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Medical screening -- Analysis, Molecular genetics -- Analysis, Diabetics -- Care and treatment, Diabetics -- Analysis, Diabetes -- Care and treatment, Diabetes -- Analysis, Medical colleges -- Analysis, Genes -- Analysis, Kidney diseases -- Care and treatment, and Kidney diseases -- Analysis

Benzene, Proline, Fluorescence, Polymers, Nanoparticles, and Catalysis

Byline: , , Patrick J. M. Stals, E. W. Meijer, Anja R. A. Palmans Keywords: aldol reaction; benzene-1,3,5-tricaboxamide; molecular recognition; organocatalysis; single-chain polymeric nanoparticles Here, a modular approach is reported to introduce a specific function into single-chain polymeric nanoparticles (SCPNs). Hereto, an amphiphilic polymer with pendant benzene-1,3,5-tricarboxamide (BTA) units is mixed with a 'free' BTA that contains a functional group, either a fluorescent naphthalimide or a catalytically active l-proline. Taking advantage of hydrophobic interactions and self-recognition properties of the BTA units, the 'free' BTAs are captured into the interior of the SCPN in water as evidenced by fluorescence studies. To illustrate that function can be readily introduced using a modular approach, l-proline-based BTAs are incorporated to procure a catalytically active SCPN in water. The aldol reaction between p-nitrobenzaldehyde and cyclohexanone shows good conversions at low catalyst loadings and substrate concentrations, and high stereoselectivities are obtained (de = 91% and ee = 98%). Article Note: These authors contributed equally to this work. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): Supplementary

Pregnant women -- Analysis, Parenting -- Analysis, Infants -- Patient outcomes, and Infants -- Analysis

Byline: Karen L. Stals, Matthew Wakeling, Julia Baptista, Richard Caswell, Andrew Parrish, Julia Rankin, Carolyn Tysoe, Garan Jones, Adam C. Gunning, Hana Lango Allen, Lisa Bradley, Angela F. Brady, Helena Carley, Jenny Carmichael, Bruce Castle, Deirdre Cilliers, Helen Cox, Charu Deshpande, Abhijit Dixit, Jacqueline Eason, Frances Elmslie, Andrew E. Fry, Alan Fryer, Muriel Holder, Tessa Homfray, Emma Kivuva, Victoria McKay, Ruth Newbury-Ecob, Michael Parker, Ravi Savarirayan, Claire Searle, Nora Shannon, Deborah Shears, Sarah Smithson, Ellen Thomas, Peter D. Turnpenny, Vinod Varghese, Pradeep Vasudevan, Emma Wakeling, Emma L. Baple, Sian Ellard Abstract Objective Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. Method Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. Results Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. Conclusion We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. [c] 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd. Article Note: Funding sources: SE is a Wellcome Trust Senior Investigator. Conflicts of interest: None declared CAPTION(S): Table S1. This table summarizes the clinical phenotype in the affected pregnancies in the 24 families where a genetic diagnosis was not identified. Table S2. This table details the results from the 26 cases where a diagnosis was made. The variant is described at the genomic, cDNA, and protein level and shows the ACMG codes and level of evidence used for classification. [Dagger]Variants were reported on the clinical report as likely pathogenic prior to implementation of the ACMG guidelines and have been reviewed following adoption. The variants were identified by a gene-agnostic approach and following discussion with referring clinicians were felt to be likely causative in these families

Pediatric research -- Health aspects, Children -- Diseases, Children -- Genetic aspects, Children -- Complications and side effects, Children -- Patient outcomes, Carrier proteins -- Genetic aspects, Carrier proteins -- Health aspects, Genetic disorders -- Complications and side effects, Genetic disorders -- Patient outcomes, Genetic disorders -- Genetic aspects, Thyroid diseases -- Genetic aspects, Thyroid diseases -- Complications and side effects, and Thyroid diseases -- Patient outcomes

