tbuckley/cabot-search huggingface dataset:
Functional characterization of the Mss4 locus mediating female-specific resistance to ethylnitrosourea-induced oncogenesis in the rat peripheral nervous system
Authors: Bernd Koelsch, Bettina Winzen, Christine Fischer, Andrea Kindler-Roehrborn
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4738 

The development of cancer is considered a complex genetic disease controlled by multiple genetic and environmental factors. Genes modifying cancer risk are interesting targets for cancer prevention, early diagnosis and therapy. The inbred BD-rat strains constitute a model system for analysis of the genetic basis of cancer susceptibility or resistance, as they exhibit differential sensitivity to the development of peripheral nerve sheath tumors (MPNST) induced by the carcinogen ethylnitrosourea (EtNU) on postnatal day one. Rats of the BDIX- and BDIV strains, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced MPNST arising predominantly in the trigeminal nerves. Seven chromosomal loci associated with susceptibility/resistance to MPNST induction were found to control tumor incidence and/or survival time in an allele and sex-specific manner. Among them the Mss4 locus on chromosome 6 mediates almost complete tumor resistance in female animals through homozygous BDIV alleles. Due to the fact that they exert nearly monogenic effects on tumor resistance the genomic fragment of interest could be narrowed down to 20 Mb by analyzing haplotypes of affected females. To verify the allele and sex-specific effects of this locus on MPNST development rats of the congenic strain BDIX (Mss4a). BDIV were treated with EtNU. This strain carries a 36 Mb BDIV fragment (RNO-6:98-134 Mb) encompassing the telomeric two thirds of Mss4 and additional adjacent sequence. While tumor incidence and latency time largely remain the same in BDIX (Mss4a). BDIV males compared to BDIX male controls we see a strongly reduced incidence and increased latency time in females. However the BDIV fragment introgressed does not mediate complete resistance in females as previously suggested by the association studies. In parallel, comparative expression profiling of female trigeminal nerves from BDIV, BDIX and the congenic BDIX (Mss4a ).BDIV rats resulted in 235 differentially expressed genes between the parental strains while the expression of 66 genes varies strongly due to the introduction of the Mss4a fragment to the BDIX genetic background (threshold 2-fold change). Seven of the 66 differentially expressed transcripts were located in the fragment inserted representing interesting candidate genes while 59 seemed to be regulated by trans-acting genome wide mechanisms. No differential expression of genes located in the Mss4a fragment was displayed between BDIX( Mss4a ).BDIV females 100 days after EtNU-treatment and age matched controls.
Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate
Authors: Shanni N. Silberberg, Leila Taher, Susan Lindtner, Magnus Sandberg, Alex S. Nord, Daniel Vogt, Gabriel L. Mckinsey, Renee Hoch, Kartik Pattabiraman, Dongji Zhang, Jose L. Ferran, Aleksandar Rajkovic, Olga Golonzhka, Carol Kim, Hongkui Zeng, Luis Puelles, Axel Visel, John L.R. Rubenstein
Journal: Neuron (2016)
Exposure to Gestational Diabetes Mellitus: Impact on the Development of Early-Onset Type 2 Diabetes in Canadian First Nations and Non–First Nations Offspring
Authors: Elizabeth A.C. Sellers, Heather J. Dean, Leigh Anne Shafer, Patricia J. Martens, Wanda Phillips-Beck, Maureen Heaman, Heather J. Prior, Allison B. Dart, Jonathan McGavock, Margaret Morris, Ali A. Torshizi, Sora Ludwig, Garry X. Shen
Journal: Diabetes Care (2016)

