretion regardless of the cause, in restoring gonadal function and fertility, and in decreasing the size of prolactin-secreting pituitary tumors. Most patients with acromegaly have clinical improvement with this drug. When bromocriptine is added to a regimen of levodopa or carbidopa, patients with Parkinson's disease frequently have additional clinical improvement and, in most patients, the levodopa or carbidopa dose can be reduced. Withdrawal of bromocriptine therapy is associated in most patients with reversal of its beneficial effects—return of hyperprolactinemia, return of excess growth hormone secretion, and exacerbation of Parkinson's disease.
The Value of Sound Research Practices Even Facing Pandemics
Authors: Abigail B. Shoben
Journal: The American Journal of Bioethics (2013)

Click to increase image sizeClick to decrease image size Acknowledgments 1. Case fatality rate, often colloquially referred to as a “death rate,” is the proportion of people with the disease who end up dying within a specified period of time. For example, if 25 out of 100 people with a new disease died within 4 weeks of infection, the case fatality rate would be 25%.
Treatment Outcome and Physician-Patient Communication in Primary Care Patients With Chronic, Recurrent Depression
Authors: Thomas L. Schwenk, Dwight L. Evans, Sally K. Laden, Lydia Lewis
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors’ goal was to assess the adequacy of control, quality of life, and treatment experiences of patients with chronic, recurrent depression being treated by primary care physicians. METHOD: The sample comprised 1,001 patients 18 years old or older who had chronic, recurring depression and were currently being treated with a single antidepressant prescribed by a primary care physician. These patients had responded positively to questions regarding the presence of clinical depression and prescription of a single antidepressant by a primary care physician during a telephone survey conducted in two stages separated by 18 to 24 months. The 1,001 patients participated in a structured, 20-minute, anonymous interview conducted by trained personnel. RESULTS: Most patients had recurrent depression (median=5 episodes), and most had taken their current antidepressant for more than 1 year. The mean age at onset of depression was 33.8 years, and the mean age at time of diagnosis was 38.0 years, with treatment following a mean of 2 years later. Most patients were satisfied with the care they received from their primary care physician, but many also reported incomplete symptom resolution and substantial side effects from medications that were not discussed with or by their primary care physician. A majority of patients reported that treatment decisions were made in conjunction with their physician, a method that was preferred by three-quarters of the group. Although 752 patients reported that they had mild or moderate depression, 729 were satisfied with their life and 600 said they were in good or excellent health. CONCLUSIONS: Despite being mostly satisfied with the care received from their primary care physician, patients with chronic, recurring depression had substantial levels of continuing dysfunction, distress, unrelieved symptoms, and medication side effects, which suggests several possible physician-centered, patient-centered, or system-centered barriers to treatment to full function and wellness.
As Ebola Epidemic Begins to Slow, Trials of Drugs and Vaccines Speed Up
Authors: Bridget M. Kuehn
Journal: JAMA (2015)

