tbuckley/cabot-search huggingface dataset:
Abstract CT334: Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile
Authors: Sumanta K. Pal, Dewan Md Sakib Hossain, Qifang Zhang, Chan Gao, Jeremy O. Jones, Paul H. Frankel, Robert A. Figlin, Marcin Kortylewski
Journal: Cancer Research (2014)

Abstract Background: Pazopanib was assessed in a phase III study conducted in patients (pts) with mRCC who were either cytokine-refractory or treatment-naïve, and clinical outcomes with pazopanib have been associated with a specific immunologic profile (IP). The activity of pazopanib in the third-line setting and temporal changes in molecular profile during therapy are poorly understood, however. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received pazopanib 800 mg/daily on a 28d cycle. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). IPs were assessed monthly on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen). Results: 28 pts were enrolled with a median age of 63 (range, 45-86). In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. Median progression-free survival for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities included hypertension (46%) and proteinuria (14%). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, VEGF, IL-6, IL-8 and soluble IL-2R (P&amp;lt;0.05 for each). Non-responders also showed increased numbers of myeloid-derived suppressor cells (MDSCs) at both time intervals. Phenotypic and functional studies confirmed that MDSCs from these mRCC patients were granulocytic. Conclusions: The ORR observed with pazopanib in the current study is the highest to date in a third-line trial in mRCC. Differences in cytokine profile and granulocytic MDSC quantity between responders and non-responders suggest that the mechanism of pazopanib resistance is at least partly related to generation of systemic tumor immune tolerance. Citation Format: Sumanta K. Pal, Dewan Md Sakib Hossain, Qifang Zhang, Chan Gao, Jeremy O. Jones, Paul H. Frankel, Robert A. Figlin, Marcin Kortylewski. Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile. [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 CT334. doi:10.1158/1538-7445.AM2014-CT334
Effects of probucol on changes of antioxidant enzymes in adriamycin-induced cardiomyopathy in rats
Authors: T Li
Journal: Cardiovascular Research (2000)

Objective: The clinical usefulness of doxorubicin (adriamycin, ADR) is restricted by the risk of developing congestive heart failure. Probucol has been reported to completely prevent ADR cardiomyopathy without interfering with its antitumor effects. The current study investigated the effects of ADR and probucol on antioxidant enzyme gene expression during adriamycin-induced cardiomyopathy in a rat model. Methods: The mRNA abundance by Northern and immunoreactive protein levels by Western blotting of myocardial antioxidant enzymes, glutathione peroxidase (GSHPx), manganese superoxide dismutase (MnSOD) and catalase (CAT) were examined in relation to the enzyme activities in hemodynamically assessed control and treated animals. Results: At 3 weeks post-treatment duration, ADR caused heart failure which was prevented by probucol. MnSOD mRNA abundance as well as protein levels were depressed by ADR treatment by 45% and 20%, respectively, and this change was prevented by probucol. However, the mRNA and protein levels of GSHPx and CAT were not significantly changed by ADR or probucol. ADR had no effect on SOD activity but this enzyme activity was increased by probucol and probucol plus ADR. GSHPx enzyme activity was decreased and oxidative stress as indicated by TBARS was increased by ADR and these changes were also modulated by probucol. Conclusion: An increase in oxidative stress, GSHPx inactivation and MnSOD downregulation during ADR cardiomyopathy were prevented by probucol treatment.
Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy.
Authors: D Lin, A Bobkova, E Homsher, L S Tobacman
Journal: Journal of Clinical Investigation (1996)

Familial hypertrophic cardiomyopathy (HCM) can be caused by dominant missense mutations in cardiac troponin T (TnT), alpha-tropomyosin, C-protein, or cardiac myosin heavy chain genes. The myosin mutations are known to impair function, but any functional consequences of the TnT mutations are unknown. This report describes the in vitro function of troponin containing an IIe91Asn mutation in rat cardiac TnT, corresponding to the HCM-causing Ile79Asn mutation in man. Mutant and wild-type TnT cDNAs were expressed in bacteria and the proteins purified and reconstituted with the other troponin subunits, the mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, CA(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the CA2+ concentration dependence of this regulation. However, the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin in in vitro motility assays. The increased sliding speed suggests an unexpected role for the amino terminal region of TnT in which this mutation occurs. The relationship between this faster motility and altered cardiac contraction in patients with HCM is discussed.
Automaticity, triggered activity, and responses to adrenergic stimulation in cat subendocardial Purkinje fibers after healing of myocardial infarction.
Authors: S Kimura, A L Bassett, T Kohya, P L Kozlovskis, R J Myerburg
Journal: Circulation (1987)