OBJECTIVE Type 2 diabetes is increasing in children worldwide, with Canadian First Nations (FN) children disproportionally affected. The prevalence of gestational diabetes mellitus (GDM) also is increasing. The objective of this study was to evaluate the impact of GDM exposure in utero and FN status on the subsequent risk of type 2 diabetes in offspring in the first 30 years of life. RESEARCH DESIGN AND METHODS In this population-based historical prospective cohort study, we used administrative databases linked to a clinical database to explore the independent association and interaction between GDM and FN status on the subsequent development of type 2 diabetes in offspring. RESULTS Among 321,008 births with a median follow-up of 15.1 years, both maternal GDM and FN status were independently associated with subsequent risk of type 2 diabetes in offspring in the first 30 years of life (hazard ratio 3.03 [95% CI 2.44–3.76; P &amp;lt; 0.0001] vs. 4.86 [95% CI 4.08–5.79; P &amp;lt; 0.0001], respectively). No interaction between GDM and FN status on type 2 diabetes risk was observed. FN status had a stronger impact on the development of type 2 diabetes in offspring than GDM. CONCLUSIONS GDM is an important modifiable risk factor for type 2 diabetes, and its prevention may reduce the prevalence of subsequent type 2 diabetes in offspring. This study adds unique and rigorous evidence to the global public health debate about the impact of GDM on the long-term health of offspring.
Hydroxyurea-Induced Changes of Components Involved In the Modulation of Adenosine Levels, In Blood Cells From Sickle Cell Disease Patients
Authors: Rodrigo Alexandre Panepucci, Ana Cristina S Pinto, Carolina Dias-Carlos, Felipe Saldanha-Araujo, Patricia VB Palma, Jacques Elion, Dimas T Covas, Marco A Zago
Journal: Blood (2010)
A physician-reported neurological signs and symptoms worksheet (NSS WS) in EGF105084: A phase II study of lapatinib (lap) for pts with recurrent brain metastases (BM) from HER2+ breast cancer (BC)
Authors: N. U. Lin, H. H. Roché, V. Dieras, D. Skarlos, H. J. Stemmler, M. Liu, B. Dharan, D. Zembryki, K. Stepewski, S. D. Rubin
Journal: Journal of Clinical Oncology (2008)

1078 Background: BM are frequently accompanied by a variety of NSS. Development of a systematic assessment tool for NSS may aid in the evaluation of clinical benefit. Based on a list of tumor-related NSS derived from the literature (Bezjak 2002), we developed a physician-reported NSS WS comprised of 13 AEs selected from the NCI CTCAE v3.0 grouped into 7 categories: level of consciousness, neurological symptoms, cranial nerves, language, strength, sensation, and ataxia. Objective: To assess clinical feasibility of the NSS WS and evaluate concordance between tumor volume (vol) reduction and improvement in NSS. Methods: Eligible pts had HER2+ BC, prior trastuzumab and cranial RT, PS 0–2, and radiographic evidence of progressive BM. Pts received lap 750 mg PO BID. Improvement in tumor-related NSS was a secondary endpoint defined by all of the following: decrease by ≥ 1 grades from baseline of any NSS with confirmation at least 4 weeks later, no development or worsening in any NSS, no radiographic evidence of CNS or non-CNS disease progression, stable or decreasing steroids. Physicians were to complete the NSS WS at every 4-week visit. Results: Among 205 pts with NSS at baseline, improvement on therapy was observed in: 11.2% (23/205) of pts overall; 6.6% (9/136) of pts who had either vol increase of CNS lesions as best response or withdrew from study for any reason without documented vol decrease; 16.7% (6/36) of pts with 0- 20% vol reduction; and 24% (8/33) of pts with ≥ 20% vol reduction of CNS lesions and no steroid increase. Physician narratives were obtained as part of an ad hoc analysis and compared to NSS WS findings. Among 8 pts with a ≥ 20% vol reduction of CNS lesions and improvement on NSS WS, 7 pt narratives were received, and 5 of these described NSS concordant with those recorded on the WS. Analysis is ongoing. Conclusions: This physician-reported NSS WS based on selected CTCAEs and gradings appears clinically feasible. An association between improvement in NSS and vol reduction of CNS lesions was observed. Concordance of narratives with NSS WS is encouraging. Further testing in randomized, blinded studies of pts with BM is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Genentech, GlaxoSmithKline
Advances in Systemic Therapy for Metastatic or Advanced Gastric Cancer
Authors: Kohei Shitara, Atsushi Ohtsu
Journal: Journal of the National Comprehensive Cancer Network (2016)

