tbuckley/cabot-search huggingface dataset:
Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic <i>BRAF</i>-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor
Authors: Kevin B. Kim, Richard Kefford, Anna C. Pavlick, Jeffrey R. Infante, Antoni Ribas, Jeffrey A. Sosman, Leslie A. Fecher, Michael Millward, Grant A. McArthur, Patrick Hwu, Rene Gonzalez, Patrick A. Ott, Georgina V. Long, Olivia S. Gardner, Daniele Ouellet, Yanmei Xu, Douglas J. DeMarini, Ngocdiep T. Le, Kiran Patel, Karl D. Lewis
Journal: Journal of Clinical Oncology (2012)

BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery
Authors: José González-Alonso, David B. Olsen, Bengt Saltin
Journal: Circulation Research (2002)

Blood flow to contracting skeletal muscle is tightly coupled to the oxygenation state of hemoglobin. To investigate if ATP could be a signal by which the erythrocyte contributes to the regulation of skeletal muscle blood flow and oxygen (O2) delivery, we measured circulating ATP in 8 young subjects during incremental one-legged knee-extensor exercise under conditions of normoxia, hypoxia, hyperoxia, and CO+normoxia, which produced reciprocal alterations in arterial O2 content and thigh blood flow (TBF), but equal thigh O2 delivery and thigh O2 uptake. With increasing exercise intensity, TBF, thigh vascular conductance (TVC), and femoral venous plasma [ATP] augmented significantly (P<0.05) in all conditions. However, with hypoxia, TBF, TVC, and femoral venous plasma [ATP] were (P<0.05) or tended (P=0.14) to be elevated compared with normoxia, whereas with hyperoxia they tended to be reduced. In CO+normoxia, where femoral venous O2Hb and (O2+CO)Hb were augmented compared with hypoxia despite equal arterial deoxygenation, TBF and TVC were elevated, whereas venous [ATP] was markedly reduced. At peak exercise, venous [ATP] in exercising and nonexercising limbs was tightly correlated to alterations in venous (O2+CO)Hb (r2=0.93 to 0.96; P<0.01). Intrafemoral artery infusion of ATP at rest in normoxia (n=5) evoked similar increases in TBF and TVC than those observed during exercise. Our results in humans support the hypothesis that the erythrocyte functions as an O2 sensor, contributing to the regulation of skeletal muscle blood flow and O2 delivery, by releasing ATP depending on the number of unoccupied O2 binding sites in the hemoglobin molecule.
p53 protein expression in cutaneous T-cell lymphomas
Authors: A. F. LAURITZEN, G. L. VEJLSGAARD, K. HOU-JENSEN, E. RALFKIAER
Journal: British Journal of Dermatology (2006)

p53 is an oncosuppressor gene located on chromosome 17p. Point mutations of the p53 gene are seen frequently in human malignancies, and are closely associated with malignant transformation under in vitro conditions. Mutated p53 protein shows a slow cell turnover rate, and accumulates in cells at the nuclear and/or cytoplasmic level. As a result, mutated p53 protein can be detected more readily by immunohistology than the wild-type protein. In this study, we used a monoclonal anti-p53 antibody (clone D07) to examine the expression of p53 protein in 25 cutaneous T-cell lymphomas (CTCL) of low- and high-grade malignancy, i.e. mycosis fungoides (n = 6), Sézary's syndrome (n = 2), and large cell lymphomas of pleomorphic (n = 14) or anaplastic (n= 3) subtype. The results showed that easily detectable p53 protein was present in many of the neoplastic cells in half of the high-grade lymphomas. In contrast, in the low-grade lymphomas no, or only very few, p53-positive neoplastic cells could be detected. These findings suggest that molecular and/or genetic alterations of p53 may be implicated in the pathogenesis of high-grade CTCL, but are unlikely to be of critical importance in low-grade CTCL.
Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon assay
Authors: G Matulis, P Juni, P M Villiger, S D Gadola
Journal: Annals of the Rheumatic Diseases (2007)