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
Anti-AT(1)R and anti-ET(A)R autoantibodies in systemic sclerosis: clues for possible involvement in disease pathology
Authors: Angela Kill, Mike O Becker, Jeannine Guenther, Harald Heidecke, Duska Dragun, Gabriela Riemekaste
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Autoantibodies that target the angiotensin-II type-1 receptor (AT1R-Abs) and the endothelin-1 receptor type A (ETAR-Abs) were recently identified in systemic sclerosis (SSc). They showed strong association with clinical symptoms such as vascular and fibrotic complications including development of pulmonary arterial hypertension (PAH) and death, thus implicating their contribution to SSc pathogenesis. Here, different autoantibody-mediated effects and their blockade by receptor inhibitors were studied in an in vitro setting. <h3>Methods</h3> Human microdermal endothelial cells-1 (HMEC-1) were treated with IgG from SSc patients containing anti-AT(1)R and anti-ET(A)R autoantibodies and with IgG of healthy donors as a negative control. In parallel, cells were pre- treated with various receptor antagonists alone and in combination. IgG mediated effects via AT(1)R and ET(A)R on different cytokines, growth factors and cell viability were measured by for example, toxicity test, qRT-PCR and ELISA. <h3>Results</h3> Treatment of HMEC-1 cells with SSc- IgG led to a strong upregulation of several mediators compared to negative control treatment. In case of IL-8, the mRNA and protein expression levels were upregulated. Moreover, expression of mRNA was downregulated and partially reduced on the protein levels using pre- treatment with receptor inhibitors. Interestingly, treatment with natural ligands did not result in interleukin 8 (IL-8) up-regulation. Treatment with SSc-IgG led also to a significantly reduced cell viability compared to negative control treatment. These effects were partially abolished by pretreatment with AT(1)R- inhibitor, but completely abolished using one but not another ET – inhibitor. <h3>Conclusion</h3> Our results suggest an autoantibody-driven cytotoxicity and inflammatory activation of endothelial cells by angiotensin/endothelin-receptors in vitro. The data also suggest a high heterogeneity of antibody-mediated effects within IgG samples from different SSc patients, a role of other possible autoantibodies present in the SSc-IgG, and different responses to inhibitors and natural ligands. Whether these in vitro data could be used to identify responders or non- responsers to therapy remains to be studied. In vivo experiments are underway to give better insight into the complex nature of the SSc-antibody-mediated effects.
Carcinoma at the Site of Herpes Simplex Infection
Authors: Gordon A. Caron
Journal: JAMA (1980)

<h3>To the Editor.—</h3> A squamous cell carcinoma of the lip developed in a 55-year-old man at the site of a localized herpes simplex infection that had been recurrent for the previous 20 years. During this time grouped blisters occurred on the lower lip, resolving after a few weeks at intervals of a few months up to two years. In 1973, findings from a smear examination (done elsewhere) of the base of one of the blisters yielded a diagnosis of a virus infection presumably from the presence of multinucleate balloon epithelial cells. For the last two years a lesion had been present all the time. He recently had extensive induration 2 cm in thickness involving almost the entire length of the lower lip with superficial erosions and crusting. There were no enlarged regional lymph nodes. A punch biopsy specimen (by a consultant, Jon Hanifin, MD) uncovered a squamous cell carcinoma. Radiotherapy
Congenital bronchobiliary fistula: first case in an adult.
Authors: C R de Carvalho, C S Barbas, R M Guarnieri, J R de Campos, L T Filomeno, P H Saldiva, J V Barbas Filho
Journal: Thorax (1988)

Abstract The first adult case of a congenital communication between the biliary tract and the right main bronchus is reported. Treatment by surgical excision and pneumonectomy was successful.
ARSENIURETED HYDROGEN POISONING.WITH REPORT OF FIVE CASES.
Authors: NOBLE WILEY JONES
Journal: JAMA (1907)

Our knowledge of the toxic effect of arseniureted hydrogen gas, ASH<sub>3</sub>, on the animal body is limited yet to the experimental results of certain investigators of the origin of icterus, notably of Stadelmann, Minkowsky and Naunyn and Eppinger and to the scattered clinical reports of less than one hundred cases of poisoning in man. It was believed at the time of the occurrence of these five cases here detailed that numerous others would be reported from the different mining districts which had made use of the MacArthur-Forest cyanid process in the working of low grade gold ores, owing to the numerous attempts to smelt locally the zinc "product," which contains the gold values. But after the lapse of eight years these cases remain the only instances of such poisoning from this source that have come to my attention. Hunting through the meager literature of the subject, I have been
Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response
Authors: Susan N. Thomas, Efthymia Vokali, Amanda W. Lund, Jeffrey A. Hubbell, Melody A. Swartz
Journal: Biomaterials (2013)