We studied automaticity, triggered activity, and responses to alpha- and beta-adrenergic stimulation in subendocardial Purkinje fibers overlying healed infarct scars (infarct preparation) and from remote normal zones (noninfarct preparation) of cat left ventricles. The preparations were studied 2 to 4 months after ligation of multiple distal tributaries of the left anterior descending and circumflex arteries. Subendocardial Purkinje fibers from corresponding areas of normal hearts served as control samples (control preparation). Transmembrane action potential characteristics and rates of automaticity (spontaneous phase 4 depolarization) did not differ among control, noninfarct, and infarct preparations. However, overdrive at cycle lengths of less than 400 msec suppressed automaticity to a greater degree in Purkinje fibers of infarct preparations than those of control and noninfarct preparations. Changes in automatic rate during superfusion with isoproterenol (10(-10)M to 10(-6)M) were not different among the three groups of preparations, but exposure to phenylephrine (10(-9)M to 10(-5)M) in the presence of 5 X 10(-7)M propranolol reduced the automatic rate to a greater degree in Purkinje fibers of infarct preparations than those of control or noninfarct preparations. Triggered activity arising from delayed afterdepolarizations was recorded in 10 of 29 infarct preparations (34%), but not in 12 control and 10 noninfarct preparations. These afterpotentials were augmented by increasing extracellular Ca++ concentration, 10(-7)M isoproterenol, and 10(-5)M phenylephrine in the presence of 5 X 10(-7)M propranolol. We conclude that Purkinje fibers overlying healed infarct scars have altered physiology of spontaneous automaticity, enhanced responses to alpha-adrenergic interventions, and a tendency to triggered activity, and that both alpha- and beta-adrenergic effects may result in worsening of arrhythmias by augmentation of afterpotentials in healed myocardial infarction.
The Dying Experience
Authors: Robert H. Palmer
Journal: Annals of Internal Medicine (1997)

Letters1 August 1997The Dying ExperienceRobert H. Palmer, MDRobert H. Palmer, MDSmithKline Beecham Pharmaceuticals; Collegeville, PA 19426-0989Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-3-199708010-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I commend the authors of the recent paper on perceptions of the dying experience of older and seriously ill patients [1] for their efforts to characterize and improve that experience. However, some may be tempted to make inferences that are improper because the study was not controlled. Only the experiences of those patients who did die are described, and we do not know what would have been experienced by a similar set of patients who did not die. Thus, some lay reporters have inferred that the aggressive treatment given in the last 3 days of life was ...References1. Lynn J, Teno JM, Phillips RS, Wu AW, Desbiens N, Harrold J, et al. Perceptions by family members of the dying experience of older and seriously ill patients. Ann Intern Med. 1997; 126:97-106. Google Scholar Author, Article, and Disclosure InformationAffiliations: SmithKline Beecham Pharmaceuticals; Collegeville, PA 19426-0989 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByBecky's Legacy: Personal and Professional Reflections on Loss and Hope 1 August 1997Volume 127, Issue 3Page: 243KeywordsDatabasesPatientsPerceptionQuality of life Issue Published: 1 August 1997 CopyrightCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...
Evaluation of definitions for adult respiratory distress syndrome.
Authors: W A Knaus, X Sun, R B Hakim, D P Wagner
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

We conducted a cohort study of 423 intensive care unit (ICU) admissions with a primary clinical diagnosis of acute respiratory failure, a PaO2/FIO2 on ICU admission of < 300 mm Hg, and an ICD-9 discharge diagnosis of adult respiratory distress syndrome (ARDS) (518.5 or 518.82) drawn from a nationally representative database of 17,440 ICU admissions to evaluate current and proposed revisions for definitions of ARDS. A variety of nonpulmonary physiologic risk factors, from shock to elevated serum bilirubin measurements, were significant (p < 0.01) for hospital mortality. Multivariable analysis using the admission APACHE III score, primary ICU admission diagnosis, and treatment location before ICU admission provided greater accuracy in prediction (ROC = 0.80) than the individual PaO2/FIO2 (ROC = 0.68). Patients were given an individual risk of hospital mortality based on their admission APACHE III score, treatment location before ICU admission, and ICU admitting diagnosis. Dividing the patient population into groups using a PaO2/FIO2 < or = 150 resulted in a wide range of individual risk for hospital mortality, from < 10 to > 90% in both groups. We conclude that ARDS is a complex clinical entity with a variety of pulmonary and nonpulmonary risk factors for both its development and its prognosis. Current and proposed categorical definitions based on the severity of hypoxemia result in a wide distribution of individual patient risks. Use of these findings in the design and conduct of future clinical trials would improve the evaluation of new therapies.
Abstract SY24-01: Pluripotency genes as targets for cancer prevention
Authors: Kavita Dhodapkar
Journal: Cancer Research (2011)

