tbuckley/cabot-search huggingface dataset:
MICROCIRCULATORY DYSFUNCTION IN HIV INFECTED PATIENTS
Authors: Ignatios Ikonomidis, John Lekakis, Sotirios Tsiodras, John Palios, Garyfalia Poulakou, Periklis Panagopoulos, Periklis Panagopoulos, Antonios Papadopoulos, Anastasia Antoniadou, Helen Giamarellou, Dimitrios Kremastinos
Journal: Journal of the American College of Cardiology (2010)
Cytotoxic T Cell Responses against Mesothelioma by Apoptotic Cell-pulsed Dendritic Cells
Authors: Frédéric Ebstein, Carole Sapede, Pierre-Joseph Royer, Marie Marcq, Catherine Ligeza-Poisson, Isabelle Barbieux, Laurent Cellerin, Gérard Dabouis, Marc Grégoire
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Malignant pleural mesothelioma is an uncommon tumor largely confined to the thoracic cavity, which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2+ DCs from healthy donors was apoptotic HLA-A2− mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-α and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2+ mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an HLA-A2+ melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative, promising approach for the therapy of patients with malignant pleural mesothelioma.
Thoracoscopic sympathicolysis for essential hyperhidrosis: effects on pulmonary function
Authors: M Noppen, W Vincken
Journal: European Respiratory Journal (1996)

Bilateral interruption of the upper dorsal sympathetic chain at the D2 and D3 level represents the only permanent cure for essential hyperhidrosis. Following surgical sympathectomy, significant and symptomatic changes in pulmonary function have been observed. Since functional effects of the surgical intervention cannot be excluded, we wondered whether such alterations also occurred after thoracoscopic sympathicolysis; these should then be attributable to the surgical denervation itself. Pulmonary function tests (PFTs), including spirometry and body plethysmographic measurement of lung volumes and airway resistance and conductance, were compared before and 6 weeks after thoracoscopic sympathicolysis in 47 patients. In order to virtually exclude any effects of thoracoscopy on the test results PFTs were repeated 6 months after thoracoscopic sympathicolysis in 35 patients. Essential hyperhidrosis was completely relieved in all patients, thereby confirming the interruption of the D2-D3 sympathetic chain. None of the patients developed respiratory symptoms after thoracoscopic sympathicolysis. Forced expiratory volume in one second (FEV1) (-3%), forced expiratory flow after exhaling 75% of vital capacity (FEF75) (-8%) and total lung capacity (TLC) (-3%) were slightly but significantly reduced at six weeks after thoracoscopic sympathicolysis; whereas airway resistance (Raw) had increased (+12%). After correction for the small decrease in lung volume (FEV1/forced vital capacity (FVC), specific airway resistance (sRaw), specific airway conductance (sGaw))significant changes in "volume-dependent" PFT parameters were no longer observed. Smoking status had no influence on the reduction in FEF75. At 6 months after thoracoscopic sympathicolysis, TLC had returned to preoperative values, whereas FEF75 remained decreased (-8.6%). The decrease in airway calibre was confirmed by small but significant changes in FEV1/FVC (-2%) and Raw (+29%). We conclude that thoracoscopic sympathicolysis in patients with essential hyperhidrosis causes only minimal and subclinical changes in pulmonary function secondary to a temporary small decrease in lung volume, which in turn is probably inherent to the thoracoscopic procedure. D2-D3 sympathicolysis, in itself, is responsible only for a small and permanent decrease in forced expiratory flow, which suggests that, at least in essential hyperhidrosis patients, airway bronchomotor tone is influenced by sympathetic innervation.
Complex I Dysfunction and Tolerance to Nitroglycerin
Authors: Juan V. Esplugues, Milagros Rocha, Cristina Nuñez, Irene Bosca, Sales Ibiza, Jose R. Herance, Angel Ortega, Juan M. Serrador, Pilar D’Ocon, Victor M. Victor
Journal: Circulation Research (2006)