Summary Background Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1*5 years and between patients who were or were not underweight by age 1--3 years (defined as a bodyweight-for-age Z score <--2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. Findings Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24*0 months (IQR 12*0-60*0, range 0*0-744*0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35*0 years (95% CI 8*3--61*7). Individuals who did not attain head control by age 1*5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3*46, 95% CI 1*76--8*34; log-rank test p=0*0041). Patients who were underweight during age 1--3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4*71, 95% CI 1*26--17*58, p=0*021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. Interpretation Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. Funding Netherlands Organisation for Health Research and Development, and the Sherman Foundation. Author Affiliation: (a) Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands (b) Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey (c) Pediatric Neurology Section, Hospital Francesc de Borja de Gandia, Valencia, Spain (d) Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (e) Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada (f) University of Louisville, Louisville, KY, USA (g) Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania (h) Department of Neurosciences, Paediatric Neurology Discipline II, Carol Davila University of Medicine, Bucharest, Romania (i) Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy (j) Division of Endocrinology, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy (k) Sophia Children's Hospital, Division of Paediatric Cardiology, Erasmus Medical Centre, Rotterdam, Netherlands (l) Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, Netherlands (m) Division of Paediatric Radiology, Erasmus Medical Centre, Rotterdam, Netherlands (n) Department of Translational Medicine, Federico II University, Naples, Italy (o) Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy (p) Department of Child Neurology, Center for Childhood White Matter Diseases, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, Netherlands (q) Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands (r) Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (s) Departamento de Neurologia Pediatrica, Clinica Las Condes, Santiago, Chile (t) Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK (u) Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers, France (v) John Hunter Children's Hospital and University of Newcastle, Newcastle, NSW, Australia (w) Lancashire Teaching Hospitals NHS Trust, Lancashire, UK (x) Sheffield Children's NHS Foundation Trust, Sheffield Hallam University and University of Sheffield, Sheffield, UK (y) Universita Vita-Salute San Raffaele, Milan, Italy (z) Medanta Superspeciality Hospital, Indore, India (aa) Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland (ab) Department of Diabetes and Endocrinology, Women's and Children's Hospital, North Adelaide, SA, Australia (ac) Plymouth Hospitals NHS Trust, Plymouth, UK (ad) Department of Endocrinology, St. John's Medical College Hospital, Bengaluru, Karnataka, India (ae) Centre for Endocrinology, William Harvey Research institute, Queen Mary University London, London, UK (af) Dept of Paediatric Endocrinology, Barts Health NHS Trust, London, UK (ag) Department of Paediatrics, Semmelweis University, Budapest, Hungary (ah) Department of Endocrinology & Diabetes, Queensland Children's Hospital, South Brisbane, QLD, Australia (ai) Department of Chemical Pathology, Mater Pathology, South Brisbane, QLD, Australia (aj) Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia (ak) Medical University of Gdansk, Department of Paediatrics, Haematology & Oncology, Department of General Nursery, Gdansk, Poland (al) Division of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland (am) Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center (Radboudumc), Nijmegen, Netherlands (an) Department of Paediatric Endocrinology and Diabetology, Charite-Universitatsmedizin Berlin, Berlin, Germany (ao) Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System Tacoma, WA, USA (ap) Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic (aq) Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany (ar) Teaching Hospital of Universidade Federal de Pelotas, Pelotas, Brazil (as) Faculdade de Medicina, Centro Universitario Estacio de Ribeirao Preto, Ribeirao Preto, Brazil (at) Department of Child Neurology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands (au) Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA, USA (av) Institute of Maternal and Child Research, University of Chile, Santiago, Chile (aw) Department of Pediatrics, Clinica Las Condes, Santiago, Chile (ax) Pediatric Endocrinology Group, Santa Catarina Hospital, Sao Paulo, Brazil (ay) University of Debrecen, Pediatric Institute, Debrecen, Hungary (az) Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse University Hospital, Toulouse, France (ba) Department of Paediatrics, Christian Medical College, Vellore, India (bb) Paediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children's University Hospital, Imagine Institute, Paris, France (bc) Department of Paediatrics, AOU Citta della Salute e della Scienza di Torino, University of Torino, Torino, Italy (bd) Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil (be) Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Duesseldorf, Germany (bf) Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul, Turkey (bg) Royal Children's Hospital, Parkville, Melbourne, VIC, Australia (bh) Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (bi) Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy (bj) Department of Cardiology and Intensive Care Medicine, Erasmus Medical Centre, Rotterdam, Netherlands (bk) Panorama Medical Centre, Cape Town, South Africa (bl) University of Lille, Lille, France (bm) Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany (bn) KUNO Children's University Hospital, Campus St. Hedwig, University of Regensburg, Regensburg, Germany (bo) Paediatric Endocrinology Unit, Kaplan Medical Center, Rehovot, Israel (bp) Hebrew University of Jerusalem, Jerusalem, Israel (bq) Emma Children's Hospital, Department of Paediatric Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands * Correspondence to: Dr W Edward Visser, Department of Internal Medicine, Erasmus Medical Centre Rotterdam, 3015 GD Rotterdam, Netherlands Byline: Stefan Groeneweg, MD (a), Ferdy S van Geest, MD (a), Prof Ayhan Abaci, MD (b), Alberto Alcantud, MD (c), Gautem P Ambegaonkar, MRCPCH (d), Christine M Armour, MD (e), Priyanka Bakhtiani, MD (f), Diana Barca, MD (g,h), Prof Enrico S Bertini, MD (i), Ingrid M van Beynum, MD (k), Prof Nicola Brunetti-Pierri, MD (n,o), Marianna Bugiani, MD (p,q), Marco Cappa, MD (j), Gerarda Cappuccio, MD (n,o), Barbara Castellotti, MD (r), Claudia Castiglioni, MD (s), Prof Krishna Chatterjee, FRCP (t), Irenaeus F M de Coo, MD (l), Prof Regis Coutant, MD (u), Prof Dana Craiu, MD (g,h), Patricia Crock, DMed (v), Christian DeGoede, FRCPCH (w), Korcan Demir, MD (b), Alice Dica, MD (g,h), Prof Paul Dimitri, PhD (x), Anna Dolcetta-Capuzzo, MD (a,y), Marjolein H G Dremmen, MD (m), Rachana Dubey, DM (z), Anina Enderli, MD (aa), Jan Fairchild, FRACP (ab), Jonathan Gallichan, MBChB (ac), Belinda George, DM (ad), Evelien F Gevers, PhD (ae,af), Annette Hackenberg, MD (aa), Zita Halasz, MD (ag), Bianka Heinrich, Med Pract (aa), Tony Huynh, PhD (ah,ai,aj), Anna Klosowska, MD (ak), Prof Marjo S van der Knaap, MD (p), Marieke M van der Knoop, MSc (l), Prof Daniel Konrad, MD (al), David A Koolen, MD (am), Prof Heiko Krude, MD (an), Amy Lawson-Yuen, MD (ao), Prof Jan Lebl, MD (ap), Michaela Linder-Lucht, MD (aq), Claudia F Lorea, MD (ar), Charles M Lourenco, MD (as), Roelineke J Lunsing, MD (at), Greta Lyons, RGN (t), Jana Malikova, MD (ap), Edna E Mancilla, MD (au), Anne McGowan, MD (t), Prof Veronica Mericq, MD (av,aw), Felipe M Lora, MD (ax), Carla Moran, MB (t), Katalin E Muller, MD (ay), Isabelle Oliver-Petit, MD (az), Laura Paone, MD (j), Praveen G Paul, MD (ba), Prof Michel Polak, MD (bb), Francesco Porta, MD (bc), Fabiano O Poswar, MD (bd), Christina Reinauer, MD (be), Klara Rozenkova, MD (ap), Tuba S Menevse, MD (bf), Peter Simm, MBBS (bg), Anna Simon, MD (ba), Yogen Singh, MD (bh), Marco Spada, MD (bc), Jet van der Spek, MD (am), Milou A M Stals, MD (a), Athanasia Stoupa, MD (bb), Gopinath M Subramanian, FRACP (v), Davide Tonduti, MD (bi), Prof Serap Turan, MD (bf), Corstiaan A den Uil, MD (bj), Joel Vanderniet, MBBS (v), Adri van der Walt, MD (bk), Prof Jean-Louis Wemeau, MD (bl), Jolante Wierzba, MD (ak), Marie-Claire Y de Wit, MD (l), Nicole I Wolf, MD (p), Michael Wurm, MD (bm,bn), Federica Zibordi, MD (bi), Prof Amnon Zung, MD (bo,bp), Nitash Zwaveling-Soonawala, MD (bq), W Edward Visser, MD [w.e.visser@erasmusmc.nl] (a)