Abstract Recent studies have suggested an overlap between the core pathways that maintain pluripotency in embryonal stem (ES) or induced pluripotency stem (iPS) cells and those implicated in oncogenesis. The presence of ES/iPS signature genes can be demonstrated in diverse cancers and correlates with a poorer outcome. The ES pathways have been shown to be particularly expressed in the putative cancer stem cell (CSC) population within the tumor bulk. Therefore pathways that regulate stemness are being actively targeted in human cancer. Here, I will discuss evidence for immune-mediated targeting of the core ES genes, such as OCT4 and SOX2 in humans. Initial studies suggested that humoral and cellular responses against SOX2 can be detected in patients with preneoplastic monoclonal gammopathy of undetermined significance (MGUS). Presence of anti-SOX2 T cell responses correlated with reduced risk of progression to clinical myeloma. Surprisingly, T cell responses against OCT4, a common marker of ES cells, can be readily detected in healthy human donors. OCT4-specific T cell response resides predominantly in the CD4+ T cell compartment and comprises of CD45RO+ memory T cells. These T cells can be readily expanded in culture using autologous dendritic cells loaded with OCT4-expressing germ cell tumors. In contrast to the finding with healthy donors, T cell immunity to OCT4 is deficient in freshly isolated circulating T cells from patients with germ cell tumors (GCTs). However, these T cells can be observed after chemotherapy-induced cell death of tumor cells in vivo. The capacity of the human immune system to target both of the core pluripotency genes (SOX2 and OCT4) may facilitate harnessing the immune system against GCTs and putative CSCs in diverse tumor types. ES-associated genes such as OCT4 seem to be dispensable for the function of adult stem cells in mice, suggesting that targeting these genes in the setting of cancer might not carry adverse effects against normal adult stem cells. As these immune responses seem to be engaged during early stages of carcinogenesis, including in preneoplastic states, we suggest that they may also be particularly attractive targets for immune-mediated cancer prevention in diverse high-risk settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-01. doi:10.1158/1538-7445.AM2011-SY24-01
Repeated inhalation challenge with exogenous and endogenous histamine released by acetaldehyde inhalation in asthmatic patients.
Authors: S Myou, M Fujimura, Y Kamio, T Bando, Y Nakatsumi, T Matsuda
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We previously reported that inhaled acetaldehyde, a metabolite of ethanol and a main factor in alcohol-induced asthma, causes bronchoconstriction indirectly through endogenously released histamine in asthmatic subjects. No study has examined the difference between tachyphylaxis in response to endogenous as opposed to exogenous histamine. Therefore, we examined tachyphylaxis occurring in response to repeated inhalation of histamine or acetaldehyde in nine asthmatic subjects. The mean acetaldehyde concentration causing a 20% decrease in FEV1 increased significantly from 18.4 (geometric standard error of the mean (GSEM = 0.14) to 45.2 (GSEM = 0.14) mg/ml over a period of 1 h (p < 0.002), whereas the mean histamine concentrations causing a 20% decrease in FEV1 were identical. No correlations were observed between the change in bronchial responsiveness to each solution and the change in baseline FEV1. These results suggest that tachyphylaxis in response to histamine is observed only when the latter is released endogenously. We believe that this is the first report suggesting tachyphylaxis caused by endogenous histamine.
Will Physician-Level Measures of Clinical Performance Be Used in Medical Malpractice Litigation?
Authors: Aaron S. Kesselheim, Timothy G. Ferris, David M. Studdert
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
Sustained phenotypic correction of hemophilia a mice following oncoretroviral-mediated expression of a bioengineered human factor VIII gene in long-term hematopoietic repopulating cells
Authors: Morvarid Moayeri, Ali Ramezani, Richard A. Morgan, Teresa S. Hawley, Robert G. Hawley
Journal: Molecular Therapy (2004)