To analyse the performance of a new M. tuberculosis-specific interferon gamma (IFNgamma) assay in patients with chronic inflammatory diseases who receive immunosuppressive drugs, including tumour necrosis factor alpha (TNFalpha) inhibitors.Cellular immune responses to the M. tuberculosis-specific antigens ESAT-6, CFP-10, TB7.7 were prospectively studied in 142 consecutive patients treated for inflammatory rheumatic conditions. Results were compared with tuberculin skin tests (TSTs). Association of both tests with risk factors for latent M. tuberculosis infection (LTBI) and BCG vaccination were determined and the influence of TNFalpha inhibitors, corticosteroids, and disease modifying antirheumatic drugs (DMARDs) on antigen-specific and mitogen-induced IFNgamma secretion was analysed.126/142 (89%) patients received immunosuppressive therapy. The IFNgamma assay was more closely associated with the presence of risk factors (odds ratio (OR) = 23.8 (95% CI 5.14 to 110) vs OR = 2.77 (1.22 to 6.27), respectively; p = 0.009), but less associated with BCG vaccination than the TST (OR = 0.47 (95% CI 0.15 to 1.47) vs OR = 2.44 (0.74 to (8.01), respectively; p = 0.025). Agreement between the IFNgamma assay and TST results was low (kappa = 0.17; 95% CI 0.02 to 0.32). The odds for a positive IFNgamma assay strongly increased with increasing prognostic relevance of LTBI risk factors. Neither corticosteroids nor conventional DMARDs significantly affected IFNgamma responses, but the odds for a positive IFNgamma assay were decreased in patients treated with TNFalpha inhibitors (OR = 0.21 (95% CI 0.07 to 0.63), respectively; p = 0.006).These results demonstrate that the performance of the M. tuberculosis antigen-specific IFNgamma ELISA is better than the classic TST for detection of LTBI in patients receiving immunosuppressive therapy for treatment of systemic autoimmune disorders.
Targeting the Right Treatments for Neuroblastoma
Authors: N. J. Nelson
Journal: JNCI Journal of the National Cancer Institute (2011)

L ike most childhood cancers, neuroblastoma is relatively rare. But it is the most commonly diagnosed cancer in the first year of life, and more than half of children diagnosed develop aggressive forms of the disease that are difficult to cure. “Not only are there a lot of deaths in the high-risk population, but high-risk patients require very, very intensive therapy to cure them,” said Darrell Yamashiro, M.D., Ph.D., professor of pediatrics and pathology at the Columbia University Medical Center in New York. “These treatments include autologous bone marrow and stem cell transplant, so the morbidity associated with these is signifi cant as well.” Most of today ’ s research focuses on improving the survival of these high-risk children. With more than 100 trials actively recruiting patients, most for relapsed or unresponsive patients, researchers are testing a broad range of treatments. Among them are various kinase inhibitors, vaccines, and methods of stimulating the immune system, as well as new combinations of standard chemotherapies and radiation. “It ’ s an exciting time for clinical scientists but also a challenging time for physicians and parents,” said Peter Zage, M.D., Ph.D., assistant professor in the department of pediatrics at Baylor College of Medicine in Houston. “There is a wide range of new drugs and treatment strategies available for children with neuroblastoma.”
Serum Lipid Levels in Patients With Dissociative Disorder
Authors: Mehmet Yücel Agargun, Ömer Akil Özer, Hayrettin Kara, Ramazan Şekeroğlu, Yavuz Selvi, Buket Eryonucu
Journal: American Journal of Psychiatry (2004)

There may be an association between a low serum cholesterol level and dissociative disorders.The subjects of the study were 16 patients with dissociative disorder and 16 normal comparison subjects (two men and 14 women in each group). Total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein levels were compared.Patients with dissociative disorders had lower serum triglyceride, total cholesterol, low-density lipoprotein, and very low density lipoprotein levels than normal comparison subjects.Low serum lipid concentrations may be related to a high incidence of self-injurious behaviors and borderline features in patients with dissociative disorders.
Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer
Authors: José Baselga, Milvia Zambetti, Antoni Llombart-Cussac, Georgy Manikhas, Ernst Kubista, Günther G. Steger, Anatoly Makhson, Sergei Tjulandin, Heinz Ludwig, Mark Verrill, Eva Ciruelos, Suzanne Egyhazi, Li-An Xu, Kim E. Zerba, Hyerim Lee, Edwin Clark, Susan Galbraith
Journal: Journal of Clinical Oncology (2008)