Accumulating evidence implicates the tumor-draining lymph node (TDLN) in tumor-induced immune escape, as it drains regulatory molecules and leukocytes from the tumor microenvironment. We asked whether targeted delivery of adjuvant to the TDLN, presumably already bathed in tumor antigens, could promote anti-tumor immunity and hinder tumor growth. To this end, we used 30 nm polymeric nanoparticles (NPs) that effectively target dendritic cells (DCs, CD11c(+)) within the lymph node (LN) after intradermal administration. These NPs accumulated within the TDLN when administered in the limb ipsilateral (i.l.) to the tumor or in the non-TDLN when administered in the contralateral (c.l.) limb. Incorporating the adjuvants CpG or paclitaxel into the NPs (CpG-NP and PXL-NP) induced DC maturation in vitro. When administered daily i.l. and thus targeting the TDLN of a B16-F10 melanoma, adjuvanted NPs induced DC maturation within the TDLN and reshaped the CD4(+) T cell distribution within the tumor towards a Th1 (CXCR3(+)) phenotype. Importantly, this also led to an increase in the frequency of antigen-specific CD8(+) T cells within the tumor. This correlated with slowed tumor growth, in contrast to unhindered tumor growth after c.l. delivery of adjuvanted NPs (targeting a non-TDLN) or i.l. delivery of free adjuvant. CpG-NP treatment in the i.l. limb also was associated with an increase in CD8(+)/CD4(+) T cell ratios and frequencies of activated (CD25(+)) CD8(+) T cells within the TDLN whereas PXL-NP treatment reduced the frequency of regulatory T (FoxP3(+) CD4(+)) cells in the TDLN. Together, these data implicate the TDLN as a delivery target for adjuvant therapy of solid tumors.
T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes.
Authors: H B Nuss, S R Houser
Journal: Circulation Research (1993)

Macroscopic T-type Ca2+ currents, which are often observed in fetal and neonatal cardiac muscle cells, were not found in normal (0 of 17) adult feline ventricular myocytes. However, they were present in most (15 of 21) myocytes isolated from adult feline left ventricles with long-standing pressure-overload-induced hypertrophy. This is the first study to provide evidence in a large mammal, such as the cat, that T-type Ca2+ channels may be reexpressed in adults in association with hypertrophy resulting from slow progressive pressure overload. Importantly, this expression was stable for the duration of the hypertrophy process and was not associated with abrupt pressure overload. T-type Ca2+ currents were separated from L-type Ca2+ currents by exploiting the differences in their voltage dependence of steady-state inactivation. Depolarizations from -80 mV revealed a rapidly activating inward current that peaked in magnitude at -30 mV (-1.8 +/- 0.9 [mean +/- SD] pA/pF) and fully inactivated within 100 milliseconds in 15 of 21 hypertrophied myocytes studied. Further depolarizations activated progressively less T-type Ca2+ current, so that at +10 mV the L-type Ca2+ current predominated. In the hypertrophied myocytes that demonstrated both T-type and L-type Ca2+ currents, two distinct peaks occurred in their current-voltage relations. T-type Ca2+ currents were not evident in any of the 17 normal adult feline left ventricular myocytes studied. The purpose of T-type Ca2+ currents in hypertrophy is unclear. However, their presence may make hypertrophied myocardium more prone to spontaneous action potentials and increase the likelihood for arrhythmias in partially depolarized hypertrophied myocardium.
Using Admission Characteristics to Predict Short-term Mortality From Myocardial Infarction in Elderly Patients
Authors: Sharon-Lise T. Normand
Journal: JAMA (1996)

<h3>Objective.</h3> —To develop a prediction model of death within 30 days of hospital admission for Medicare patients with acute myocardial infarction that would permit use of risk-adjusted mortality rates as hospital quality measures. <h3>Design.</h3> —Retrospective cohort study using data created from medical charts and administrative files. <h3>Setting.</h3> —All acute care hospitals in Alabama, Connecticut, Iowa, or Wisconsin. <h3>Patients.</h3> —A cohort of 14 581 patients with acute myocardial infarction covered by Medicare in 1993. <h3>Results.</h3> —The unadjusted 30-day mortality rate was 21%, ranging from 18% in Connecticut to 23% in Alabama. The 4 largest contributors to variability in mortality rates were mean arterial pressure, age, respiratory rate, and serum urea nitrogen level. The area under the receiver operator characteristic curve was 0.79 in a developmental sample of 10 936 patients and 0.78 in a validation sample of 3645 patients. Based on admission variables, we were able to explain 27% of the variability in 30-day mortality rates. During the index admission, aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and thrombolytic agents were used in 72%, 39%, 32%, and 15% of patients, respectively. Explained variation increased by 6 percentage points to 33% when drug therapies and revascularization procedures performed during the index admission were added to the model predictors. <h3>Conclusions.</h3> —Short-term mortality remains high for elderly patients with acute myocardial infarction, and a large percentage of variation remains unexplained after controlling for admission severity. Part of the unexplained variability can be explained by the location of the admitting hospital; some of the remaining unexplained variation may reflect differences in quality of care or unmeasured differences in disease severity. Researchers should develop quality indicators based on process measures for acute myocardial infarction and should incorporate these measures into mortality models to determine whether quality accounts for variation in 30-day mortality rates beyond that explained by clinical status at admission. (<i>JAMA</i>. 1996;275:1322-1328)
Symptom Reduction and Suicide Risk Among Patients Treated With Placebo in Antipsychotic Clinical Trials: An Analysis of the Food and Drug Administration Database
Authors: Arif Khan, Shirin R. Khan, Robyn M. Leventhal, Walter A. Brown
Journal: American Journal of Psychiatry (2001)

