tbuckley/cabot-search huggingface dataset:
Alzheimer's disease: synapses gone cold
Authors: Robert M Koffie, Bradley T Hyman, Tara L Spires-Jones
Journal: Molecular Neurodegeneration (2011)

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.
Computed Tomography Brain Scanning in Alcohol Withdrawal Seizures
Authors: JOHN R. FEUSSNER
Journal: Annals of Internal Medicine (1981)

We evaluated the usefulness of computed tomography (CT) brain scanning in alcoholic patients with withdrawal seizures (n = 151) and other neurologic problems (n = 87) and compared the findings of a detailed neurologic examination to the results of CT scanning. In patients with seizures, nearly 50% of CT scans were normal, 34% showed generalized cerebral atrophy, and only 15% showed focal structural lesions. When focal neurologic deficits were present, 30% of CT scaris showed focal structural lesions compared to 6% when such deficits were absent (p < 0.0002). The frequency of potentially reversible lesions was 18% in patients with and 1% in patients without focal neurologic deficits (p < 0.0002). Of patients treated surgically, 9% had focal neurologic deficits and 1% did not (p < 0.03). Results were similar in alcoholic patients with other neurologic problems. Careful use of the neurologic examination adequately determines which patients need prompt CT scanning. In the absence of either focal deficits on neurologic examination or signs of acute head trauma, CT brain scanning does not improve the evaluation of patients with alcohol withdrawal seizures.
Gray Matter Structural Alterations in Psychotropic Drug-Naive Pediatric Obsessive-Compulsive Disorder: An Optimized Voxel-Based Morphometry Study
Authors: Philip R. Szeszko, Christopher Christian, Frank MacMaster, Todd Lencz, Yousha Mirza, S. Preeya Taormina, Phillip Easter, Michelle Rose, G.A. Michalopoulou, David R. Rosenberg
Journal: American Journal of Psychiatry (2008)

Although several magnetic resonance imaging (MRI) studies have been conducted in adults with obsessive-compulsive disorder (OCD), few studies have used voxel-based morphometry to examine brain structure, especially in psychotropic drug-naive pediatric patients.MRI examinations of 37 psychotropic drug-naive pediatric OCD patients and 26 age- and sex-matched healthy volunteers were acquired on a 1.5 T MRI system, normalized to a customized template, and segmented with optimized voxel-based morphometry.Pediatric OCD patients had significantly more gray matter in regions predicted to differ a priori between groups, including the right and left putamen and orbital frontal cortex. Among patients, more gray matter in the left putamen and right lateral orbital frontal cortex correlated significantly with greater OCD symptom severity, but not with anxiety or depression. Manual region-of-interest measurements confirmed more gray matter in the orbital frontal cortex and putamen in patients compared to healthy volunteers. More anterior cingulate gray matter was evident among patients compared to healthy volunteers with regional volumetry but not with voxel-based morphometry. Regions of significantly less gray matter in OCD were confined to the occipital cortex and were not predicted a priori.Our results suggest that OCD is characterized by more gray matter in brain regions comprising cortical-striatal-thalamic-cortical circuits. These findings are consistent with functional neuroimaging studies reporting hypermetabolism and increased regional cerebral blood flow in striatal, anterior cingulate, and orbital frontal regions among OCD patients while in a resting state.
Pseudotumor Cerebri Treated
Authors: Gary D. Vander Ark
Journal: JAMA (1971)

Occasionally pseudotumor cerebri is refractory to all forms of medical therapy. Indications for surgical treatment are the visual complications of raised intracranial pressure. For three patients with these complications who required operative treatment, the technique of lumbar-subarachnoid-peritoneal shunt was used effectively. This technique is recommended as the surgical treatment of choice.
The cardiovascular effects of erythropoietin
Authors: K Smith
Journal: Cardiovascular Research (2003)

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.
Genomic Characterization of Esophageal Squamous Cell Carcinoma from a High-Risk Population in China
Authors: Nan Hu, Chaoyu Wang, David Ng, Robert Clifford, Howard H. Yang, Ze-Zhong Tang, Quan-Hong Wang, Xiao-You Han, Carol Giffen, Alisa M. Goldstein, Philip R. Taylor, Maxwell P. Lee
Journal: Cancer Research (2009)

