tbuckley/cabot-search huggingface dataset:
Assessment and treatment relevance in elderly glioblastoma patients
Authors: L. Bauchet, S. Zouaoui, A. Darlix, N. Menjot de Champfleur, E. Ferreira, M. Fabbro, C. Kerr, L. Taillandier
Journal: Neuro-Oncology (2014)

Glioblastoma (GBM) is the most common malignant primary brain tumor. Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and "standards of care" do not exist for GBM patients aged >70 years. We review epidemiology, tumor biology/molecular factors, prognostic factors (clinical, imaging data, therapeutics), and their assessments as well as classic and specific endpoints plus recent and ongoing clinical trials for elderly GBM patients. This work includes perspectives and personal opinions on this topic. Although there are no standards of care for elderly GBM patients, we can hypothesize that (i) Karnofsky performance status (KPS), probably after steroid treatment, is one of the most important clinical factors for determining our oncological strategy; (ii) resection is superior to biopsy, at least in selected patients (depending on location of the tumor and associated comorbidities); (iii) specific schedules of radiotherapy yield a modest but significant improvement; (iv) temozolomide has an acceptable tolerance, even when KPS <70, and could be proposed for methylated elderly GBM patients; and (v) the addition of concomitant temozolomide to radiotherapy has not yet been validated but shows promising results in some studies, yet the optimal schedule of radiotherapy remains to be determined. In the future, specific assessments (geriatric, imaging, biology) and use of new endpoints (quality of life and toxicity measures) will aid clinicians in determining the balance of potential benefits and risks of each oncological strategy.
ABT-888 Plus Bendamustine Is Safe and Has Shown Preliminary Efficacy In Patients With Lymphoma
Authors: John F. Gerecitano, Gary K Schwartz, Richard Carvajal, Matthew Fury, Jason Konner, David M. Hyman, Mrinal Gounder, Devika Gajria, Jerrold Teitcher, Zhigang Zhang, Craig H. Moskowitz, Jan H Beumer, Alice Chen, Richard F Little, Fallon France, Juho Whang, Jennifer Winkelman, Megan Stasi, Corey Russell, Naomi Cazeau, Katherine Kargus, Andrew D. Zelenetz
Journal: Blood (2013)
Suppression of Murine Cardiac Allograft Arteriopathy by Long-Term Blockade of CD40-CD154 Interactions
Authors: Catherine Y. Wang, Sean P. Mazer, Kanji Minamoto, Shin Takuma, Shunichi Homma, Michael Yellin, Leonard Chess, Ali Fard, Susan L. Kalled, Mehmet C. Oz, David J. Pinsky
Journal: Circulation (2002)

Background — The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure. Methods and Results — A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days −1, 1, and 3; long-term blockade consisted of MR1 given on days −1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43±7% and 50±12%, respectively ( P =NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19±3% ( P &lt;0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control ( P &lt;0.05). Conclusions — These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.
Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy
Authors: Y. Akiyama, K. Fujita, F. Nagashima, W. Yamamoto, H. Endo, Y. Sunakawa, K. Yamashita, H. Ishida, K. Mizuno, K. Araki, W. Ichikawa, T. Miya, M. Narabayashi, K. Kawara, M. Sugiyama, T. Hirose, Y. Ando, Y. Sasaki
Journal: Annals of Oncology (2008)
<b> <i>In Vitro</i> </b> Studies with Methylproamine
Authors: Roger F. Martin, Sam Broadhurst, Monica E. Reum, Christopher J. Squire, George R. Clark, Pavel N. Lobachevsky, Jonathan M. White, Chris Clark, Denise Sy, Melanie Spotheim-Maurizot, David P. Kelly
Journal: Cancer Research (2004)

Abstract New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that methylproamine is ∼100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)2 confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.
Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein
Authors: Eva M. Schmelz, Hu Xu, Radha Sengupta, Jianhua Du, Sanjeev Banerjee, Fazlul H. Sarkar, Arun K. Rishi, Adhip P.N. Majumdar
Journal: Cancer Research (2007)

Abstract A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/or severity. Our recently identified pan-erbB inhibitor EGFR-related protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APCMin+/− (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 μg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 ± 3.0 (controls) to 14.9 ± 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P &amp;lt; 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P &amp;lt; 0.05) and reduced their size (P &amp;lt; 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor κB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer. [Cancer Res 2007;67(11):5389–96]
Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells.
Authors: R F Bargatze, S Kurk, E C Butcher, M A Jutila
Journal: The Journal of Experimental Medicine (1994)

Specific arrest of neutrophils in venules is central to their rapid accumulation during local inflammatory responses. Initial neutrophil rolling on endothelium is mediated by leukocyte L-selectin and the inducible vascular adhesion proteins P- and E-selectin. This rolling is a prerequisite for endothelial-dependent neutrophil arrest. Here we describe rolling of neutrophils on the surface of previously arrested neutrophils and demonstrate that this interaction involves L-selectin exclusively on rolling cells. The adherent neutrophil support of L-selectin-dependent neutrophil rolling in vivo can promote continuous and augmented leukocyte recruitment at sites of previous neutrophil accumulation.
Tenascin-C Is Induced With Progressive Pulmonary Vascular Disease in Rats and Is Functionally Related to Increased Smooth Muscle Cell Proliferation
Authors: Peter Lloyd Jones, Marlene Rabinovitch
Journal: Circulation Research (1996)