Nitroglycerin (GTN) tolerance was induced in vivo (rats) and in vitro (rat and human vessels). Electrochemical detection revealed that the incubation dose of GTN (5×10 −6 mol/L) did not release NO or modify O 2 consumption when administered acutely. However, development of tolerance produced a decrease in both mitochondrial O 2 consumption and the K m for O 2 in animal and human vessels and endothelial cells in a noncompetitive action. GTN tolerance has been associated with impairment of GTN biotransformation through inhibition of aldehyde dehydrogenase (ALDH)-2, and with uncoupling of mitochondrial respiration. Feeding rats with mitochondrial-targeted antioxidants (mitoquinone [MQ]) and in vitro coincubation with MQ (10 −6 mol/L) or glutathione (GSH) ester (10 −4 mol/L) prevented tolerance and the effects of GTN on mitochondrial respiration and ALDH-2 activity. Biotransformation of GTN requires functionally active mitochondria and induces reactive oxygen species production and oxidative stress within this organelle, as it is inhibited by mitochondrial-targeted antioxidants and is absent in HUVECρ 0 cells. Experiments analyzing complex I–dependent respiration demonstrate that its inhibition by GTN is prevented by mitochondrial-targeted antioxidants. Furthermore, in presence of succinate (10×10 −3 mol/L), a complex II electron donor added to bypass complex I–dependent respiration, GTN-treated cells exhibited O 2 consumption rates similar to those of controls, thus suggesting that complex I was affected by GTN. We propose that, following prolonged treatment with GTN in addition to ALDH-2, complex I is a target for mitochondrially generated reactive oxygen species. Our data also suggest a role for mitochondrial-targeted antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use.
Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents
Authors: Janet E. Dancey, Kevin K. Dobbin, Susan Groshen, J. Milburn Jessup, Andrew H. Hruszkewycz, Maria Koehler, Ralph Parchment, Mark J. Ratain, Lalitha K. Shankar, Walter M. Stadler, Lawrence D. True, Amy Gravell, Michael R. Grever
Journal: Clinical Cancer Research (2010)

The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) charged the Biomarker Task Force to develop recommendations to improve the decisions about incorporation of biomarker studies in early investigational drug trials. The Task Force members reviewed biomarker trials, the peer-reviewed literature, NCI and U.S. Food and Drug Administration (FDA) guidance documents, and conducted a survey of investigators to determine practices and challenges to executing biomarker studies in clinical trials of new drugs in early development. This document provides standard definitions and categories of biomarkers, and lists recommendations to sponsors and investigators for biomarker incorporation into such trials. Our recommendations for sponsors focus on the identification and prioritization of biomarkers and assays, the coordination of activities for the development and use of assays, and for operational activities. We also provide recommendations for investigators developing clinical trials with biomarker studies for scientific rationale, assay criteria, trial design, and analysis. The incorporation of biomarker studies into early drug trials is complex. Thus the decision to proceed with studies of biomarkers should be based on balancing the strength of science, assay robustness, feasibility, and resources with the burden of proper sample collection on the patient and potential impact of the results on drug development. The Task Force provides these guidelines in the hopes that improvements in biomarker studies will enhance the efficiency of investigational drug development.
Comorbidity of Axis I and Axis II Disorders in Patients Who Attempted Suicide
Authors: Keith Hawton, Kelly Houston, Camilla Haw, Ellen Townsend, Louise Harriss
Journal: American Journal of Psychiatry (2003)

The authors compared the characteristics of suicide attempters with and without comorbid psychiatric and personality disorders to identify factors that explain the high suicide risk associated with psychiatric comorbidity.A representative group of 111 patients who had attempted suicide (72 female and 39 male) was assessed for psychiatric and personality disorders according to ICD-10 criteria. The characteristics of patients with both types of disorder were compared with those of patients without comorbid disorders. A semistructured interview schedule and standardized questionnaires were used to investigate patients' background characteristics, the circumstances of the suicide attempts, psychological characteristics, and outcome after 12-20 months.Comorbidity of psychiatric and personality disorders was present in 49 patients (44%). More patients with comorbid disorders had made previous suicide attempts (N=41 [84%] versus N=28 [45%]) and repeated attempts during the follow-up period (N=25 [51%] versus N=9 [15%]). Differences in precipitants and motives for the index episode were also found: patients with comorbid disorders were more depressed and hopeless, reported more episodes of aggression, were more impulsive, and had lower self-esteem and poorer problem-solving skills. Differences in self-esteem and problem-solving skills distinguished between the groups in a stepwise discriminant function analysis. More of the patients with comorbid disorders reported not being loved by their parents and parental suicidal behavior.Suicide attempters with comorbid psychiatric and personality disorders show marked differences from those without both of these disorders. Comorbidity may contribute to greater suicide risk. Some of the characteristics of patients with comorbid disorders pose major clinical challenges that should be addressed in an effort to reduce suicide risk.
Prospective Study of <sup>68</sup>Ga-NOTA-NFB: Radiation Dosimetry in Healthy Volunteers and First Application in Glioma Patients
Authors: Zhe Wang, Mingru Zhang, Liang Wang, Shengjun Wang, Fei Kang, Guoquan Li, Orit Jacobson, Gang Niu, Weidong Yang, Jing Wang, Xiaoyuan Chen
Journal: Theranostics (2015)

