tbuckley/cabot-search huggingface dataset:
Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration
Authors: Charlotte Sonigo, Justine Bouilly, Nadège Carré, Virginie Tolle, Alain Caraty, Javier Tello, Fabian-Jesus Simony-Conesa, Robert Millar, Jacques Young, Nadine Binart
Journal: Journal of Clinical Investigation (2012)

Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists.
Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis
Authors: T Hayakawa
Journal: Gut (2005)

Although prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), and microsomal prostaglandin E synthase 1 (mPGES-1) are known to play a role in various inflammatory events, their roles in the pathogenesis of gastro-oesophageal reflux disease are not known.We examined the dynamics of COX-1, COX-2, mPGES-1, mPGES-2, cytosolic PGES (cPGES), and PGE2 synthetic activity in rat acid reflux oesophagitis and the effects of COX-2 inhibitors on the severity of oesophagitis.Acid reflux oesophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus. Rats were killed on day 3 (acute phase) or day 21 (chronic phase) after induction of oesophagitis.Expression of COX-2 and mPGES-1 was markedly increased in oesophagitis while modest changes in COX-1, cPGES, and mPGES-2 expression were observed. COX-2 and mPGES-1 were colocalised in epithelial cells of the basal layer, as well as inflammatory and mesenchymal cells in the lamina propria and submucosa. COX-2 inhibitors significantly reduced the severity of chronic oesophagitis but did not affect acute oesophageal lesions. COX-2 inhibitors significantly inhibited the increase in PGE2 synthesis in oesophageal lesions on both days 3 and 21. Epithelial proliferation was significantly increased in the basal layer on day 21. Inflammatory cells and epithelial cells of the basal layer exhibited reactions for EP4 in oesophagitis.PGE2 derived from COX-2 and mPGES-1 plays a significant role in the pathogenesis of chronic acid reflux oesophagitis, and possibly in basal hyperplasia and persistent inflammatory cell infiltration.
Analysis of somatic mutation in five B cell subsets of human tonsil.
Authors: V Pascual, Y J Liu, A Magalski, O de Bouteiller, J Banchereau, J D Capra
Journal: The Journal of Experimental Medicine (1994)

Using a series of phenotypic markers that include immunoglobulin (Ig)D, IgM, IgG, CD23, CD44, Bcl-2, CD38, CD10, CD77, and Ki67, human tonsillar B cells were separated into five fractions representing different stages of B cell differentiation that included sIgD+ (Bm1 and Bm2), germinal center (Bm3 and Bm4), and memory (Bm5) B cells. To establish whether the initiation of somatic mutation correlated with this phenotypic characterization, we performed polymerase chain reaction and subsequent sequence analysis of the Ig heavy chain variable region genes from each of the B cell subsets. We studied the genes from the smallest VH families (VH4, VH5, and VH6) in order to facilitate the mutational analysis. In agreement with previous reports, we found that the somatic mutation machinery is activated only after B cells reach the germinal center and become centroblasts (Bm3). Whereas 47 independently rearranged IgM transcripts from the Bm1 and Bm2 subsets were nearly germline encoded, 57 Bm3-, and Bm4-, and Bm5-derived IgM transcripts had accumulated an average of 5.7 point mutations within the VH gene segment. gamma transcripts corresponding to the same VH gene families were isolated from subsets Bm3, Bm4, and Bm5, and had accumulated an average of 9.5 somatic mutations. We conclude that the molecular events underlying the process of somatic mutation takes place during the transition from IgD+, CD23+ B cells (Bm2) to the IgD-, CD23-, germinal center centroblast (Bm3). Furthermore, the analysis of Ig variable region transcripts from the different subpopulations confirms that the pathway of B cell differentiation from virgin B cell throughout the germinal center up to the memory compartment can be traced with phenotypic markers. The availability of these subpopulations should permit the identification of the functional molecules relevant to each stage of B cell differentiation.
Cell-Surface Major Glycoprotein of BALB/c Mouse Plasmacytoma 58-8 Cells2
Authors: Haruhiko Tokuyama, Shunsuke Migita
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Cell-Surface Major Glycoprotein of BALB/c Mouse Plasmacytoma 58-8 Cells Get access Haruhiko Tokuyama, Haruhiko Tokuyama 4 3Department of Molecular Immunology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan. 4Address reprint requests to Dr. Tokuyama at his present address: Department of Immunology Research, Roswell Park Memorial Institute, 666 Elm St., Buffalo, N.Y. 14263 Search for other works by this author on: Oxford Academic PubMed Google Scholar Shunsuke Migita Shunsuke Migita 3Department of Molecular Immunology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan. 5We are grateful to Dr. Shunnosuke Sakai, Dr. Osami Daimaru, and Dr. Yukio Kaneko, Department of Molecular Immunology, Cancer Research Institute, Kanazawa University, for their discussions and support. We also thank Dr. Nobuyuki Tanigaki, Department of Immunology Research, Roswell Park Memorial Institute, for constructive criticism and editorial assistance. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 1, July 1978, Pages 203–208, https://doi.org/10.1093/jnci/61.1.203 Published: 01 July 1978 Article history Received: 07 October 1977 Accepted: 15 January 1978 Published: 01 July 1978
Weight Gain in the First Week of Life and Overweight in Adulthood
Authors: Nicolas Stettler, Virginia A. Stallings, Andrea B. Troxel, Jing Zhao, Rita Schinnar, Steven E. Nelson, Ekhard E. Ziegler, Brian L. Strom
Journal: Circulation (2005)

Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity.A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index > or =25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population.In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.
Distribution of mast cells in human dermis: development of a mapping technique
Authors: T. Cowen, P. Trigg, R.A.J. Eady
Journal: British Journal of Dermatology (1979)

A new method was developed to define the distribution of mast cells in normal human skin. The population density was determined in a number of zones of different depth in the dermis. Two regions of the same limb were studied systematically. Both were shown to have mast cell populations of similar size and distribution, with a maximum density immediately below the dermo-epidermal junction, gradually falling to a minimum density in the deeper layers of the dermis. Small secondary peaks were less clearly defined at the base of the dermis. These findings should provide baseline data for comparisons with mast cell population size and distribution in different areas of normal skin, or in similar areas in clinical disorders or experimental conditions.
Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Egbert F. Smit, Sjaak A. Burgers, Bonne Biesma, Hans J.M. Smit, Pier Eppinga, Anne-Marie C. Dingemans, Markus Joerger, Jan H. Schellens, Andrew Vincent, Nico van Zandwijk, Harry J.M. Groen
Journal: Journal of Clinical Oncology (2009)

We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy.Main eligibility criteria were histologic or cytologic proof of advanced non-small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m(2) (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m(2) (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (alpha = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, gamma-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients.Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03).PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.
Cost-Effectiveness Analysis of Computerized Tomography in the Routine Follow-Up of Patients After Primary Treatment for Hodgkin’s Disease
Authors: Beverly A. Guadagnolo, Rinaa S. Punglia, Karen M. Kuntz, Peter M. Mauch, Andrea K. Ng
Journal: Journal of Clinical Oncology (2006)