Tenascin-C, an extracellular matrix glycoprotein prominent during tissue remodeling, has been linked to cell migration, proliferation, and apoptosis. To determine its potential role in the pathobiology of pulmonary hypertension, we compared tenascin expression in adult and infant rat pulmonary arteries (PAs) after injection of the toxin monocrotaline. Immunohistochemistry, in situ hybridization, and Northern blot analysis demonstrated induction of tenascin in adult rat central and peripheral PA. Tenascin was not, however, detected in infant vessels, which show spontaneous regression of vascular lesions. To determine a function for tenascin, we correlated its expression with evidence of apoptosis and cell proliferation using the TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay and 5-bromo-2'-deoxyuridine labeling, respectively. Apoptosis was observed only in the adult rat PA endothelial cell layer, preceding the induction of tenascin, which colocalized both temporally and spatially with proliferating smooth muscle cells (SMCs). A cause-and-effect relationship was documented in cultured rat PA SMCs, where tenascin promoted growth in response to basic fibroblast growth factor and was a prerequisite for epidermal growth factor-induced proliferation. These data provide novel functional information suggesting that endothelial cell apoptosis precedes progressive pulmonary hypertension and that induction of tenascin may be critical to growth factor-dependent SMC proliferation.
Increasing mortality among HIV/HCV coinfected patients treated with highly active antiretroviral therapy (HAART)
Authors: J. Macias, J.A. Pineda, I. Melguizo, M. Leal, J. Delgado, R. Rosa, A. Sanchez-Quijano, J.M. Rivera, E. Lissen
Journal: Journal of Hepatology (2001)
Risk Factors for Adult Onset Wheeze
Authors: COREEN H. BODNER, SUE ROSS, JULIAN LITTLE, J. GRAHAM DOUGLAS, JOSEPH S. LEGGE, JAMES A. R. FRIEND, DAVID J. GODDEN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Risk factors associated with adult onset wheeze were examined in a case control study of subjects aged 39–45 yr derived from a community cohort of 2,056 asymptomatic children originally studied in 1964. Participants included 102 cases with adult onset wheeze (since age 15) and 217 controls with no wheeze. Logistic regression analysis was used to determine independent risk factors for wheeze among all cases and three subgroups: doctor diagnosed asthma (n = 24), wheeze with chronic cough and phlegm (n = 31), and other wheeze (n = 47). The risk of adult onset wheeze among all cases increased with low socioeconomic status (relative risk [RR] 2.36), current smoking (RR 2.01), positive atopic status (RR 3.28), and positive family history of atopic disease (RR 5.49). Gender was not related to the risk of wheezing. The pattern of significant independent risk factors differed between the subgroups of cases. Socioeconomic status was associated with cough and phlegm and other wheeze. Smoking habit was only related to cough and phlegm. Atopy was associated with doctor diagnosed asthma and cough and phlegm. Family history of atopic disease was related to all subgroups, suggesting that despite apparent heterogeneity in diagnostic labeling, concurrent symptoms, and other risk factors, the different forms of adult onset wheeze may share a common allergic basis.
Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning
Authors: D. J. Hausenloy, S. Y. Lim, S.-G. Ong, S. M. Davidson, D. M. Yellon
Journal: Cardiovascular Research (2010)

It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 ± 2% WT vs. 17 ± 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 ± 9% WT vs. 56 ± 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 ± 3.5% HPC vs. 43.7 ± 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 ± 1.4% HPC vs. 24.4 ± 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts.The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.
Antidepressant Pharmacotherapy in Adults With Type 2 Diabetes
Authors: Ryan J. Anderson, Britt M. Gott, Gregory S. Sayuk, Kenneth E. Freedland, Patrick J. Lustman
Journal: Diabetes Care (2009)

