tbuckley/cabot-search huggingface dataset:
Galantamine for the Treatment of Cognitive Impairments in People With Schizophrenia
Authors: Robert W Buchanan, Robert R Conley, Dwight Dickinson, M Patricia Ball, Stephanie Feldman, James M Gold, Robert P McMahon
Journal: American Journal of Psychiatry (2007)

People with schizophrenia are characterized by a broad range of cognitive impairments. Despite appropriate treatment with conventional or second-generation antipsychotics, they continue to exhibit pronounced impairments. The current study was designed to examine the efficacy and safety of galantamine, an acetylcholinesterase inhibitor that also acts as an allosteric modulator at the alpha(4)beta(2) and alpha(7) nicotinic receptors, for the treatment of these impairments.Eighty-six people with schizophrenia were entered into a 12-week double-blind, placebo-controlled, randomized clinical trial. Forty-two subjects were assigned to galantamine and 44 were assigned to placebo. The efficacy of galantamine for cognitive impairments was evaluated with neuropsychological measures of attention, motor speed, processing speed, verbal and visual memory, and working memory.The treatment effect for the overall composite score was not significant, but the heterogeneity of treatment effect analysis was significant. Follow-up analyses revealed that the subjects taking galantamine exhibited significant improvements on the WAIS-III digit symbol and verbal memory measures. In contrast, the subjects taking placebo showed a significant improvement on the GDS distractibility test. The group differences on the WAIS-III digit symbol and GDS distractibility test remained significant after correction for multiple comparisons. There were no significant between-group differences in motor speed or working memory. In general, safety analyses revealed that galantamine was well tolerated.Study results suggest that galantamine may have selective benefits for aspects of processing speed and verbal memory but interferes with practice effects during the performance of an attention task.
Rapid Identification of Clinical Relevant Minor Histocompatibility Antigens via Genome-Wide Zygosity-Genotype Correlation Analysis
Authors: Robbert M. Spaapen, Ron A.L. de Kort, Kelly van den Oudenalder, Maureen van Elk, Andries C. Bloem, Henk M. Lokhorst, Tuna Mutis
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Identification of minor histocompatibility antigens (mHag) with classic methods often requires sophisticated technologies, determination, and patience. We here describe and validate a nonlaborious and convenient genetic approach, based on genome-wide correlations of mHag zygosities with HapMap single-nucleotide polymorphism genotypes, to identify clinical relevant mHags within a reasonable time frame. Experimental Design: Using this approach, we sought for the mHag recognized by a HLA-DRB1*1501–restricted T-cell clone, isolated from a multiple myeloma patient during a strong graft-versus-tumor effect associated with acute graft-versus-host disease grade 3. Results: In a period of 3 months, we determined the mHag phenotype of 54 HapMap individuals, deduced the zygosity of 20 individuals, defined the mHag locus by zygosity-genotype correlation analyses, tested the putative mHag peptides from this locus, and finally showed that the mHag is encoded by the arginine (R) allele of a nonsynonymous single-nucleotide polymorphism in the SLC19A1 gene. Conclusions: We conclude that this powerful and convenient strategy offers a broadly accessible platform toward rapid identification of mHags associated with graft-versus-tumor effect and graft-versus-host disease. (Clin Cancer Res 2009;15(23):7137–43)
Negative-Pressure Ventilation
Authors: Francesco Grasso, Doreen Engelberts, Emma Helm, Helena Frndova, Steven Jarvis, Omid Talakoub, Colin McKerlie, Paul Babyn, Martin Post, Brian P Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Conventional positive-pressure ventilation delivers pressure to the airways; in contrast, negative pressure is delivered globally to the chest and abdomen.To test the hypothesis that ventilation with negative pressure results in better oxygenation and less injury than with positive pressure.Anesthetized, surfactant-depleted rabbits were ventilated for 2.5 hours in pairs (positive or negative). Tidal volume was 12 ml . kg(-1), normocapnia was maintained by adjusting respiratory rate, and Fi(O(2)) was 1.0.Lung injury was assessed with histologic scoring, perfusion using thermodilution (global perfusion), and injected intravascular microspheres (regional perfusion); and dynamic computed tomography was used to determine inflation patterns. Negative pressure was associated with a higher Pa(O(2)), a lower Pa-Pet(CO(2)) gradient (despite identical minute ventilation), and less lung injury. Lung perfusion (global and regional) was similar with positive and negative pressure. Positive end-expiratory pressure applied to the airway was more efficiently transmitted to the pleural space than comparable levels of negative end-expiratory pressure applied to the chest wall; however, the oxygenation associated with any level of end-expiratory lung volume was greater when achieved by negative versus positive pressure. Dynamic computed tomography suggested that lung distension achieved with negative pressure is characterized by greater proportions of normally aerated lung (with less atelectasis) during inspiration and at end-expiration.Negative-pressure ventilation results in superior oxygenation that is unrelated to lung perfusion and may be explained by more effective inflation of lung volume during both inspiration and expiration.
Abstract 16262: Risk of Congenital Heart Surgery in Adults
Authors: Juergen Hoerer, Masamichi Ono, Jelena Kasnar-Samprec, Julie Cleuziou, Melchior Burri, Martina Strbad, Manfred Vogt, Rüdiger Lange, Christian Schreiber
Journal: Circulation (2014)

