tbuckley/cabot-search huggingface dataset:
Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians
Authors: Amir Qaseem, Vincenza Snow, Thomas D. Denberg, Mary Ann Forciea, Douglas K. Owens
Journal: Annals of Internal Medicine (2008)

Description: The American College of Physicians developed this guideline to present the available evidence on the pharmacologic management of the acute, continuation, and maintenance phases of major depressive disorder; dysthymia; subsyndromal depression; and accompanying symptoms, such as anxiety, insomnia, or neurovegetative symptoms, by using second-generation antidepressants. Methods: Published literature on this topic was identified by using MEDLINE, EMBASE, PsychLit, the Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007. Searches were limited to English-language studies in adults older than 19 years of age. Keywords for search included terms for depressive disorders and 12 specific second-generation antidepressantsbupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxineand their specific trade names. This guideline grades the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system. Recommendation 1: The American College of Physicians recommends that when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences (Grade: strong recommendation; moderate-quality evidence). Recommendation 2: The American College of Physicians recommends that clinicians assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy (Grade: strong recommendation; moderate-quality evidence). Recommendation 3: The American College of Physicians recommends that clinicians modify treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 weeks of the initiation of therapy for major depressive disorder (Grade: strong recommendation; moderate-quality evidence). Recommendation 4: The American College of Physicians recommends that clinicians continue treatment for 4 to 9 months after a satisfactory response in patients with a first episode of major depressive disorder. For patients who have had 2 or more episodes of depression, an even longer duration of therapy may be beneficial (Grade: strong recommendation; moderate-quality evidence).
Limbic Activation During Cue-Induced Cocaine Craving
Authors: Anna Rose Childress, P. David Mozley, William McElgin, Josh Fitzgerald, Martin Reivich, Charles P. O’Brien
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: Since signals for cocaine induce limbic brain activation in animals and cocaine craving in humans, the objective of this study was to test whether limbic activation occurs during cue-induced craving in humans. METHOD: Using positron emission tomography, the researchers measured relative regional cerebral blood flow (CBF) in limbic and comparison brain regions of 14 detoxified male cocaine users and six cocaine-naive comparison subjects during exposure to both non-drug-related and cocaine-related videos and during resting baseline conditions. RESULTS: During the cocaine video, the cocaine users experienced craving and showed a pattern of increases in limbic (amygdala and anterior cingulate) CBF and decreases in basal ganglia CBF relative to their responses to the nondrug video. This pattern did not occur in the cocaine-naive comparison subjects, and the two groups did not differ in their responses in the comparison regions (i.e., the dorsolateral prefrontal cortex, cerebellum, thalamus, and visual cortex). CONCLUSIONS: These findings indicate that limbic activation is one component of cue-induced cocaine craving. Limbic activation may be similarly involved in appetitive craving for other drugs and for natural rewards.
Viral Superantigen Drives Extrafollicular and Follicular B Cell Differentiation Leading to Virus-specific Antibody Production
Authors: Sanjiv A. Luther, Adam Gulbranson-Judge, Hans Acha-Orbea, Ian C.M. MacLennan
Journal: The Journal of Experimental Medicine (1997)

Mouse mammary tumor virus (MMTV[SW]) encodes a superantigen expressed by infected B cells. It evokes an antibody response specific for viral envelope protein, indicating selective activation of antigen-specific B cells. The response to MMTV(SW) in draining lymph nodes was compared with the response to haptenated chicken gamma globulin (NP-CGG) using flow cytometry and immunohistology. T cell priming occurs in both responses, with T cells proliferating in association with interdigitating dendritic cells in the T zone. T cell proliferation continues in the presence of B cells in the outer T zone, and B blasts then undergo exponential growth and differentiation into plasma cells in the medullary cords. Germinal centers develop in both responses, but those induced by MMTV(SW) appear later and are smaller. Most T cells activated in the T zone and germinal centers in the MMTV(SW) response are superantigen specific and these persist for weeks in lymph nodes draining the site MMTV(SW) injection; this contrasts with the selective loss of superantigen-specific T cells from other secondary lymphoid tissues. The results indicate that this viral superantigen, when expressed by professional antigen-presenting cells, drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.
Experimental Conversion of a Defensin into a Neurotoxin: Implications for Origin of Toxic Function
Authors: Shunyi Zhu, Steve Peigneur, Bin Gao, Yoshitaka Umetsu, Shinya Ohki, Jan Tytgat
Journal: Molecular Biology and Evolution (2014)