Genomic instability plays an important role in most human cancers. To characterize genomic instability in esophageal squamous cell carcinoma (ESCC), we examined loss of heterozygosity (LOH), copy number (CN) loss, CN gain, and gene expression using the Affymetrix GeneChip Human Mapping 500K (n = 30 cases) and Human U133A (n = 17 cases) arrays in ESCC cases from a high-risk region of China. We found that genomic instability measures varied widely among cases and separated them into two groups: a high-frequency instability group (two-thirds of all cases with one or more instability category of > or =10%) and a low-frequency instability group (one-third of cases with instability of <10%). Genomic instability also varied widely across chromosomal arms, with the highest frequency of LOH on 9p (33% of informative single nucleotide polymorphisms), CN loss on 3p (33%), and CN gain on 3q (48%). Twenty-two LOH regions were identified: four on 9p, seven on 9q, four on 13q, two on 17p, and five on 17q. Three CN loss regions-3p12.3, 4p15.1, and 9p21.3-were detected. Twelve CN gain regions were found, including six on 3q, one on 7q, four on 8q, and one on 11q. One of the most gene-rich of these CN gain regions was 11q13.1-13.4, where 26 genes also had RNA expression data available. CN gain was significantly correlated with increased RNA expression in over 80% of these genes. Our findings show the potential utility of combining CN analysis and gene expression data to identify genes involved in esophageal carcinogenesis.
The 3p21.3 Tumor Suppressor <i>NPRL2</i> Plays an Important Role in Cisplatin-Induced Resistance in Human Non–Small-Cell Lung Cancer Cells
Authors: Kentaro Ueda, Hiroyuki Kawashima, Shoichiro Ohtani, Wu-Guo Deng, Murali Ravoori, Jim Bankson, Boning Gao, Luc Girard, John D. Minna, Jack A. Roth, Vikas Kundra, Lin Ji
Journal: Cancer Research (2006)

Abstract NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to be involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non–small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of −0.677 (P &amp;lt; 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle–mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2- to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nanoparticles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P &amp;lt; 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment. (Cancer Res 2006; 66(19): 9682-90)
MicroRNA profiles of t(14;18)–negative follicular lymphoma support a late germinal center B-cell phenotype
Authors: Ellen Leich, Alberto Zamo, Heike Horn, Eugenia Haralambieva, Bernhard Puppe, Randy D. Gascoyne, Wing-Chung Chan, Rita M. Braziel, Lisa M. Rimsza, Dennis D. Weisenburger, Jan Delabie, Elaine S. Jaffe, Jude Fitzgibbon, Louis M. Staudt, Hans-Konrad Mueller-Hermelink, Mariarita Calaminici, Elias Campo, German Ott, Luis Hernández, Andreas Rosenwald
Journal: Blood (2011)
Phase 1 Study of Aflibercept Administered Subcutaneously to Patients with Advanced Solid Tumors
Authors: William P. Tew, Michael Gordon, John Murren, Jakob Dupont, Sandra Pezzulli, Carol Aghajanian, Paul Sabbatini, David Mendelson, Lawrence Schwartz, Scott Gettinger, Amanda Psyrri, Jesse M. Cedarbaum, David R. Spriggs
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. Experimental Design: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. Results: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 μg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t1/2 of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for &amp;gt;1 year. Conclusion: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. Clin Cancer Res; 16(1); 358–366
Cardioprotective effects of nitrite during exercise
Authors: J. W. Calvert
Journal: Cardiovascular Research (2010)

Exercise training has been shown to reduce many risk factors related to cardiovascular disease, including high blood pressure, high cholesterol, obesity, and insulin resistance. More importantly, exercise training has been consistently shown to confer sustainable protection against myocardial infarction in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise training is able to protect the heart, but some studies have suggested that it increases a number of classical signalling molecules. For instance, exercise can increase components of the endogenous antioxidant defences (i.e. superoxide dismutase and catalase), increase the expression of heat shock proteins, activate ATP-sensitive potassium (KATP) channels, and increase the expression and activity of endothelial nitric oxide (NO) synthase resulting in an increase in NO levels. This review article will provide a brief summary of the role that these signalling molecules play in mediating the cardioprotective effects of exercise. In particular, it will highlight the role that NO plays and introduce the idea that the stable NO metabolite, nitrite, may play a major role in mediating these cardioprotective effects.
Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia
Authors: Andreas Rosenwald, Ash A. Alizadeh, George Widhopf, Richard Simon, R. Eric Davis, Xin Yu, Liming Yang, Oxana K. Pickeral, Laura Z. Rassenti, John Powell, David Botstein, John C. Byrd, Michael R. Grever, Bruce D. Cheson, Nicholas Chiorazzi, Wyndham H. Wilson, Thomas J. Kipps, Patrick O. Brown, Louis M. Staudt
Journal: The Journal of Experimental Medicine (2001)

