tbuckley/cabot-search huggingface dataset:
Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition
Authors: Joan Albanell, Federico Rojo, Steve Averbuch, Andrea Feyereislova, Jose Manuel Mascaro, Roy Herbst, Patricia LoRusso, Danny Rischin, Silvia Sauleda, Julia Gee, Robert I. Nicholson, Jose Baselga
Journal: Journal of Clinical Oncology (2002)

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27(KIP1), and maturation were also assessed.Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P <.001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P <.001). In addition, ZD1839 inhibited MAPK activation (P <.001) and reduced keratinocyte proliferation index (P <.001). Concomitantly, ZD1839 increased the expression of p27(KIP1) (P <.001) and maturation markers (P <.001) and increased apoptosis (P <.001). These effects were observed at all dose levels, before reaching dose-limiting toxicities.ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.
Colonial Medicine
Journal: JAMA (2001)

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
Colorectal Cancer Awareness Issue
Journal: Endoscopy (2014)

The month of March is internationally recognized as Colorectal Cancer Awareness Month, and this March issue of Endoscopy is dedicated to important news from colorectal cancer research. With their concern for prevention, early detection, and better treatment, endoscopists have long been at the forefront in promoting awareness of colorectal cancer. As demonstrated in this issue of the Journal, endoscopy research is still a very important driving force in the fight against colorectal malignancy, one of the leading cancer killers.
Randomized phase III trial of gemcitabine and cisplatin versus gemcitabine alone in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) 2: CAPPA-2 study.
Authors: Alessandro Morabito, Vittorio Gebbia, Saverio Cinieri, Maria Grazia Viganò, Roberto Bianco, Santi Barbera, Luigi Cavanna, Filippo De Marinis, Vincenzo Montesarchio, Raffaele Costanzo, Claudia Sandomenico, Agnese Montanino, Gianfranco Mancuso, Angelo Nacci, Pasqualina Giordano, Gennaro Daniele, Cesare Gridelli, Gaetano Rocco, Ciro Gallo, Massimo Di Maio
Journal: Journal of Clinical Oncology (2013)

8066 Background: Platinum-based chemotherapy (CT) is the standard treatment for patients (pts) with advanced NSCLC, but the evidence of its efficacy among ECOG PS2 pts is weak, because these pts are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard CT in these pts. No prospective randomized trial has tested the addition of cisplatin to single-agent CT in pts with advanced NSCLC and PS2. Methods: CAPPA-2 was a multicentre, randomized phase III study for first-line treatment of PS2 pts with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI ed.) and adequate organ function. Patients in standard arm received gemcitabine 1,200 mg/m 2 dd1 and 8.Patients in experimental arm received cispaltin 60 mg/m 2 d1 plus gemcitabine 1,000 mg/m 2 dd1 and 8. All treatments were repeated q3w, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. Results: The study was stopped in June 2012 after the enrolment of 57 pts, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin + gemcitabine (HR 0.52, 95% CI 0.28-0.98, p=0.039). Combination CT produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p=0.017) and higher response rate (4% vs. 18%, p=0.19), without substantial increase in toxicity. Conclusions: Addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC. Clinical trial information: NCT00526643.
Wilson's disease (hepatolenticular degeneration) and pregnancy
Authors: F. E. Dreifuss
Journal: JAMA (1966)

SUCCESSFUL PREGNANCY punctuating Wilson's disease (hepatolenticular degeneration) has been rarely reported.<sup>1-5</sup>Most case reports on women in the child-bearing age mention scanty and irregular menses, and it is further likely that the early development of tremor or cirrhosis might constitute a bar to marriage and pregnancy. Both Wilson's disease and pregnancy are associated with alteration in copper metabolism, in particular, that of ceruloplasmin. While this protein is markedly reduced in most cases of Wilson's disease, it is usually increased in pregnancy and by the administration of estrogens.<sup>6,7</sup>In pregnant patients with Wilson's disease, ceruloplasmin was found by Sternlieb and Scheinberg<sup>5</sup>to rise to almost normal concentrations, but other observers<sup>2</sup>found no significant increase. Uniformly, however, there appears to have been significant clinical improvement in the severity of Wilson's disease during, and in the months following, pregnancy. The following case report describes a patient with long-standing Wilson's
Abstract 383: Modulating Calcium Dysregulation in Troponin T Linked Hypertrophic Cardiomyopathy
Authors: Sarah Lehman, Lauren Grinspan, Mark E Anderson, Jil C Tardiff
Journal: Circulation Research (2017)