Scorpion K+ channel toxins and insect defensins share a conserved three-dimensional structure and related biological activities (defense against competitors or invasive microbes by disrupting their membrane functions), which provides an ideal system to study how functional evolution occurs in a conserved structural scaffold. Using an experimental approach, we show that the deletion of a small loop of a parasitoid venom defensin possessing the "scorpion toxin signature" (STS) can remove steric hindrance of peptide-channel interactions and result in a neurotoxin selectively inhibiting K+ channels with high affinities. This insect defensin-derived toxin adopts a hallmark scorpion toxin fold with a common cysteine-stabilized α-helical and β-sheet motif, as determined by nuclear magnetic resonance analysis. Mutations of two key residues located in STS completely diminish or significantly decrease the affinity of the toxin on the channels, demonstrating that this toxin binds to K+ channels in the same manner as scorpion toxins. Taken together, these results provide new structural and functional evidence supporting the predictability of toxin evolution. The experimental strategy is the first employed to establish an evolutionary relationship of two distantly related protein families.
The Use of Genomics in Clinical Trial Design
Authors: Richard Simon
Journal: Clinical Cancer Research (2008)

Abstract Many cancer treatments benefit only a minority of patients who receive them. This results in an enormous burden on patients and on the health care system. The problem will become even greater with the increasing use of molecularly targeted agents whose benefits are likely to be more selective unless the drug development process is modified to include codevelopment of companion diagnostics. Whole genome biotechnology and decreasing costs of genome sequencing make it increasingly possible to achieve an era of predictive medicine in oncology therapeutics. The challenges are numerous and substantial but are not primarily technological. They involve organizing publicly funded diagnostics of deregulated pathways, adopting new paradigms for drug development, and developing incentives for industry to incur the complexity and expense of codevelopment of drugs and companion diagnostics. This article reviews some designs for phase III clinical trials that may facilitate movement to a more predictive oncology.
Reproductive Technologies and the Risk of Birth Defects
Authors: Michael J. Davies, Vivienne M. Moore, Kristyn J. Willson, Phillipa Van Essen, Kevin Priest, Heather Scott, Eric A. Haan, Annabelle Chan
Journal: New England Journal of Medicine (2012)

The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain.We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility.Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects.The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).
Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy
Authors: G. Sonpavde, P.O. Periman, D. Bernold, D. Weckstein, M.T. Fleming, M.D. Galsky, W.R. Berry, F. Zhan, K.A. Boehm, L. Asmar, T.E. Hutson
Journal: Annals of Oncology (2009)
Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1
Authors: J. Brøgger, V. M. Steen, H. G. Eiken, A. Gulsvik, P. Bakke
Journal: European Respiratory Journal (2006)

There is evidence of a hereditary component in chronic obstructive pulmonary disease (COPD). A number of genetic association studies have been performed to find susceptibility genes of COPD. The current authors performed a case–control, genetic-association study and a meta-analysis of 16 studies, involving seven polymorphisms in three well-studied genes: microsomal epoxide hydroxylase (EPHX1); tumour necrosis factor; and β 2 -adrenoreceptor. A total of 492 Caucasian smokers and former smokers were recruited from hospital databases and population cohort studies. In the present study, a protective effect of the EPHX1 Tyr113His polymorphism was found (homozygous odds ratio (OR) 0.5). In the meta-analysis, homozygotes for this single nucleotide polymorphism (SNP) also had a pooled OR of 0.5. The same effect has been found in several lung cancer studies. Effects for other candidate SNPs were weak or statistically insignificant, and probable genotyping error was common. In conclusion, the present data and meta-analysis support a role for microsomal epoxide hydroxylase in the aetiology of chronic obstructive pulmonary disease.
Loss of the Ceramide Transfer Protein Augments EGF Receptor Signaling in Breast Cancer
Authors: Johanna Heering, Nicole Weis, Monika Holeiter, Felix Neugart, Annette Staebler, Tanja N. Fehm, Annabell Bischoff, Jürgen Schiller, Stephan Duss, Simone Schmid, Thomas Korte, Andreas Herrmann, Monilola A. Olayioye
Journal: Cancer Research (2012)

Abstract Triple-negative breast cancers (TNBC) are especially refractory to treatment due to their negative hormone receptor and ErbB2/HER2 status. Therefore, the identification of cancer-associated deregulated signaling pathways is necessary to develop improved targeted therapies. Here, we show that expression of the ceramide transfer protein CERT is reduced in TNBCs. CERT transfers ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin (SM). We provide evidence that by regulating cellular SM levels, CERT determines the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in approximately 70% of TNBCs. CERT downregulation in breast cancer cells enhanced ErbB1 lateral mobility, ligand-induced autophosphorylation, internalization, and chemotaxis. Together, our findings provide a link between lipid metabolism at the Golgi with signaling at the plasma membrane, thereby implicating CERT loss in the progression of TNBCs. Cancer Res; 72(11); 2855–66. ©2012 AACR.
Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer
Authors: Susan M. Molineaux
Journal: Clinical Cancer Research (2011)