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party
Authors: G. D'Arena, C.G. Valentini, G. Pietrantuono, R. Guariglia, M.C. Martorelli, G. Mansueto, O. Villani, D. Onofrillo, A. Falcone, G. Specchia, G. Semenzato, N. Di Renzo, L. Mastrullo, A. Venditti, F. Ferrara, A. Palumbo, L. Pagano, P. Musto
Journal: Annals of Oncology (2011)

The best therapeutic approach for primary plasma cell leukemia (PPCL) remains unknown so far. In very limited studies, the poor clinical outcome of this aggressive variant of multiple myeloma seemed to be ameliorated by the use of the proteasome inhibitor bortezomib. Aiming to provide more consolidated data, this multicenter retrospective survey focused on unselected and previously untreated PPCL patients who had received bortezomib as frontline therapy.Twenty-nine patients with PPCL were collected. Bortezomib was given at standard doses and schedules, in various combinations with dexamethasone, thalidomide, doxorubicin, melphalan, prednisone, vincristine, and cyclophosphamide.An overall response rate of 79% was observed, with 38% of at least very good partial remission. Grade 3-4 hematological, neurological, infectious, and renal toxic effects occurred in 20%, 21%, 16%, and 4% of patients, respectively. After a median follow-up of 24 months, 16 patients were alive (55%), 12 of whom were in remission phase and 4 relapsed. The best long-term results were achieved in patients who received stem-cell transplantation after bortezomib induction.Bortezomib, used as initial therapy, is able to increase the percentage and the quality of responses in PPCL patients, producing a significant improvement of survival.
Outbreak of<i>Mycobacterium chelonae</i>Infection Associated with Tattoo Ink
Authors: Byron S. Kennedy, Brenden Bedard, Mary Younge, Deborah Tuttle, Eric Ammerman, John Ricci, Andrew S. Doniger, Vincent E. Escuyer, Kara Mitchell, Judith A. Noble-Wang, Heather A. O'Connell, William A. Lanier, Linda M. Katz, Robert F. Betts, Mary Gail Mercurio, Glynis A. Scott, Matthew A. Lewis, Mark H. Goldgeier
Journal: New England Journal of Medicine (2012)

In January 2012, on the basis of an initial report from a dermatologist, we began to investigate an outbreak of tattoo-associated Mycobacterium chelonae skin and soft-tissue infections in Rochester, New York. The main goals were to identify the extent, cause, and form of transmission of the outbreak and to prevent further cases of infection.
A major zebrafish polymorphism resource for genetic mapping
Authors: Kevin M Bradley, J Bradford Elmore, Joan P Breyer, Brian L Yaspan, Jason R Jessen, Ela W Knapik, Jeffrey R Smith
Journal: Genome biology (2007)

We have identified 645,088 candidate polymorphisms in zebrafish and observe a single nucleotide polymorphism (SNP) validation rate of 71% to 86%, improving with polymorphism confidence score. Variant sites are non-random, with an excess of specific novel T- and A-rich motifs. We positioned half of the polymorphisms on zebrafish genetic and physical maps as a resource for positional cloning. We further demonstrate bulked segregant analysis using the anchored SNPs as a method for high-throughput genetic mapping in zebrafish.
Intervention Effects on Diurnal Cortisol Rhythms of Child Protective Services–Referred Infants in Early Childhood
Authors: Kristin Bernard, Camelia E. Hostinar, Mary Dozier
Journal: JAMA Pediatrics (2014)