Mutations in cardiac troponin T (cTnT) account for approximately 5-10% of all Hypertrophic Cardiomyopathy (HCM). Residue Arg92 of cTnT represents a HCM-mutational hotspot, including Arg92Leu (R92L) and Arg92Trp (R92W). These mutations, although differing by only a single amino acid, present with varying degrees of cardiac remodeling and disease severity in the human population. Studying the differential effects of the R92 mutations on Ca 2+ homeostasis revealed an age-dependent disruption in down-stream calcium handling in R92W mice, including differential diastolic calcium levels and SERCA2a uptake activity. To determine the effects of treating this differential calcium handling disruption, R92L and R92W mice were treated with diltiazem hydrochloride, an L-type Ca 2+ channel blocker. While R92L mice showed a progressive worsening in diastolic function and remodeling throughout treatment, R92W mice showed improvement in diastolic function but no change in cardiac remodeling, suggesting an improvement but not amelioration of disease with diltiazem treatment. Of note, previous studies also suggested an increase in phospholamban (PLB) phosphorylation at Thr17 (CaMK-II-mediated) over time in R92W mice only. Thus, we hypothesized a mutation-specific role of CaMK-II in cTnT-linked HCM progression. We tested this via genetic partial inhibition of CaMK-II (AC3-I peptide) in both R92W and R92L transgenic mice. Both R92W and AC3-IxRW hearts exhibited a normalization of SERCA2a activity to non-transgenic levels over time. This improved Ca 2+ re-uptake was coupled with a decrease in atrial mass, improved ventricular relaxation, and normalized diastolic function only in AC3-IxRW animals, consistent with blunting of disease progression in vivo . In contrast, AC3-IxRL mice showed depressed SERCA2a activity, increased atrial mass and ventricular thickening, and diastolic dysfunction as compared to R92L alone mice, indicating a CaMK-II independent progression to HCM. These results suggest that closely related primary mutations can result in specific ventricular remodeling and targeting these discrete molecular secondary effects represent a novel targeted treatment approach in HCM.
Detection of lipocortin 1 in human lung lavage fluid: lipocortin degradation as a possible proteolytic mechanism in the control of inflammatory mediators and inflammation.
Authors: S F Smith, T D Tetley, A Guz, R J Flower
Journal: Environmental Health Perspectives (1990)

Lipocortins are structurally related, glucocorticoid-inducible proteins that inhibit phospholipase A2 (PLA2), thereby reducing the liberation of arachidonic acid from phospholipids and so limiting the synthesis of eicosanoid inflammatory mediators. This study is the first demonstration of one lipocortin, lipocortin 1 (Lc 1; 37 kDa), in human lung lavage supernatants. In lavage fluid from healthy volunteers, a higher percentage (greater than 70%) of the detected Lc 1 was in its native form, compared to that from patients with abnormal lungs. In patients' lavage fluids, Lc 1 was more likely to be partially degraded (34 kDa). In abnormal bronchoalveolar lavage fluid (BALF), the more polymorphonuclear neutrophils (PMN)/lavage, the lower the proportion of Lc 1 in the native (37 kDa) form (n = 7 pairs, rs = -0.8214, p less than 0.05). Furthermore, when BALF cells were cultured and the harvested conditioned media incubated with pure human recombinant Lc 1, degradation of the 37 kDa form increased with the percentage of PMN (n = 10 pairs, s = -0.7200 after 1 hr; n = 6 pairs, rs = -0.9241 after 6 hr). These results suggest that factors released from the PMN are responsible for Lc 1 degradation in man. When recombinant human Lc 1 was incubated with human neutrophil elastase, the enzyme degraded Lc 1 in a dose-dependent way, suggesting that neutrophil elastase may be one such factor. Since PMNs are ubiquitous at sites of inflammation, it is possible that Lc 1 degradation is a permissive mechanism, which ensures that sufficient inflammation occurs to destroy the provocative stimulus. However, it is equally possible that, in some circumstances, the mechanism may be pathological and that the inactivation of Lc 1 leads to chronic, uncontrolled inflammation.
Cytokine secretion requires phosphatidylcholine synthesis
Authors: Yong Tian, Caroline Pate, Alberto Andreolotti, Limin Wang, Elaine Tuomanen, Kelli Boyd, Enrique Claro, Suzanne Jackowski
Journal: The Journal of Experimental Medicine (2008)