In recent years, various new agents have been investigated for the treatment of advanced gastric cancer (AGC). The anti-HER2 antibody trastuzumab has been shown to prolong the overall survival of patients with HER2-positive AGC and has become a standard treatment. However, lapatinib, or ado-trastuzumab emtansine (T-DM1), did not show survival benefit in AGC, although it has shown remarkable efficacy for HER2-positive breast cancer. The efficacy of the anti–vascular endothelial growth factor receptor monoclonal antibody ramucirumab for pretreated gastric cancer is a milestone for antiangiogenic therapy for AGC. Early clinical trials of TAS-118, TAS-102, and STAT3 inhibitors; IMAB362 (anti–Claudin 18.2); and immune checkpoint inhibitors are all encouraging. These findings warrant further evaluation in larger clinical trials.
Are Fish Consumption Advisories for the Great Lakes Adequately Protective against Chemical Mixtures?
Authors: Nilima Gandhi, Ken G. Drouillard, George B. Arhonditsis, Sarah B. Gewurtz, Satyendra P. Bhavsar
Journal: Environmental Health Perspectives (2016)

Background:The North American Great Lakes are home to > 140 types of fish and are famous for recreational and commercial fishing. However, the presence of toxic substances has resulted in the issuance of fish consumption advisories that are typically based on the most restrictive contaminant.Objectives:We investigated whether these advisories, which typically neglect the existence of a mixture of chemicals and their possible additive adverse effects, are adequately protective of the health of humans consuming fish from the Canadian waters of the Great Lakes.Methods:Using recent fish contaminant monitoring data collected by the government of Ontario, Canada, we simulated advisories using most-restrictive-contaminant (one-chem) and multi-contaminant additive effect (multi-chem) approaches. The advisories from the two simulations were compared to determine if there is any deficiency in the currently issued advisories.Results:Approximately half of the advisories currently issued are potentially not adequately protective. Of the four Great Lakes studied, the highest percentage of advisories affected are in Lake Ontario if an additive effect is considered. Many fish that are popular for consumption, such as walleye, salmon, bass and trout, would have noticeably more stringent advisories.Conclusions:Improvements in the advisories may be needed to ensure that the health of humans consuming fish from the Great Lakes is protected. In this region, total polychlorinated biphenyls (PCBs) and mercury are the major contaminants causing restrictions on consuming fish, whereas dioxins/furans, toxaphene, and mirex/photomirex are of minor concern. Regular monitoring of most organochlorine pesticides and metals in fish can be discontinued.Citation:Gandhi N, Drouillard KG, Arhonditsis GB, Gewurtz SB, Bhavsar SP. 2017. Are fish consumption advisories for the Great Lakes adequately protective against chemical mixtures? Environ Health Perspect 125:586–593; http://dx.doi.org/10.1289/EHP104
High levels of periostin correlate with increased fracture rate, diffuse MRI pattern, abnormal bone remodeling and advanced disease stage in patients with newly diagnosed symptomatic multiple myeloma
Authors: E Terpos, D Christoulas, E Kastritis, T Bagratuni, M Gavriatopoulou, M Roussou, A Papatheodorou, E Eleutherakis-Papaiakovou, N Kanellias, C Liakou, I Panagiotidis, M Migkou, P Kokkoris, L A Moulopoulos, M A Dimopoulos
Journal: Blood Cancer Journal (2016)

Abstract Periostin is an extracellular matrix protein that is implicated in the biology of normal bone remodeling and in different cancer cell growth and metastasis. However, there is no information on the role of periostin in multiple myeloma (MM). Thus, we evaluated periostin in six myeloma cell lines in vitro ; in the bone marrow plasma and serum of 105 newly diagnosed symptomatic MM (NDMM) patients and in the serum of 23 monoclonal gammopathy of undetermined significance (MGUS), 33 smoldering MM (SMM) patients, 30 patients at the plateau phase post-first-line therapy, 30 patients at first relapse and 30 healthy controls. We found high levels of periostin in the supernatants of myeloma cell lines compared with ovarian cancer cell lines that were not influenced by the incubation with the stromal cell line HS5. In NDMM patients the bone marrow plasma periostin was almost fourfold higher compared with the serum levels of periostin and correlated with the presence of fractures and of diffuse magnetic resonance imaging pattern of marrow infiltration. Serum periostin was elevated in NDMM patients compared with healthy controls, MGUS and SMM patients and correlated with advanced disease stage, high lactate dehydrogenase, increased activin-A, increased bone resorption and reduced bone formation. Patients at first relapse had also elevated periostin compared with healthy controls, MGUS and SMM patients, while even patients at the plateau phase had elevated serum periostin compared with healthy controls. These results support an important role of periostin in the biology of myeloma and reveal periostin as a possible target for the development of antimyeloma drugs.
Sport and exercise medicine in the UK: what juniors should know to get ahead
Authors: Liam Richard West, Steffan Griffin
Journal: British Journal of Sports Medicine (2016)