A number of interventions for at-risk children have shown benefits for children's hypothalamic-pituitary-adrenal axis activity immediately after treatment. It is critical to examine whether such changes are maintained over time, given that physiological regulation is implicated in later mental and physical health outcomes.To examine whether differences in diurnal cortisol production between children receiving the active parenting intervention and children in the control group persisted at a preschool follow-up (approximately 3 years following intervention).Between-subject comparison of cortisol patterns among 2 groups of children (experimental and control groups) involved with Child Protective Services following allegations of neglect. The participants included 115 children (43.5% female) between 46.5 and 69.6 months of age (mean [SD], 50.73 [4.98] months) who had been previously randomly assigned to either the Attachment and Biobehavioral Catch-up (ABC) intervention (n = 54) or the control intervention (n = 61).The experimental ABC intervention focused on 3 aims: increasing parental nurturance to child distress, increasing synchronous interactions, and decreasing frightening parental behavior. The control intervention provided educational information about child development to parents. Both interventions were manualized and involved 10 sessions implemented by a trained parent coach in the families' homes or other places of residence.Salivary cortisol samples collected at waking and bedtime for children on 3 separate days.Analyses revealed significant differences in cortisol production at the preschool follow-up, such that children in the ABC intervention group showed more typical patterns of cortisol production than children in the control intervention group. Specifically, children in the ABC group exhibited higher mean (SD) log-transformed morning levels than children in the control group (-0.87 [0.45] vs -1.05 [0.43] μg/dL, respectively [to convert to nanomoles per liter, multiply by 27.588]; β = 0.18; P = .03). Bedtime cortisol levels did not differ significantly between the ABC and DEF groups (mean [SD], -1.19 [0.49] vs -1.17 [0.48] μg/dL, respectively; β01 = -0.01; P = .87). Those in the ABC group showed a steeper decline in cortisol across the day (mean, -0.31 μg/dL) than those in the control group, who showed a blunted cortisol rhythm (mean, -0.12 μg/dL) (β = -0.19; P = .02).Differences in cortisol production between the experimental and control groups persisted at the preschool follow-up and resembled differences initially observed 3 months following intervention. This is encouraging evidence that the ABC intervention for Child Protective Services-referred children may have long-lasting effects on a physiological stress system critical for health and adjustment.clinicaltrials.gov Identifier: NCT02093052.
Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma
Authors: A. M. Sonabend, A. S. Carminucci, B. Amendolara, M. Bansal, R. Leung, L. Lei, R. Realubit, H. Li, C. Karan, J. Yun, C. Showers, R. Rothcock, J. O, A. Califano, P. Canoll, J. N. Bruce
Journal: Neuro-Oncology (2014)

Glioblastoma subtypes have been defined based on transcriptional profiling, yet personalized care based on molecular classification remains unexploited. Topoisomerase II (TOP2) contributes to the transcriptional signature of the proneural glioma subtype. Thus, we targeted TOP2 pharmacologically with etoposide in proneural glioma models. TOP2 gene expression was evaluated in mouse platelet derived growth factor (PDGF)+phosphatase and tensin homolog (PTEN)−/−p53−/− and PDGF+PTEN−/− proneural gliomas and cell lines, as well as human glioblastoma from The Cancer Genome Atlas. Correlation between TOP2 transcript levels and etoposide susceptibility was investigated in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia public dataset and in mouse proneural glioma cell lines. Convection-enhanced delivery (CED) of etoposide was tested on cell-based PDGF+PTEN−/−p53−/− and retroviral-based PDGF+PTEN−/− mouse proneural glioma models. TOP2 expression was significantly higher in human proneural glioblastoma and in mouse proneural tumors at early as well as late stages of development compared with normal brain. TOP2B transcript correlated with susceptibility to etoposide in mouse proneural cell lines and in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia. Intracranial etoposide CED treatment (680 μM) was well tolerated by mice and led to a significant survival benefit in the PDGF+PTEN−/−p53−/− glioma model. Moreover, etoposide CED treatment at 80 μM but not 4 μM led to a significant survival advantage in the PDGF+PTEN−/− glioma model. TOP2 is highly expressed in proneural gliomas, rendering its pharmacological targeting by intratumoral administration of etoposide by CED effective on murine proneural gliomas. We provide evidence supporting clinical testing of CED of etoposide with a molecular-based patient selection approach.