OBJECTIVE Initial treatment with antidepressant medication is insufficiently effective in some patients with type 2 diabetes, and factors predicting treatment outcome are poorly understood. RESEARCH DESIGN AND METHODS Aggregate data from two published trials were analyzed to determine the rates and predictors of response to antidepressant pharmacotherapy in adults with type 2 diabetes using conventional markers of initial treatment outcome (improvement, response, partial remission, and remission). Three hundred eighty-seven patients who received up to 16 weeks of open-label, acute-phase treatment using bupropion (n = 93) or sertraline (n = 294) were studied. Logistic regression was used to identify predictors of poor treatment outcome. Candidate predictors included age, race, sex, initial Beck Depression Inventory (iBDI) score, treatment received (sertraline or bupropion), family history of depression, extant diabetes complications (eDC), and A1C level. RESULTS Of 387 patients initiated on treatment, 330 (85.3%) met criteria for improvement, 232 (59.9%) for response, 207 (53.5%) for partial remission, and 179 (46.3%) for full remission. Significant independent predictors of poor outcome included eDC (for no improvement); sertraline treatment, eDC, and younger age (for nonresponse); sertraline treatment, eDC, and higher iBDI (for failure to partially remit); and younger age and higher iBDI (for failure to fully remit). Higher pain scores predicted three of the four markers of poor outcome in the subset with pain data. CONCLUSIONS In patients with type 2 diabetes, poor initial response to antidepressant medication is predicted by multiple factors. Auxiliary treatment of pain and impairment may be required to achieve better outcomes.
Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment
Authors: Christina K. Augustine, Yasunori Yoshimoto, Mukur Gupta, Patricia A. Zipfel, M. Angelica Selim, Phillip Febbo, Ann Marie Pendergast, William P. Peters, Douglas S. Tyler
Journal: Cancer Research (2008)

Abstract Malignant transformation in melanoma is characterized by a phenotype “switch” from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin–expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma. [Cancer Res 2008;68(10):3777–84]
Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome
Authors: C. Bauer, P. Duewell, C. Mayer, H. A. Lehr, K. A. Fitzgerald, M. Dauer, J. Tschopp, S. Endres, E. Latz, M. Schnurr
Journal: Gut (2010)

<h3>Background</h3> The proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. <h3>Methods</h3> IL-1β production in response to DSS was studied in macrophages of wild-type, caspase-1<sup>−/−</sup>, NLRP3<sup>−/−</sup>, ASC<sup>−/−</sup>, cathepsin B<sup>−/−</sup> or cathepsin L<sup>−/−</sup> mice. Colitis was induced in C57BL/6 and NLRP3<sup>−/−</sup> mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. <h3>Results</h3> Macrophages incubated with DSS in vitro secreted high levels of IL-1β in a caspase-1-dependent manner. IL-1β secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1β secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3<sup>−/−</sup> mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. <h3>Conclusions</h3> The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.
Detecting cardiac involvement in sarcoidosis: a call for prospective studies of newer imaging techniques
Authors: C. Pandya, R. C. Brunken, P. Tchou, P. Schoenhagen, D. A. Culver
Journal: European Respiratory Journal (2007)

Diagnosis of cardiac involvement in sarcoidosis is challenging and usually relies on a combination of clinical findings and imaging abnormalities. The case of a 53-yr-old female is described who presented with ventricular tachycardia and suspected angiosarcoma involving the right atrium and superior vena cava. A combination of magnetic resonance imaging and (18)F-2-fluoro-2-deoxyglucose-positron emission tomography were essential to the diagnosis of cardiac sarcoidosis. Reversibility of the disease was predicted more clearly by (18)F-2-fluoro-2-deoxyglucose-positron emission tomography than by magnetic resonance imaging, and clinical activity was predicted by persistent hypermetabolism on serial (18)F-2-fluoro-2-deoxyglucose-positron emission tomography.
FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease
Authors: Tae-In Kam, Sungmin Song, Youngdae Gwon, Hyejin Park, Ji-Jing Yan, Isak Im, Ji-Woo Choi, Tae-Yong Choi, Jeongyeon Kim, Dong-Keun Song, Toshiyuki Takai, Yong-Chul Kim, Key-Sun Kim, Se-Young Choi, Sukwoo Choi, William L. Klein, Junying Yuan, Yong-Keun Jung
Journal: Journal of Clinical Investigation (2013)

Amyloid-β (Aβ) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcγ receptor II-b (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aβ-induced cell death in vitro. Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aβ neurotoxicity, we demonstrated that soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aβ neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aβ-mediated neuronal dysfunction.
Malnutrition is associated to poor exercise capacity irrespective of dynamic hyperinflation in COPD patients
Authors: Elisabetta Teopompi, Panagiota Tzani, Marina Aiello, Sara Ramponi, Emilio Marangio, Enrico Clini, Alfredo Chetta
Journal: European Respiratory Journal (2013)

In patients with COPD, we investigated the effect of the fat-free mass (FFM) on maximal exercise capacity and the relationship with changes in operational lung volumes during exercise.  In a cross-sectional study fifty-seven patients (16 females; age 65 ± 8 yrs) were consecutively assessed by resting lung function, symptom-limited cardiopulmonary exercise test, and body composition by means of bioelectrical impedance analysis to measure the FFM index (FFMI, kg/m2).  Patients were categorized as depleted (n = 14) or non depleted (n = 43) according to FFMI. No significant difference in gender, age and in resting lung function was found between depleted and non depleted patients. When compared with non depleted, the depleted COPD patients had a significantly lower O2 uptake at peak of exercise and at anaerobic threshold as well as peak O2Pulse, O2 uptake efficiency slope (OUES) and heart rate recovery (HRR) (p   This study shows that malnutrition per se plays a part in the reduction of exercise capacity of COPD patients. FFM depletion was strictly associated to poor cardiovascular response to exercise and to leg fatigue but not to dyspnoea.