The assumption that psychotic patients assigned to placebo in clinical trials of antipsychotics are exposed to substantial morbidity and mortality is not based on data about what actually happens to such patients. This study assesses symptoms and risks of suicide and suicide attempts in psychotic patients assigned to receive placebo in clinical trials.The authors used the Food and Drug Administration database to assess suicides, suicide attempts, and psychotic symptom reduction in clinical trials of three new antipsychotics.Among 10,118 participating patients, 26 committed suicide and 51 attempted suicide. Rates of suicide and attempted suicide did not differ significantly between the placebo-treated and the drug-treated groups. Annual rates of suicide and attempted suicide based on patient exposure years were 1.8% and 3.3%, respectively, with placebo; 0.9% and 5.7% with an established antipsychotic; and 0.7% and 5.0% with a new antipsychotic. Symptom reduction was 16.6% with new antipsychotics (N=1,203), 17.3% with established antipsychotics (N=261), and 1.1% with placebo (N=462).These data may help inform discussions about the use of placebo in antipsychotic clinical trials.
The Paradox of the Bone-Marrow Graft in the Immunologically Deficient Host
Authors: R. E. Billingham, J. Wayne Streilein
Journal: New England Journal of Medicine (1971)

Many patients suffering from immunologic deficiency disorders have been found to be lacking certain lymphohematopoietic stem cells, and the evidence suggests that this cellular deficiency is the basis of their disease. For these patients, a graft of homologous bone marrow would appear to afford an ideal therapeutic solution by providing the "missing" stem cells. From the collective points of view of the donors, recipients and clinicians, a marrow graft presents fewer immediate technical problems than allografts of solid tissues and organs. With renal allografts, success turns largely upon the clinician's ability to thwart, with immunosuppressive agents, the host's persistent attempts . . .
Do we need an encompassing speed/accuracy trade-off theory?
Authors: Arnold J. W. M. Thomassen, Ruud G. J. Meulenbroek
Journal: Behavioral and Brain Sciences (1997)

Even if we recognize that the delta-lognormal model provides an excellent fit to a large variety of data, the question remains as to what we actually learn from such a model, which could be seen as merely another multiparameter account? Do we welcome such an encompassing account, or do we expect to learn more from the limitations that become apparent when applying dedicated models addressing specific classes of movements?
Lesson of the week: Scurvy in patients with cancer
Authors: O. Fain, E. Mathieu, M. Thomas
Journal: BMJ (1998)

Scurvy is caused by a deficiency of vitamin C (ascorbic acid) and still occurs in developed countries. Those most at risk of scurvy are elderly people, men who live alone, people who are dependent on alcohol, people with fadish diets,1 mentally ill patients, and those undergoing peritoneal dialysis and haemodialysis.2 Scurvy is not usually reported in patients with cancer but its frequency is probably underestimated.

We describe six cases of scurvy in patients with cancer.

From January 1993 to September 1996 we observed six cases of scurvy in 3723 patients with non-cancerous conditions and six cases in 219 patients with cancer. Tables 1 and 2 give details of the six cases in the patients with cancer. All of the patients were men. Two of them (cases 2 and 4) lived alone and three (cases 1, 2, and 4) drank heavily. …