Objective:  There are currently no risk stratification models available for predicting the outcome following congenital heart surgery in adults. The Aristotle Basic Complexity (ABC), the Aristotle Comprehensive Complexity (ACC), the Risk Adjustment in Congenital Heart Surgery (RACHS-1), and the Society of Thoracic Surgeons (STS) - European Association for Cardiothoracic Surgery (EACTS) score are suitable for children. We sought to evaluate the predictive power of the ABC, ACC, RACHS-1, and STS-EACTS score for hospital mortality and complications after congenital heart surgery in adults.   Methods and results:  Data of all consecutive patients aged 18 years or more, who underwent surgery for congenital heart disease between 2004 and 2014 at our institution, were collected. Complications were defined as reoperation, mechanical circulatory support, mechanical ventilatory support >24 hours, renal failure requiring dialysis, mediastinitis, persisting neurological deficit, and death during hospital admission or within 30 days. The discriminatory power of the scores was assessed using the area under the receiver operating characteristics (AuROC) curve.  846 operations were performed. Hospital mortality was 2.9%. Complications occurred in 15.6% of the patients. The prognostic significance of the ABC, ACC, RACHS-1, and STS-EACTS score for mortality was 0.67, 0.76, 0.60, and 0.74, respectively. The prognostic significance for complications was 0.65, 0.73, 0.60, and 0.70, respectively. Single ventricle physiology (p   Conclusions:  The ACC score outperforms the ABC score since procedure dependent and independent factors are considered. The STS-EACTS score outperforms the RACHS-1 score since procedures can be categorized more precisely. The discriminative power of the ACC and the STS-EACTS score may be improved by including additional risk factors that are specifically present in the adult population.
INT6/EIF3E Interacts with ATM and Is Required for Proper Execution of the DNA Damage Response in Human Cells
Authors: Christelle Morris, Nozomi Tomimatsu, Derek J. Richard, David Cluet, Sandeep Burma, Kum Kum Khanna, Pierre Jalinot
Journal: Cancer Research (2012)

Abstract Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G2–M checkpoint control. RNA interference–mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response. Cancer Res; 72(8); 2006–16. ©2012 AACR.
The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region
Authors: Raquel Herrero, Osamu Kajikawa, Gustavo Matute-Bello, Yi Wang, Naoki Hagimoto, Steve Mongovin, Venus Wong, David R. Park, Nathan Brot, Jay W. Heinecke, Henry Rosen, Richard B. Goodman, Xiaoyun Fu, Thomas R. Martin
Journal: Journal of Clinical Investigation (2011)

Acute lung injury (ALI) is a life-threatening condition in critically ill patients. Injury to the alveolar epithelium is a critical event in ALI, and accumulating evidence suggests that it is linked to proapoptotic Fas/FasL signals. Active soluble FasL (sFasL) is detectable in the bronchoalveolar lavage (BAL) fluid of patients with ALI, but the mechanisms controlling its bioactivity are unclear. We therefore investigated how the structure of sFasL influences cellular activation in human and mouse lungs and the role of oxidants and proteases in modifying sFasL activity. The sFasL in BAL fluid from patients with ALI was bioactive and present in high molecular weight multimers and aggregates. Oxidants generated from neutrophil myeloperoxidase in BAL fluid promoted aggregation of sFasL in vitro and in vivo. Oxidation increased the biological activity of sFasL at low concentrations but degraded sFasL at high concentrations. The amino-terminal extracellular stalk region of human sFasL was required to induce lung injury in mice, and proteolytic cleavage of the stalk region by MMP-7 reduced the bioactivity of sFasL in human cells in vitro. The sFasL recovered from the lungs of patients with ALI contained both oxidized methionine residues and the stalk region. These data provide what we believe to be new insights into the structural determinants of sFasL bioactivity in the lungs of patients with ALI.
Emergence of Stereotactic Body Radiation Therapy and Its Impact on Current and Future Clinical Practice
Authors: Robert D. Timmerman, Joseph Herman, L. Chinsoo Cho
Journal: Journal of Clinical Oncology (2014)