With the approval by the U.S. Food and Drug Administration of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma, the proteasome was clinically validated as a target in oncology. The proteasome is part of a complex cellular pathway that controls the specificity and rate of degradation of the majority of proteins in the cell. The search for additional drug targets in the proteasomal pathway is ongoing. In parallel, the next generation of proteasome inhibitors, exhibiting some properties distinct from that of bortezomib, are currently being studied in clinical trials. The key question will be whether these distinctions can improve upon the clinical efficacy and safety standards established by bortezomib and refine our understanding of the mechanism by which proteasome inhibitors are effective in the treatment of cancer.
Osteoclasts Direct Bystander Killing of Bone Cancer
Authors: Margaret L. Ramnaraine, Wendy E. Mathews, James M. Donohue, Christine M. Lynch, Michael J. Goblirsch, Denis R. Clohisy
Journal: Cancer Research (2006)

Abstract Primary and metastatic bone cancers are difficult to eradicate and novel approaches are needed to improve treatment and extend life. As bone cancer grows, osteoclasts, the principal bone-resorbing cells of the body, are recruited to and activated at sites of cancer. In this investigation, we determined if osteoclast lineage cells could function as a cell-based gene delivery system to bone cancers. We used the cytosine deaminase (CD) 5-fluorocytosine (5-FC) enzyme/prodrug system and studied bone marrow and bones from transgenic mice expressing a novel CD gene regulated by the osteoclast tartrate-resistant acid phosphatase (TRAP) gene promoter (Tg/NCD). DsRed2-labeled 2472 sarcoma cells were placed in Tg/NCD osteoclastogenic cultures and treated with 5-FC. 5-FC treatment resulted in profound bystander killing (90%; P &amp;lt; 0.05). The effect of 5-FC treatment on osteoclast lineage cells was most dramatic when administered at the beginning of the 7-day cultures, suggesting that mature osteoclasts are less sensitive to 5-FC. Evaluation of osteoclast-directed bystander killing in vivo revealed dramatic killing of bone cancer with only a modest effect on osteoclast number. Specifically, 5-FC treatment of tumor-bearing Tg/NCD mice or Tg/NCD bone marrow transplanted C3H mice (Tg/NCD-C3H) resulted in 92% and 44% reductions in tumor area, respectively (P &amp;lt; 0.05). Eight of ten 5-FC-treated Tg/NCD mice had complete bone tumor killing and five of six 5-FC-treated Tg/NCD-C3H mice had reduced tumor compared with controls. In addition, Tg/NCD osteoclasts were resistant to 5-FC treatment in vivo, a very important feature, as it identifies osteoclasts as an ideal CD gene delivery system. (Cancer Res 2006; 66(22): 10929-35)
A Japanese case of segmental Darier's disease caused by mosaicism for the ATP2A2 mutation
Authors: T. Wada, Y. Shirakata, H. Takahashi, S. Murakami, H. Iizuka, H. Suzuki, K. Hashimoto
Journal: British Journal of Dermatology (2003)

Journal Article A Japanese case of segmental Darier's disease caused by mosaicism for the ATP2A2 mutation Get access T. Wada, T. Wada Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Shigenobucho, Onsengun, Ehime 791‐0295, Japan Departments of Search for other works by this author on: Oxford Academic Google Scholar Y. Shirakata, Y. Shirakata Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Shigenobucho, Onsengun, Ehime 791‐0295, Japan Departments of Y. Shirakata E‐mail: shirakat@m.ehime‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Takahashi, H. Takahashi Dermatology and Search for other works by this author on: Oxford Academic Google Scholar S. Murakami, S. Murakami Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Shigenobucho, Onsengun, Ehime 791‐0295, Japan Departments of Search for other works by this author on: Oxford Academic Google Scholar H. Iizuka, H. Iizuka Dermatology and Search for other works by this author on: Oxford Academic Google Scholar H. Suzuki, H. Suzuki Biochemistry, Asahikawa Medical College, 2‐1‐1 Midorigaoka Higashi, Asahikawa, 078‐8510 Japan Search for other works by this author on: Oxford Academic Google Scholar K. Hashimoto K. Hashimoto Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Shigenobucho, Onsengun, Ehime 791‐0295, Japan Departments of Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 149, Issue 1, 1 July 2003, Pages 185–188, https://doi.org/10.1046/j.1365-2133.2003.05412.x Published: 01 July 2003 Article history Accepted: 14 December 2002 Published: 01 July 2003
Converting enzyme inhibitors in cardiovascular therapy: current status and future potential
Authors: T. Unger, P. Gohlke
Journal: Cardiovascular Research (1994)