ApoE, apolipoprotein E; CCT, cytidylyltransferase; CDP -Cho, cytidine diphosphocholine; C/EPT, choline/ethanolamine phosphotransferase; CPT, choline phosphotransferase; ERGIC-53, ER -Golgi intermediate compartment 53-kD protein; edelfosine, Et-18-OCH 3 ; fMLP, formyl-methionylleucylphenylalanine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-1 ␤ , interleukin-1 ␤ ; IL-6, interleukin-6; LCM, L cell -conditioned medium; LPS, lipopolysaccharide; lysoPC, lysophosphatidylcholine; PEMT, phosphatidylethanolamine methyltransferase; PGE 2 ,
England first, America second: The ecological predictors of life history and innovation
Authors: Severi Luoto, Markus J. Rantala, Indrikis Krams
Journal: Behavioral and Brain Sciences (2019)

Abstract We present data from 122 nations showing that Baumard's argument on the ecological predictors of life history strategies and innovation is incomplete. Our analyses indicate that wealth, parasite stress, and cold climate impose orthogonal effects on life histories, innovation, and industrialization. Baumard also overlooks the historical exploitation of other nations which significantly enlarged the “pooled energy budget” available to England.
Intoxication with echothiophate iodide. An acute cholinergic crisis
Authors: M. Hallett
Journal: JAMA (1972)

A patient with glaucoma was poisoned with his echothiophate iodide eye drops and experienced an acute cholinergic crisis. Treatment with atropine and pralidoxime chloride produced a rapid recovery. While it is likely that the intoxication was by the oral route, it is possible that routine topical application alone was responsible. At least the partial cholinesterase depression produced by topical therapy predisposed the patient to crisis.
Pulsus alternans
Authors: M. J Lab, W A. Seed
Journal: Cardiovascular Research (1993)

Journal Article Pulsus alternans Get access Max J Lab, Max J Lab Charing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF, United Kingdom — British Heart Foundation Cardiac Arrhythmia Research Group, Department of Physiology: M J Lab; Department of Medicine: W A Seed. Correspondence to Dr Lab. Search for other works by this author on: Oxford Academic PubMed Google Scholar W Anthony Seed W Anthony Seed Charing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF, United Kingdom — British Heart Foundation Cardiac Arrhythmia Research Group, Department of Physiology: M J Lab; Department of Medicine: W A Seed. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 8, August 1993, Pages 1407–1412, https://doi.org/10.1093/cvr/27.8.1407 Published: 01 August 1993 Article history Received: 23 December 1992 Accepted: 08 February 1993 Published: 01 August 1993
Cluster of Suicides and Suicide Attempts—New Jersey
Journal: JAMA (1988)

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
Abstract 1002: An association between Annexin A1 (ANXA1) and loss of progesterone receptor expression in estrogen receptor-positive breast cancer
Authors: Sung Gwe Ahn, Soong June Bae, Chihwan Cha, Chang Ik Yoon, So Eun Park, Joon Jeong
Journal: Cancer Research (2019)

Abstract Purpose: There is a strong body of evidence that low expression of progesterone receptor has a negative prognostic value in estrogen receptor (ER)-positive breast cancer. To discover key factors associated with PR-loss in ER-positive cancer, we conducted cell line experiments and investigated clinical samples. Methods: We generated PR knock-down MCF7 and T47D cell lines using lentiviral transfection with PR shRNA. Gene expression microarray analyses were performed using Illumina Chip. Annexin A1 (ANXA1) was evaluated for tissue microarray (TMA) using HER2-negative human breast carcinoma. Results: When PR-intact and PR-knockdown cells were compared using gene-expression profiles, ANXA1 was commonly identified as a molecule associated PR-knockdown in both MCF7 and T47D cell lines. Further, the mRNA expression of ANXA1 was elevated by PR-knockdown in both cell lines. In HER2-negative patients (n=370), ANXA1-positive tumors were associated with a lack of PR expression (P&amp;lt;0.001). The patients with ANXA1-positivity had a poor survival outcome in terms of overall survival and metastasis-free survival. Conclusions: Our findings inform that ANXA1 may act a role in tumor progression of PR-lacking breast cancer. Citation Format: Sung Gwe Ahn, Soong June Bae, Chihwan Cha, Chang Ik Yoon, So Eun Park, Joon Jeong. An association between Annexin A1 (ANXA1) and loss of progesterone receptor expression in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1002.
WEIGHT AND HEALTH.
Journal: JAMA (2006)