Stereotactic body radiation therapy (SBRT) is generally a tumor-ablative radiation modality using essential technologies capable of accurately and precisely damaging the target with a high dose while geometrically sparing innocent normal tissues. The intent, conduct, and tissue biology are all dramatically distinct from conventionally fractionated radiotherapy such that new understanding is required for its optimization. It is most practical, tolerable, and tumoricidal in its most potent form treating tumors in the lung and liver. However, it is increasingly being used for tumors adjacent to bowels and nervous tissue, albeit with somewhat less ablative potency. Its strengths include high rates of tumor eradication via a noninvasive, convenient outpatient treatment. Its weakness relates to the possibility of causing difficult-to-manage toxicity (eg, ulceration, stenosis, fibrosis, and even necrosis) that may occur considerably later after treatment, particularly in the vicinity of the body's many tubular structures (eg, organ hila, bowel). However, clinical trials in a variety of organs and sites have shown SBRT to result in good outcomes in properly selected patients. Given its short course, lack of need for recovery, and favorable overall toxicity profile, there is great hope that SBRT will find a prominent place in the treatment of metastatic cancer as a consolidative partner with systemic therapy. With considerable published experience, available required technologies and training, and many patients in need of local therapy, SBRT has found a place in the routine cancer-fighting arsenal.
Cardiac and Renal Effects of Standard Versus Rigorous Blood Pressure Control in Autosomal-Dominant Polycystic Kidney Disease
Authors: Robert Schrier, Kimberly McFann, Ann Johnson, Arlene Chapman, Charles Edelstein, Godela Brosnahan, Tevfik Ecder, Lyn Tison
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. This study sought to investigate the cardiac and renal effects of rigorous <i>versus</i> standard BP control on autosomal-dominant polycystic kidney disease (ADPKD). A prospective, randomized, 7-yr study was performed to examine the effect of rigorous (&lt;120/80 mmHg) <i>versus</i> standard (135–140/85–90 mmHg) BP control on left ventricular mass index (LVMI) and kidney function in 75 hypertensive ADPKD patients with left ventricular hypertrophy. LVMI was measured by echocardiogram at baseline and at 1 and 7 yr. Renal function was assessed by measuring serum creatinine and 24-h creatinine clearance every 6 mo for 3 yr, then annually for an additional 4 yr. The baseline characteristics were comparable in the two groups. During the study, average mean arterial pressure was 90 ± 5 mmHg for the rigorous group and 101 ± 4 mmHg for the standard group (<i>P</i> &lt; 0.0001). The LVMI decreased by 21% in the standard group and by 35% in the rigorous group. A mixed model longitudinal data analysis revealed that rigorous BP control was significantly more effective in decreasing LVMI (<i>P</i> &lt; 0.01). There was no statistically significant difference in renal function between the two groups. In conclusion, left ventricular hypertrophy, a major cardiovascular risk factor, was decreased to a significantly greater extent by rigorous than standard BP control. This finding has particular clinical importance because cardiovascular complications are the most common cause of death in ADPKD patients.
Phase II Trial of Gliadel plus <i>O</i>6-Benzylguanine in Adults with Recurrent Glioblastoma Multiforme
Authors: Jennifer A. Quinn, Sara Xiaoyin Jiang, James Carter, David A. Reardon, Annick Desjardins, James J. Vredenburgh, Jeremy N. Rich, Sridharan Gururangan, Allan H. Friedman, Darell D. Bigner, John H. Sampson, Roger E. McLendon, James E. Herndon, Stevie Threatt, Henry S. Friedman
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. Experimental Design: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. Results: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%). Conclusion: The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.
Type I Interferon as a Powerful Adjuvant for Monocyte-Derived Dendritic Cell Development and Activity in Vitro and in Hu-Pbl-Scid Mice
Authors: Stefano M. Santini, Caterina Lapenta, Mariantonia Logozzi, Stefania Parlato, Massimo Spada, Tiziana Di Pucchio, Filippo Belardelli
Journal: The Journal of Experimental Medicine (2000)