This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations.Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles.One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in <or= 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. CONCLUSION ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR.indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.
A MENINGO-ENCEPHALITIS IN CHICKS PRODUCED BY THE INTRACEREBRAL INJECTION OF FOWL POX VIRUS
Authors: G. John Buddingh
Journal: The Journal of Experimental Medicine (1938)

1. Intracerebral inoculation of fowl pox virus in young chicks produces a disease characterized by the development of drowsiness and somnolence 4 to 5 days after inoculation. This is followed by spastic paralysis and convulsions on the 6th and 7th day. The majority of inoculated chicks die on the 7th or 8th day. 2. The pathological lesions are found chiefly in the meninges, perivascular structures, the choroid plexus, paranasal sinuses, mastoid cells, the bone marrow of the cranial bones, and the orbital tissues. No affinity for nervous tissue per se develops. 3. In this environment the virus has a high virulence for the choroidal plexus epithelium and acquires the capacity for infecting cells of mesodermal origin. All infected cells of whatever origin undergo a similar structural change. Fowl pox inclusions can be demonstrated within them and they become spherical in shape and detached from each other. 4. The virus has been carried through 14 successive intracerebral passages. The symptoms and lesions in the chicks inoculated with the 14th passage showed no marked difference from those of the first passage. No enhancement of the changes brought about in the virus by the intracerebral environment seems to take place upon repeated passage.
Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta.
Authors: B Tesfamariam, M L Brown, D Deykin, R A Cohen
Journal: Journal of Clinical Investigation (1990)

The effects of glucose on endothelium-dependent responses and vasoactive prostanoid production were determined by incubating isolated rabbit aortae in control (5.5 or 11 mM) or elevated (44 mM) glucose for 6 h to mimic euglycemic and hyperglycemic conditions. Rings of aortae incubated in elevated glucose, contracted submaximally by phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with the aortae incubated in control glucose. Treatment with indomethacin, a cyclooxygenase inhibitor, or SQ29548, a prostaglandin H2/thromboxane A2 receptor antagonist, restored acetylcholine relaxations of rings in elevated glucose to normal, while these agents had no effect on the relaxation of rings incubated in control glucose. Aortae incubated with mannose (44 mM) as a hyperosmotic control relaxed to acetylcholine normally. The relaxations in response to A23187 and sodium nitroprusside were not different between rings exposed to control and elevated glucose. Radioimmunoassay measurements showed a significant increase in acetylcholine-stimulated release of thromboxane A2 and prostaglandin F2 alpha in aortae with, but not without endothelium incubated with elevated, but not with control glucose. Thus a possible mechanism for endothelium dysfunction in diabetes mellitus is the hyperglycemia-induced increased generation of endothelium-derived vasoconstrictor prostanoids.
Identification of Allorecognition Loci in<i>Neurospora crassa</i>by Genomics and Evolutionary Approaches
Authors: Jiuhai Zhao, Pierre Gladieux, Elizabeth Hutchison, Joanna Bueche, Charles Hall, Fanny Perraudeau, N. Louise Glass
Journal: Molecular Biology and Evolution (2015)

Understanding the genetic and molecular bases of the ability to distinguish self from nonself (allorecognition) and mechanisms underlying evolution of allorecognition systems is an important endeavor for understanding cases where it becomes dysfunctional, such as in autoimmune disorders. In filamentous fungi, allorecognition can result in vegetative or heterokaryon incompatibility, which is a type of programmed cell death that occurs following fusion of genetically different cells. Allorecognition is genetically controlled by het loci, with coexpression of any combination of incompatible alleles triggering vegetative incompatibility. Herein, we identified, characterized, and inferred the evolutionary history of candidate het loci in the filamentous fungus Neurospora crassa. As characterized het loci encode proteins carrying an HET domain, we annotated HET domain genes in 25 isolates from a natural population along with the N. crassa reference genome using resequencing data. Because allorecognition systems can be affected by frequency-dependent selection favoring rare alleles (i.e., balancing selection), we mined resequencing data for HET domain loci whose alleles displayed elevated levels of variability, excess of intermediate frequency alleles, and deep gene genealogies. From these analyses, 34 HET domain loci were identified as likely to be under balancing selection. Using transformation, incompatibility assays and genetic analyses, we determined that one of these candidates functioned as a het locus (het-e). The het-e locus has three divergent allelic groups that showed signatures of positive selection, intra- and intergroup recombination, and trans-species polymorphism. Our findings represent a compelling case of balancing selection functioning on multiple alleles across multiple loci potentially involved in allorecognition.
Pseudohypoxic Pathways in Renal Cell Carcinoma
Authors: Gennady Bratslavsky, Sunil Sudarshan, Len Neckers, W. Marston Linehan
Journal: Clinical Cancer Research (2007)

Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor-alpha. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions. Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches.
P182 Appraisal Of An Indwelling Pleural Catheter (ipc) Service At A Large Acute Trust
Authors: R. Mercer, S. Gunatilake, L. Bishop, K. Babu, A. Chauhan
Journal: Thorax (2014)

<h3>Introduction</h3> Data on indications, outcomes and complications of IPCs from clinical trials has been published.<sup>1</sup> This audit examined differences in practice and outcomes between clinical trials and day-to-day working which may influence the pleural service and provide information to other hospitals considering introducing this service. <h3>Method</h3> We retrospectively reviewed patient-related data and outcomes for IPCs inserted at our hospital from February 2011 until December 2013. We compared the findings to secondary outcomes of the IPC arm of the TIME2 trial.<sup>1</sup> <h3>Results</h3> 102 IPCs were placed into 93 patients: 43 as inpatients; 59 as outpatients. 20 inpatients and 23 outpatients had previous talc pleurodesis. 10 patients had microbiological isolation of pleural fluid throughout a total of 27.3 IPC years; not all were associated with clinical signs of a pleural infection. Only 12 (50%) patients with a C-reactive protein of &gt;200 mg/l had a sample of their pleural fluid sent for culture. Drain removal occurred in 23% of the inpatient IPCs and 29% of the outpatient compared to 57% in the TIME2 trial. The median inpatient stay after elective pleurodesis in an outpatient was 1.5 nights in 2011 (range 0–11), 1 night in 2012 (range 0–5) and 0 nights in 2013 (range 0–5). <h3>Conclusion</h3> The TIME2 cost analysis was based on a median stay of 0 nights which has been replicated in our hospital this year. The optimisation of community support and increasing confidence with the procedure led to reductions in inpatient stays. The rate of IPC removal was substantially less common in our cohort and the indication for removal was often not due to spontaneous pleurodesis alone unlike the TIME2 trial. Indications for removal included infection, pain and blockage as well as pleurodesis. The data from our centre did not exclude any patients, including those who died, and the follow up period often continued beyond 6 months. Some large differences exist between the TIME2 trial data and our cohort. While this could reflect a different patient population and setting, it could also highlight differences in outcomes between controlled clinical trials and day-to-day practice. <h3>Reference</h3> Davies HE <i>et al</i>. <i>JAMA </i>2012;307(22):2383–9
New Molecular Mechanism in Diastolic Heart Failure
Authors: Arnold M. Katz, Michael R. Zile
Journal: Circulation (2006)

n contrast to systolic heart failure (SHF), for which knowledge of pathophysiology and therapy has advanced rapidly over the past decade, little is known about diastolic heart failure (DHF).The article by van Heerebeek et al 1 in this issue of Circulation that describes an abnormal distribution of titin isoforms in DHF may herald a new approach to understanding the pathophysiology of this syndrome. Article p 1966Recognition of 2 forms of heart failure is not new; almost 70 years ago, Fishberg 2 described "those forms of cardiac insufficiency which are due to inadequate diastolic filling of the heart (hypodiastolic failure) [and] the far more common ones in which the heart fills adequately but does not empty to the normal extent (hyposystolic failure)" (p 23).This distinction has stood the test of time, because there is a growing consensus that these 2 clinical syndromes differ in epidemiology, demographics, and origin.Because DHF and SHF represent subgroups of patients with heart failure, they share many clinical features, notably the hemodynamic findings, but it is now clear that they are caused by different pathophysiological mechanisms.Hearts in SHF are characterized by eccentric hypertrophy, progressive left ventricular (LV) dilation, and abnormal LV systolic properties, whereas in DHF, the hearts generally exhibit concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function. 3,4In addition, cardiomyocyte size, shape, and molecular composition differ in these 2 syndromes.