The chemokine receptor CXCR4 is overexpressed in various types of human cancers. As a specific imaging agent of CXCR4, (68)Ga-NOTA-NFB was investigated in this study to assess its safety, biodistribution and dosimetry properties in healthy volunteers, and to preliminarily evaluate its application in glioma patients.Six healthy volunteers underwent whole-body PET scans at 0, 0.5, 1, 2 and 3 h after (68)Ga-NOTA-NFB injection (mean dose, 182.4 ± 3.7 MBq (4.93 ± 0.10 mCi)). For time-activity curve calculations, 1 mL blood samples were obtained at 1, 3, 5, 10, 30, 60, 90, 120, 150 and 180 min after the injection. The estimated radiation doses were calculated by OLINDA/EXM software. Eight patients with glioma were enrolled and underwent both (68)Ga-NOTA-NFB and (18)F-FDG PET/CT scans before surgery. The expression of CXCR4 on the resected brain tumor tissues was determined by immunohistochemical staining.(68)Ga-NOTA-NFB was safe and well tolerated by all subjects. A rapid activity clearance from the blood circulation was observed. The organs with the highest absorbed doses were spleen (193.8 ± 32.5 μSv/MBq) and liver (119.3 ± 25.0 μSv/MBq). The mean effective dose was 25.4 ± 6.1 μSv/MBq. The maximum standardized uptake values (SUVmax) and the maximum target to non-target ratios (T/NTmax) of (68)Ga-NOTA-NFB PET/CT in glioma tissues were 4.11 ± 2.90 (range, 0.45-8.21) and 9.21 ± 8.75 (range, 3.66-24.88), respectively, while those of (18)F-FDG PET/CT were 7.34 ± 2.90 (range, 3.50-12.27) and 0.86 ± 0.41 (range, 0.35-1.59). The histopathological staining confirmed that CXCR4 was overexpressed on resected tumor tissues with prominent (68)Ga-NOTA-NFB uptake.With a favorable radiation dosimetry profile, (68)Ga-NOTA-NFB is safe for clinical imaging. Compared to (18)F-FDG PET/CT, (68)Ga-NOTA-NFB PET/CT is more sensitive in detecting glioma and could have potential in diagnosing and treatment planning for CXCR4 positive patients.
Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer
Authors: Ian E. Krop, Muralidhar Beeram, Shanu Modi, Suzanne F. Jones, Scott N. Holden, Wei Yu, Sandhya Girish, Jay Tibbitts, Joo-Hee Yi, Mark X. Sliwkowski, Fred Jacobson, Stuart G. Lutzker, Howard A. Burris
Journal: Journal of Clinical Oncology (2010)

Purpose Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Patients and Methods Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Results Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels &lt; 10 ng/mL. Clearance at doses &lt; 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade &gt; 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. Conclusion At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
Severe Bronchiectasis in Patients with “Cystlike” Structures within the Ciliary Shafts
Authors: KENNETH W. T. TSANG, GEORGE TIPOE, JUNE SUN, JAMES C. M. HO, BING LAM, LING ZHENG, GAIK C. OOI, MARY IP, WAH-KIT LAM
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Cilia are minute hairlike structures which sweep the respiratory tract clean by continuous beating. Ciliary dysfunction can occur which leads to development of bronchiectasis. We describe the clinical and investigation profiles of four patients who had early-onset severe and otherwise idiopathic bronchiectasis associated with a previously undescribed ciliary defect in which numerous cystlike structures are present within the ciliary shafts. The patients had otherwise normal ciliary microtubular ultrastructure and central microtubular orientation. Our newly described ciliary abnormality appears to be a primary defect and more systematic studies should be performed to evaluate this further.
Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ
Authors: Ana Textor, Joanna J. Listopad, Lara Le Wührmann, Cynthia Perez, Anna Kruschinski, Markus Chmielewski, Hinrich Abken, Thomas Blankenstein, Jehad Charo
Journal: Cancer Research (2014)

Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.
The failing human heart
Authors: N Alpert
Journal: Cardiovascular Research (2002)

Heart failure remains a significant public health problem with an unacceptably high morbidity and mortality affecting about three persons per thousand per year [1]. The percent survival following diagnosis decreases significantly as a function of the severity of the disease with survival rates for NYHA (New York Heart Association) I–II being 65% at the end of 4 years, for NYHA III it is 50% at the 4-year period and for NYHA IV it is 50% after only 1 year [2,3],1. In the patients with heart failure, there is a significant correlation between survivability and ejection fraction [4]. The deficits in ventricular function in failing human hearts led us to examine the contributions of the contractile (acto–myosin interaction) and excitation–contraction–coupling (EC) (calcium cycling) systems to that insufficiency.