Journal Article Converting enzyme inhibitors in cardiovascular therapy: current status and future potential Get access Thomas Unger, Thomas Unger Department of Pharmacology. University of Heidelberg. Im Neuenheimer Feld 366, 69120 Heidelberg, Germany: T Unger, P Gohlke. Correspondence to Professor Unger. Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter Gohlke Peter Gohlke Department of Pharmacology. University of Heidelberg. Im Neuenheimer Feld 366, 69120 Heidelberg, Germany: T Unger, P Gohlke. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 2, February 1994, Pages 146–158, https://doi.org/10.1093/cvr/28.2.146 Published: 01 February 1994 Article history Received: 15 April 1993 Accepted: 23 November 1993 Published: 01 February 1994
On the Utility of Short Intron Sequences as a Reference for the Detection of Positive and Negative Selection in Drosophila
Authors: J. Parsch, S. Novozhilov, S. S. Saminadin-Peter, K. M. Wong, P. Andolfatto
Journal: Molecular Biology and Evolution (2010)

The detection of selection, both positive and negative, acting on a DNA sequence or class of nucleotide sites requires comparison with a reference sequence that is unaffected by selection. In Drosophila, recent findings of widespread selective constraint, as well as adaptive evolution, in both coding and noncoding regions highlight the difficulties in choosing such a reference sequence. Here, we investigate the utility of short intron sequences as a reference for the detection of selection. For a set of 119 Drosophila melanogaster genes containing 195 short introns (<or=120 bp), we analyzed polymorphism and divergence at 1) 4-fold synonymous sites, 2) all sites of introns <or=120 bp, 3) all sites of introns <or=65 bp, 4) bases 8-30 of introns <or=120 bp, and 5) bases 8-30 of introns <or=65 bp. The last class of sites shows the highest levels of both interspecific divergence and intraspecific polymorphism, suggesting that these sites are under the least selective constraint. Bases 8-30 of introns <or=65 bp also have the lowest ratio of divergence to polymorphism, which may indicate that a small proportion of substitutions in the other classes of sites are the result of adaptive evolution. Although there is little signal of selection on the primary sequence of short introns, patterns of insertion-deletion polymorphism and divergence suggest that both positive and negative selection act to maintain an optimal intron length.
Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma
Authors: M Masoli
Journal: Thorax (2005)

<b>Background:</b> There is uncertainty as to the dose of inhaled corticosteroids (ICS) at which to start concomitant long acting β agonist (LABA) treatment in patients with asthma not adequately controlled by ICS alone. <b>Methods:</b> A meta-analysis was carried out of randomised, double blind clinical trials that compared the efficacy of adding salmeterol to moderate doses of ICS (fluticasone propionate 200 μg/day or equivalent) with increasing the ICS dose by at least twofold in symptomatic adult patients with asthma. The main outcome measures were the number of subjects withdrawn from the study due to asthma and the number of subjects with at least one moderate or severe exacerbation. <b>Results:</b> Twelve studies with a total of 4576 subjects met the inclusion criteria for the analyses. The number of subjects withdrawn due to asthma and with at least one moderate or severe exacerbation was higher in the high dose ICS group (odds ratios 1.58, 95% CI 1.12 to 2.24 and 1.35, 95% CI 1.10 to 1.66, respectively). For the secondary outcome variables (forced expiratory volume in 1 second, morning and evening peak expiratory flow, and daytime β agonist use) there was significantly greater benefit in the salmeterol group. <b>Conclusions:</b> This meta-analysis shows that the addition of salmeterol to moderate doses of ICS (fluticasone 200 μg/day or equivalent) in patients with asthma symptomatic at that dose results in significantly greater clinical benefit than increasing the dose of ICS by twofold or more.
Hyperprolactinemia Associated With Empty Sella Syndrome
Authors: Tah-Hsiung Hsu
Journal: JAMA (1976)

SINCE the radioimmunoassay of human prolactin became available, hyperprolactinemia has been demonstrated in a number of pathological states.<sup>1</sup>An elevated basal prolactin concentration of more than 200 ng/ml is generally regarded as strong evidence in favor of an adenomatous pituitary lesion.<sup>2</sup>Our patient had substantial hyperprolactinemia associated with the empty sella syndrome. <h3>Report of a Case</h3> A 37-year-old woman was referred to The Johns Hopkins Hospital in December 1973 because of persistent generalized headaches of five years' duration. Three years prior to admission, she underwent extensive examinations in another hospital. Skull roentgenograms had shown enlargement of the sella turcica, with erosion of the dorsum sellae (Fig 1). A right brachial arteriogram showed no abnormalities. Pneumoencephalography was attempted twice, but no air could be driven into the ventricular system (Fig 2). The patient was obese, normotensive, and without visual field defects. Galactorrhea could not be demonstrated. Serum thyroxine level