Type I interferons (IFNs) are cytokines exhibiting antiviral and antitumor effects, including multiple activities on immune cells. However, the importance of these cytokines in the early events leading to the generation of an immune response is still unclear. Here, we have investigated the effects of type I IFNs on freshly isolated granulocyte/macrophage colony-stimulating factor (GM-CSF)–treated human monocytes in terms of dendritic cell (DC) differentiation and activity in vitro and in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID) mice. Type I IFNs induced a surprisingly rapid maturation of monocytes into short-lived tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)–expressing DCs endowed with potent functional activities, superior with respect to the interleukin (IL)-4/GM-CSF treatment, as shown by FACS® analyses, mixed leukocyte reaction assays with allogeneic PBLs, and lymphocyte proliferation responses to HIV-1–pulsed autologous DCs. Type I IFN induced IL-15 production and strongly promoted a T helper cell type 1 response. Notably, injection of IFN-treated HIV-1–pulsed DCs in SCID mice reconstituted with autologous PBLs resulted in the generation of a potent primary immune response, as evaluated by the detection of human antibodies to various HIV-1 antigens. These results provide a rationale for using type I IFNs as vaccine adjuvants and support the concept that a natural alliance between these cytokines and monocytes/DCs represents an important early mechanism for connecting innate and adaptive immunity.
Apoptosis Signal-Regulating Kinase 1/p38 Signaling Pathway Negatively Regulates Physiological Hypertrophy
Authors: Masayuki Taniike, Osamu Yamaguchi, Ikuko Tsujimoto, Shungo Hikoso, Toshihiro Takeda, Atsuko Nakai, Shigemiki Omiya, Isamu Mizote, Yuko Nakano, Yoshiharu Higuchi, Yasushi Matsumura, Kazuhiko Nishida, Hidenori Ichijo, Masatsugu Hori, Kinya Otsu
Journal: Circulation (2008)

Background— Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth. Methods and Results— To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1 −/− ) were exercised by swimming for 4 weeks. ASK1 −/− mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1 −/− mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1–induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38α-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise. Conclusions— These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.
Changing Area Socioeconomic Patterns in U.S. Cancer Mortality, 1950-1998: Part II--Lung and Colorectal Cancers
Authors: Gopal K Singh, Barry A Miller, Benjamin F Hankey
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Lung cancer and colorectal cancer are leading causes of U.S. cancer mortality. Because mortality rates for many cancers vary by socioeconomic characteristics, we used area socioeconomic indices to examine patterns in U.S. lung and colorectal cancer mortality between 1950 and 1998. Methods: A factor-based area socioeconomic index was linked to 1950–1998 county mortality data to generate annual lung and colorectal cancer mortality rates for each area socioeconomic group. Joinpoint regression analysis was used to model and identify statistically significant changes in the mortality trends. Results: Area socioeconomic patterns in U.S. lung cancer mortality changed dramatically between 1950 and 1998. Men aged 25–64 years and those aged 65 years or older in higher socioeconomic areas generally had higher lung cancer mortality than did those in lower socioeconomic areas during 1950–1964 and 1950–1980, respectively. Area socioeconomic differences in lung cancer mortality began to reverse and widen by the early 1970s for younger men and by the mid-1980s for older men. In 1998, lung cancer mortality was 56% (95% confidence interval [CI] = 49% to 64%) higher for younger men and 38% higher (95% CI = 34% to 43%) for older men in the lowest area socioeconomic group than for the same age groups in the highest area socioeconomic group. Lung cancer mortality among older women in all socioeconomic groups increased sevenfold to eightfold between 1950 and 1998, with higher mortality in higher area socioeconomic groups. The positive socioeconomic gradient in colorectal cancer mortality diminished substantially over time. Although colorectal cancer mortality among women in all area socioeconomic groups showed a consistent downward trend, colorectal cancer mortality among men in low area socioeconomic groups, but not in high area socioeconomic groups, showed an upward trend. Conclusions: Socioeconomic gradients in male lung cancer mortality reversed between 1950 and 1998, and those in colorectal cancer mortality narrowed over that time. Area measures may be useful for monitoring socioeconomic disparities in cancer mortality and for identifying areas for potential cancer control interventions.