Are you sick and tired of pushing so many pills to your patient for their various ailments that by 9:15 you can hear them rattling in the corridor? Would you rather empower them to be physically active in a safe, prescribed way to help them manage these diseases and improve their overall health? Exercise medicine might be for you.

Do you want to work with a highly motivated patient demographic that will go above and beyond to overcome illness and injury? Do you want to use your medical knowledge to increase sporting performance, all while being able to escape the clinic and share in some of the world's most iconic sporting moments? Maybe sports medicine is for you. Welcome to the exciting and refreshing approach to medicine offered by the specialty of sports and exercise medicine (SEM); putting the ‘Health’ back into the National Health Service (NHS).

A popular image is that SEM doctors just care for professional or amateur athletes, manage their medical conditions and musculoskeletal injuries in an attempt to improve their performance. However, there is an increasing need for SEM doctors to manage inactive or obese patients by providing education about and safe prescriptions for physical activity that gets patients to treat or prevent various non-communicable diseases such as diabetes mellitus and hypertension.1

SEM doctors often work in partnership and share a skill set with other specialties; for example, collaborating with neurologists to return concussed athletes safely to competition, with cardiologists to distinguish an athlete's heart from a cardiomyopathy, with radiologists to interpret scans within the clinical context and with orthopaedic surgeons to best manage musculoskeletal injuries.

In the elite sport setting, you will work with and learn from various professionals, including physiotherapists, sports scientists, osteopaths, physiologists, fitness coaches and managers, and must aim to maintain …
Exome and genome sequencing for inborn errors of immunity
Authors: Isabelle Meyts, Barbara Bosch, Alexandre Bolze, Bertrand Boisson, Yuval Itan, Aziz Belkadi, Vincent Pedergnana, Leen Moens, Capucine Picard, Aurélie Cobat, Xavier Bossuyt, Laurent Abel, Jean-Laurent Casanova
Journal: Journal of Allergy and Clinical Immunology (2016)
An epigenetic clock for gestational age at birth based on blood methylation data
Authors: Anna K. Knight, Jeffrey M. Craig, Christiane Theda, Marie Bækvad-Hansen, Jonas Bybjerg-Grauholm, Christine S. Hansen, Mads V. Hollegaard, David M. Hougaard, Preben B. Mortensen, Shantel M. Weinsheimer, Thomas M. Werge, Patricia A. Brennan, Joseph F. Cubells, D. Jeffrey Newport, Zachary N. Stowe, Jeanie L. Y. Cheong, Philippa Dalach, Lex W. Doyle, Yuk J. Loke, Andrea A. Baccarelli, Allan C. Just, Robert O. Wright, Mara M. Téllez-Rojo, Katherine Svensson, Letizia Trevisi, Elizabeth M. Kennedy, Elisabeth B. Binder, Stella Iurato, Darina Czamara, Katri Räikkönen, Jari M. T. Lahti, Anu-Katriina Pesonen, Eero Kajantie, Pia M. Villa, Hannele Laivuori, Esa Hämäläinen, Hea Jin Park, Lynn B. Bailey, Sasha E. Parets, Varun Kilaru, Ramkumar Menon, Steve Horvath, Nicole R. Bush, Kaja Z. LeWinn, Frances A. Tylavsky, Karen N. Conneely, Alicia K. Smith
Journal: Genome biology (2016)

Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.
Treatment-related hospitalization costs of pediatric acute lymphoblastic leukemia.
Authors: Anne C. Kirchhoff, Sapna Kaul, Jian Ying, Rochelle Smits-Seemann, Richard Nelson, Elizabeth A. Raetz, Mark Fluchel, Seth Andrews, Richard S. Lemons
Journal: Journal of Clinical Oncology (2015)

e17768 Background: Pediatric cancer hospitalizations cost five times as much as other pediatric hospitalizations in the United States. Yet, studies that evaluate the longitudinal costs of pediatric cancer are rare. There is limited information on the trajectory of pediatric cancer health care costs over time, components of costs and patient characteristics that contribute to this trajectory. Methods: We identified a cohort of N = 533 pediatric acute lymphoblastic leukemia (ALL) patients diagnosed ages 1-26 from 1998-2013 and treated at Primary Children’s Hospital (PCH) in Salt Lake City, Utah. PCH, part of Intermountain Healthcare (IH), serves as the sole children's hospital for the largest geographic region of the continental U.S. As part of the PCH Pediatric Cancer Program, we retrieved data from the IH’s enterprise data warehouse and cancer registry. We estimated the average annual growth rates (AAGR) of first-year per-patient hospitalization outcomes (inflation adjusted total cost, hospital days and admissions) and cost components (e.g. room/care and pharmacy). A non-linear longitudinal regression model was used to identify patient characteristics that influence hospital outcomes in the first 5 years of treatment. Results: Per-patient first-year hospital cost increased from $19,309 in 1998 to $36,589 in 2012 at an AAGR of 7.7%. Average pharmacy costs rose at 15.1% followed by room/care (9.2%) and diagnostics (5.1%) costs. During the same duration, hospital days and admissions rose at 5% and 4% AAGRs, respectively. High risk patients (coefficient = 1.48, 95% Confidence Interval: 1.35-1.61) were significantly more likely to incur higher treatment costs than standard risk ALL patients. Similarly, patients incurred significantly higher costs if they relapsed. Cost burden of hospitalizations was the highest in the first 6 months after cancer diagnosis. Conclusions: The average annual increase in pediatric ALL related costs is greater than the annual increases in national hospital care expenditures in the U.S. ( > 3%) and overall health expenditures in Utah (5.3%). Future studies should explore cost-reduction and quality improvement interventions for reducing the hospitalization burden of pediatric ALL.
Hormone therapy plus temsirolimus for endometrial carcinoma (EC): Gynecologic Oncology Group trial #248.
Authors: G. F. Fleming, V. L. Filiaci, P. Hanjani, J. J. Burke, S. A. Davidson, K. K. Leslie, R. J. Zaino
Journal: Journal of Clinical Oncology (2011)

5014 Background: Both hormonal therapy and m-TOR inhibitors have activity in the treatment of EC, and preclinical evidence suggested that combining them might be beneficial. Methods: GOG 248 was a randomized phase II trial of temsirolimus (TEM) 25 mg IV weekly or the combination of TEM 25 mg weekly plus megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks (COMB). Eligibility criteria included measurable advanced, persistent, or recurrent EC, and no prior chemotherapy for metastatic disease unless patient (pt) achieved complete response and was progression-free for at least six months after completion of therapy. The primary endpoint was objective response rate. Results: As of Dec 18 2009, the COMB arm was closed to accrual for excess venous thromboses (7 events in 22 pts). These included DVT (n=5) and nonfatal PE (n=2). In addition there was one sudden death and one myocardial infarction. Median age of pts on COMB arm was 65, range 51-88. Eleven of 21 eligible pts had prior chemotherapy. Of 7 eligible pts still on study at that time, 5 continued on COMB, 1 continued on TEM alone, and 1 stopped all study therapy. Toxicities resulting in discontinuation of COMB therapy included grade(gr)2 pneumonitis (n=2), gr2 fatigue (n=1), DVT/PE (n=1), gr3 edema associated with thrombocytopenia (n=2). Three (of 21 eligible) pts had a partial response. There had been no venous thromboses on the TEM arm as of Dec 18 2009, and it was opened to second stage of accrual (indicating at least four responses among the first 21 patients) and completed Nov 22, 2010 (total enrolled TEM n = 51). Conclusions: The combination of temsirolimus with megestrol acetate/tamoxifen results in an unacceptable rate of venous thrombosis and its activity is not sufficient to offset its risk of thrombotic events. Single agent temsirolimus results should be available in May, 2011.