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
Blood pressure and skin color
Authors: Henry S. Kahn
Journal: JAMA (1991)

<h3>To the Editor.—</h3> Klag et al<sup>1</sup>have presented interesting data about the distribution of blood pressure in US blacks. However, their analysis may have failed to consider the striking effect that the city of residence had on their blood pressure observations. The mean blood pressure in Savannah, Ga, for example, was 10/6 mm Hg higher than it was in Pueblo, Colo (Klag et al, Table 2, p 600). By way of comparison, there is a somewhat smaller difference in mean blood pressures, only 5/5 mm Hg, between subjects at the highest and lowest quartiles of skin color (unadjusted data; Table). Since the city of residence was associated both with skin color (the risk factor under examination) and with blood pressure (the outcome variable), it would have been appropriate for Klag et al to include the city of residence among the variables in their multivariate analysis. It is not clear
Differential effects of exercise on serum lipid and lipoprotein levels seen with changes in body weight. A meta-analysis
Authors: Z. V. Tran
Journal: JAMA (1985)

Ninety-five studies conducted between September 1955 and October 1983 measuring changes in human serum lipid and lipoprotein levels in response to exercise training were analyzed using meta-analysis. Change in body weight during exercise training may confound observed serum lipid and lipoprotein level changes; thus, data from these studies were partitioned into those where subjects gained body weight, maintained body weight, or lost body weight. Results showed differential changes in cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol, and cholesterol/high-density lipoprotein-cholesterol levels in the three body-weight categories. Where body weight did not change, cholesterol and LDL-C levels decreased significantly (7.3 mg/dL and 3.3 mg/dL, respectively). Where body weight decreased, cholesterol and LDL-C levels also decreased significantly (13.2 mg/dL and 11.1 mg/dL, respectively). However, with body-weight increase, cholesterol and LDL-C levels increased by 2.9 mg/dL and 3.0 mg/dL, respectively. These results suggest that reductions in cholesterol and LDL-C levels were greatest when exercise training was combined with body-weight losses. (<i>JAMA</i>1985;254:919-924)
Interspecies Comparisons of Tissue DNA Damage, Repair, Fixation, and Replication
Authors: Thomas J. Slaga
Journal: Environmental Health Perspectives (1988)

The many anatomical, physiological, and biochemical differences among various mammalian species make it difficult to extrapolate carcinogenic potency data from animals to humans. The process is further complicated by the multistep origin of most malignant tumors in animals and humans due to the interaction of target cells with both endogenous and exogenous factors. Species differences in these aspects of carcinogenesis must also be considered when attempting to evaluate the carcinogenic risks of chemicals to humans. Cancer development in animals involves at least three distinct stages: initiation, promotion, and progression. Intra- and interspecies differences in susceptibility to carcinogenesis may be related to any one or a combination of these stages. Variation in species susceptibility to tumor initiation may result from differences in the abilities of various species to metabolize a potential carcinogen to an ultimate carcinogenic form and/or to detoxify the carcinogen. Most comparative studies among species have only revealed subtle differences in metabolism. DNA adducts from several activated carcinogens have been found to be the same in a number of tissues from various species, including humans. Capacity for DNA repair is apparently a critical factor in the initiation of carcinogenesis in target cells of different species but is less critical among mice that differ in susceptibility to two-stage carcinogenesis of the skin and liver. Susceptibility variations among stocks and strains to such carcinogenesis appear to be related to alterations in tumor promotion. Additional comparative studies are critically needed on all aspects of carcinogenesis to permit effective extrapolation of carcinogenic potency data from animals to humans.