### 2.1 Myofibrillar ATPase activity and velocity of shortening

The first demonstration of a molecular alteration in the contractile system of human failing hearts was found in studies carried out on myofibrils from failing hearts (secondary to hypertensive heart disease) and non failing hearts (accident victims) [5]. The myofibrillar ATPase activity in the failing human hearts was reduced from non failing values (mean±S.D.)2 of 0.99±0.05 to 0.69±0.04 μmole Pi/mg myofibrillar protein/15 min ( P <0.001). The functional consequences of the depressed ATPase activity were not completely clear at the time these experiments were carried out although we believed the depressed activity was associated with a decrease in contractility of the heart muscle. This view was supported by a decrease in the contractility of actomyosin strands [6] and glycerinated fibers [7] from failing heart muscle. From the perspective of ventricular function, the decreased contractility involves contractile force, velocity of shortening or a combination of the two. The relationship between force and velocity of shortening was thoroughly described by Hill [8] where the hyperbolic relationship was believed to be … 

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Reduced selenium in asthmatic subjects in New Zealand.
Authors: A Flatt, N Pearce, C D Thomson, M R Sears, M F Robinson, R Beasley
Journal: Thorax (1990)

Selenium is an essential component of glutathione peroxidase, an enzyme that helps protect cells against oxidation damage and modulates the lipoxygenase pathway of arachidonic acid metabolism. Low selenium concentrations might therefore influence the inflammatory process in asthma by reducing the activity of glutathione peroxidase. Whole blood and plasma selenium concentrations and glutathione peroxidase activity have been measured in 56 asthmatic patients and 59 non-asthmatic control subjects in New Zealand, a country with a low dietary selenium intake and a high prevalence of asthma. When compared with control subjects the asthmatic patients had lower values for whole blood selenium concentrations (-4.9, 95% confidence interval -10.2 to 0.4 ng/ml) and glutathione peroxidase activity (-3.3, 95% CI -5.8 to -0.8 units/g Hb). There was a 1.9 and 5.8 fold increased risk of asthma in subjects with the lowest range of whole blood selenium concentration and glutathione peroxidase activity respectively (95% CI 0.6 to 5.6 and 1.6 to 21.2). Levels were lower in patients and control subjects without an atopic predisposition, but were not affected by prednisone use. Similar differences between the asthmatic and control subjects were not observed for selenium concentration or glutathione peroxidase activity measured in plasma, which reflects short term rather than long term selenium content. These findings are consistent with the hypothesis that low selenium concentrations may have a role in the pathogenesis of asthma in New Zealand.
Relationship of Oxidized Phospholipids on Apolipoprotein B-100 Particles to Race/Ethnicity, Apolipoprotein(a) Isoform Size, and Cardiovascular Risk Factors
Authors: Sotirios Tsimikas, Paul Clopton, Emmanouil S. Brilakis, Santica M. Marcovina, Amit Khera, Elizabeth R. Miller, James A. de Lemos, Joseph L. Witztum
Journal: Circulation (2009)

Background— Elevated levels of oxidized phospholipids (OxPLs) on apolipoprotein B-100 particles (OxPL/apoB) are associated with cardiovascular disease and predict new cardiovascular events. Elevated lipoprotein (a) [Lp(a)] levels are a risk factor for cardiovascular disease in whites and also in blacks if they carry small apolipoprotein(a) [apo(a)] isoforms. The relationship of OxPL/apoB levels to race/ethnicity, cardiovascular risk factors, and apo(a) isoforms is not established. Methods and Results— OxPL/apoB levels were measured in 3481 subjects (1831 black, 1047 white, and 603 Hispanic subjects) in the Dallas Heart Study and correlated with age, sex, cardiovascular risk factors, and Lp(a) and apo(a) isoforms. Significant differences in OxPL/apoB levels were noted among racial/ethnic subgroups, with blacks having the highest levels compared with whites and Hispanics ( P &lt;0.001 for each comparison). OxPL/apoB levels generally did not correlate with age, sex, or risk factors. In the overall cohort, OxPL/apoB levels strongly correlated with Lp(a) ( r =0.85, P &lt;0.001), with the shape of the relationship demonstrating a “reverse L” shape for log-transformed values. The highest correlation was present in blacks, followed by whites and Hispanics; was dependent on apo(a) isoform size; and became progressively weaker with larger isoforms. The size of the major apo(a) isoform (number of kringle type IV repeats) was negatively associated with OxPL/apoB ( r =−0.49, P &lt;0.001) and Lp(a) ( r =−0.61, P &lt;0.001) regardless of racial/ethnic group. After adjustment for apo(a) isoform size, the relationship between OxPL/apoB and Lp(a) remained significant ( r =0.67, P &lt;0.001). Conclusions— OxPL/apoB levels vary according to race/ethnicity, are largely independent of cardiovascular risk factors, and are inversely associated with apo(a) isoform size. The association of OxPL with small apo(a) isoforms, in which a similar relationship is present among all racial/ethnic subgroups despite differences in Lp(a) levels, may be a key determinant of cardiovascular risk.