Hematopoietic stem cells (HSCs) are an attractive target cell population for hemophilia A gene therapy because of their capacity to regenerate the hematolymphoid system permanently following transplantation. Here we transplanted bone marrow (BM) cells transduced with a splicing-optimized MSCV oncoretroviral vector expressing a secretion-improved human factor VIII gene into immunocompromised hemophilic mice that had received a reduced dose conditioning regimen. An enhanced green fluorescent protein (EGFP) reporter gene linked to an encephalomyocarditis virus internal ribosome entry site was incorporated into the vector to allow preselection of transduced cells and facile evaluation of engraftment. Sustained expression of EGFP was demonstrated in the peripheral blood, and therapeutic levels of factor VIII were detected in the plasma of the majority of the recipients for the duration of the observation period (up to 22 weeks). Coordinate expression of factor VIII and EGFP (up to 19 weeks) was transferred to secondary BM transplant recipients, indicating that long-term repopulating HSCs had been successfully gene modified. Notably, the hemophilic phenotype of all treated mice was corrected, thus demonstrating the potential of HSC-directed oncoretroviral-mediated factor VIII gene transfer as a curative therapeutic strategy for hemophilia A.
Childhood Cancer: Patterns of Protocol Participation in a National Survey
Authors: S. J. Shochat, A. M. Fremgen, S. B. Murphy, C. Hutchison, S. S. Donaldson, G. M. Haase, A. J. Provisor, R. E. Clive-Bumpus, D. P. Winchester
Journal: CA A Cancer Journal for Clinicians (2001)

Cancer is still the chief cause of death by disease in children, ages one to 14. As improved survival rates have been reported for pediatric cancer patients who are treated on controlled clinical trials, it is important to understand the national utilization of such protocols. In 1993, a survey of childhood cancer was conducted by the Commission on Cancer of the American College of Surgeons. Data regarding type of disease, protocol participation, age, sex, race, insurance, and geographical region were voluntarily submitted by more than 200 hospital cancer registries. Included in this study were 2,208 children and adolescents 21 years of age or younger who were diagnosed in 1987, and 2,293 who were diagnosed in 1992. Pediatric centers (i.e., members of the Pediatric Oncology Group or Children's Cancer Group) submitted 55.1% of the cases and other institutions, 44.9%. It was found that more patients treated at pediatric centers were on protocols (53.8%) than were those treated at other institutions (25.1%). In general, the younger the patient (five years of age or younger), the greater the chance of being on protocol (pediatric centers, 63.7%; others, 42.0%), with very poor adolescent protocol participation (pediatric centers, 34.8%; others, 12.1%). Nevertheless, overall protocol participation was still lower than expected, even in children younger than five years of age, and adolescent participation in controlled clinical trials was low and similar to adult figures. The percentage of childhood cancer cases seen at pediatric centers was smaller than in other series. It was concluded that pediatric cancer centers need to continue to encourage patient participation in controlled clinical trials, with special emphasis on adolescents.
Deprivation payments revisited (again)
Authors: R. Hobbs, T. Cole
Journal: BMJ (1996)

With the rising workload in general practice and an emerging manpower crisis, destabilising influences such as unpredictable shifts in income are to be avoided. Unfortunately, continuing to allocate deprivation payments to practices on the basis of geographical wards has resulted in large shifts in resources. This is because data from the 1991 census have now replaced the 1981 data, which had been used to calculate deprivation payments since the introduction of the new general practitioner contract in 1990.1 The short report in this week's BMJ by Majeed et al (p 669) models the effects of applying census data to the existing rigid formula for allocating deprivation awards. Small shifts in the Jarman deprivation score around the payment bands can translate to practices gaining or losing tens of thousands of pounds, with no discernible change in their clinical workloads: one practice reported a 15% shift in income after a change in a ward boundary.2 Such a lottery of winners and losers has been predicted since the introduction of deprivation payments,3 4 5 and it is depressing that nothing has …
Eosinophilic spongiosis, a clinical, histological and immunofluorescent correlation
Authors: A. G. Knight, T. J. Delaney, M. M. Black
Journal: British Journal of Dermatology (1975)

Journal Article Eosinophilic spongiosis, a clinical, histological and immunofluorescent correlation Get access A. G. Knight, A. G. Knight Department of Histopathology, London Search for other works by this author on: Oxford Academic Google Scholar T. J. Delaney, T. J. Delaney Institute of Dermatology, WC2, London, Department of Dermatology Search for other works by this author on: Oxford Academic Google Scholar M. M. Black M. M. Black St George's Hospital, SW1, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 93, Issue s11, 1 July 1975, Page 13, https://doi.org/10.1111/j.1365-2133.1975.tb06760.x Published: 01 July 1975
Epilepsy: a presentation of the Romano-Ward syndrome.
Authors: F W Ballardie, R P Murphy, J Davis
Journal: BMJ (1983)

A propos d'une famille dans laquelle 2 filles sont deja mortes au cours de convulsions de type «grand mal», et une autre fille presente des crises convulsives. L'intervalle Q-T est prolonge. 3 autres membres de la famille presentent aussi un intervalle Q-T prolonge. Il s'agit du syndrome de Romano-Ward