To estimate the clinical benefits and cost effectiveness of computed tomography (CT) in the follow-up of patients with complete response (CR) after treatment for Hodgkin's disease (HD).We developed a decision-analytic model to evaluate follow-up strategies for two hypothetical cohorts of 25-year-old patients with stage I-II or stage III-IV HD, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine-based chemotherapy with or without radiation therapy, respectively. We compared three strategies for observing asymptomatic patients after CR: routine annual CT for 10 years, annual CT for 5 years, or follow-up with non-CT modalities only. We used Markov models to calculate life expectancy, quality-adjusted life expectancy, and lifetime costs. Baseline probabilities, transition probabilities, and utilities were derived from published studies. Cost data were derived from the Medicare fee schedule and medical literature. We performed sensitivity analyses by varying baseline estimates.Annual CT follow-up is associated with minimal survival benefit. With adjustments for quality of life, we found a decrement in quality-adjusted life expectancy for early-stage patients followed with CT compared with non-CT modalities. Sensitivity analyses showed annual CT for 5 years becomes more effective than non-CT follow-up if the specificity of CT is 80% or more or if the disutility associated with a false-positive CT result is less than 0.01 quality-adjusted life years (QALYs). For advanced-stage patients, annual CT for 5 years is associated with a very small quality-adjusted survival gain over non-CT follow-up with an incremental cost-effectiveness ratio of 9,042,300 dollars/QALY.Our analysis suggests that routine CT should not be used in the surveillance of asymptomatic patients in CR after treatment for HD.
Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: a pooled analysis of population-based surveys
Authors: Gretchen A Stevens, James E Bennett, Quentin Hennocq, Yuan Lu, Luz Maria De-Regil, Lisa Rogers, Goodarz Danaei, Guangquan Li, Richard A White, Seth R Flaxman, Sean-Patrick Oehrle, Mariel M Finucane, Ramiro Guerrero, Zulfiqar A Bhutta, Amarilis Then-Paulino, Wafaie Fawzi, Robert E Black, Majid Ezzati
Journal: The Lancet Global Health (2015)

Vitamin A deficiency is a risk factor for blindness and for mortality from measles and diarrhoea in children aged 6-59 months. We aimed to estimate trends in the prevalence of vitamin A deficiency between 1991 and 2013 and its mortality burden in low-income and middle-income countries.We collated 134 population-representative data sources from 83 countries with measured serum retinol concentration data. We used a Bayesian hierarchical model to estimate the prevalence of vitamin A deficiency, defined as a serum retinol concentration lower than 0·70 μmol/L. We estimated the relative risks (RRs) for the effects of vitamin A deficiency on mortality from measles and diarrhoea by pooling effect sizes from randomised trials of vitamin A supplementation. We used information about prevalences of deficiency, RRs, and number of cause-specific child deaths to estimate deaths attributable to vitamin A deficiency. All analyses included a systematic quantification of uncertainty.In 1991, 39% (95% credible interval 27-52) of children aged 6-59 months in low-income and middle-income countries were vitamin A deficient. In 2013, the prevalence of deficiency was 29% (17-42; posterior probability [PP] of being a true decline=0·81). Vitamin A deficiency significantly declined in east and southeast Asia and Oceania from 42% (19-70) to 6% (1-16; PP>0·99); a decline in Latin America and the Caribbean from 21% (11-33) to 11% (4-23; PP=0·89) also occurred. In 2013, the prevalence of deficiency was highest in sub-Saharan Africa (48%; 25-75) and south Asia (44%; 13-79). 94 500 (54 200-146 800) deaths from diarrhoea and 11 200 (4300-20 500) deaths from measles were attributable to vitamin A deficiency in 2013, which accounted for 1·7% (1·0-2·6) of all deaths in children younger than 5 years in low-income and middle-income countries. More than 95% of these deaths occurred in sub-Saharan Africa and south Asia.Vitamin A deficiency remains prevalent in south Asia and sub-Saharan Africa. Deaths attributable to this deficiency have decreased over time worldwide, and have been almost eliminated in regions other than south Asia and sub-Saharan Africa. This new evidence for both prevalence and absolute burden of vitamin A deficiency should be used to reconsider, and possibly revise, the list of priority countries for high-dose vitamin A supplementation such that a country's priority status takes into account both the prevalence of deficiency and the expected mortality benefits of supplementation.Bill & Melinda Gates Foundation, Grand Challenges Canada, UK Medical Research Council.
Activator Protein-1 Transcription Factors Are Associated with Progression and Recurrence of Prostate Cancer
Authors: Xuesong Ouyang, Walter J. Jessen, Hikmat Al-Ahmadie, Angel M. Serio, Yong Lin, Weichung-Joseph Shih, Victor E. Reuter, Peter T. Scardino, Michael M. Shen, Bruce J. Aronow, Andrew J. Vickers, William L. Gerald, Cory Abate-Shen
Journal: Cancer Research (2008)

Abstract To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors—the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer. [Cancer Res 2008;68(7):2132–44]
Drug Approvals 2011: Focus on Companion Diagnostics
Authors: M. Goozner
Journal: JNCI Journal of the National Cancer Institute (2012)

.S. Food and Drug Administration officials and cancer care advocacy groups are hailing 2011 as a milestone year in the development of personalized medicine after the agency approved six new cancer drugs, including two with concomitantly approved biomarker tests that can identify the specific subpopulations most likely to benefit from the new therapies. Patients with rare or previously untreatable cancers also benefi ted from the uptick in activity at the FDA ’ s oncology division, which approved 13 indications for new or existing molecular entities in 2011, compared with nine the previous year. They included the fi rst FDA-approved treatments for anaplastic large-cell lymphoma (ALCL) and medullary thyroid cancer. The FDA also approved the conjugated monoclonal antibody that combats ALCL, brentuximab vedotin (Adcetris), as the fi rst new treatment since 1977 for Hodgkin lymphoma (HL), which strikes mostly younger patients. “We ’ re seeing an infl ection point,” said Janet Woodcock, M.D. , director of the FDA ’ s Center for Drug Evaluation and Research. “We ’ re moving toward having a new taxonomy of disease with cancer at the leading edge. We ’ re increasingly defi ning a disease by what ’ s gone wrong from a molecular standpoint rather than where it originated.” The newly approved biomarkerdriven drugs with associated tests included vemurafenib (Zelboraf) for late-stage melanoma patients with the BRAF V600 → E mutation. The FDA gave the drug fast-track approval in midAugust after the sponsor, Roche – Genentech, called an early halt to a single trial with 675 patients who had been randomized to receive either vemurafenib or the previously approved dacarbazine. The dacarbazine arm had an 8-month median survival time, with 64% of patients still alive when the trial was stopped, compared with 77% still alive on vemurafenib, which meant the median survival time had not yet been reached. Vemurafenib was the second new therapy that the FDA approved for metastatic melanoma last year. The fi rst, ipilimumab (Yervoy from Bristol-Myers Squibb), was the fi rst in a new class of immune system – stimulating drugs ( see J. Natl. Cancer Inst. 2011;103:997 – 9). It received FDA approval in March after it prolonged survival by 3.5 – 10 months in a single trial in 676 patients who had failed previous chemotherapy regimens, according to the FDA. Vemurafenib and ipilimumab were the fi rst therapies to extend life in patients with metastatic melanoma, according to the
Frequent and specific immunity to the embryonal stem cell–associated antigen SOX2 in patients with monoclonal gammopathy
Authors: Radek Spisek, Anjli Kukreja, Lin-Chi Chen, Phillip Matthews, Amitabha Mazumder, David Vesole, Sundar Jagannath, Henry A. Zebroski, Andrew J.G. Simpson, Gerd Ritter, Brian Durie, John Crowley, John D. Shaughnessy, Matthew J. Scanlan, Ali O. Gure, Bart Barlogie, Madhav V. Dhodapkar
Journal: The Journal of Experimental Medicine (2007)

Specific targets of cellular immunity in human premalignancy are largely unknown. Monoclonal gammopathy of undetermined significance (MGUS) represents a precursor lesion to myeloma (MM). We show that antigenic targets of spontaneous immunity in MGUS differ from MM. MGUS patients frequently mount a humoral and cellular immune response against SOX2, a gene critical for self-renewal in embryonal stem cells. Intranuclear expression of SOX2 marks the clonogenic CD138− compartment in MGUS. SOX2 expression is also detected in a proportion of CD138+ cells in MM patients. However, these patients lack anti-SOX2 immunity. Cellular immunity to SOX2 inhibits the clonogenic growth of MGUS cells in vitro. Detection of anti-SOX2 T cells predicts favorable clinical outcome in patients with asymptomatic plasmaproliferative disorders. Harnessing immunity to antigens expressed by tumor progenitor cells may be critical for prevention and therapy of human cancer.