Phenetics -- Methods, Wildlife conservation -- Methods, Biology -- Identification and classification, and Biology -- Methods

Author(s): Scott A. Thomson 1,2,*, Richard L. Pyle 3,4,*, Shane T. Ahyong 5,6, Miguel Alonso-Zarazaga 4,7, Joe Ammirati 8, Juan Francisco Araya 9, John S. Ascher 10, Tracy Lynn Audisio [...]

Diseases -- Relapse, Breast cancer, Estrogen, Tamoxifen, Menopause, and Medical records

on behalf of the South Swedish and South-East Swedish Breast Cancer Groups Keywords Adjuvant therapy; Tamoxifen; Premenopausal; Long-term follow-up Highlights * 2 years of tamoxifen reduced breast cancer events also after 30 years of follow-up. * For ER + patients, the 'carryover effect' was evident beyond 15 years. * ER + patients treated with tamoxifen had shorter survival after distant recurrence. * Tamoxifen was associated with a persistent reduction of contralateral breast cancer. Abstract Aims The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)--positive tumours, regarding breast cancer--free interval (BCFi) and distant recurrence--free interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence. Methods Premenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers. Results The median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of 15--30 years (HR = 0.53, 95% CI 0.28--0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n = 165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35--0.96, p = 0.035), whereas no differences were observed regarding other secondary malignancies. Conclusions With three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancer--related events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence. Author Affiliation: (a) Department of Oncology, Jonkoping, Region Jonkoping County, and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden (b) Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden (c) Department of Clinical and Experimental Medicine and Department of Oncology, Linkoping University, Linkoping, Sweden (d) Department of Clinical Sciences Lund, Division of Surgery, Lund University, Lund, Sweden (e) Department of Surgery and Gastroenterology, Skane University Hospital, Lund, Sweden * Corresponding author: Department of Clinical Sciences Lund Division of Oncology and Pathology, Lund University, Medicon Village, Building 404, Scheelevagen 8, SE-223 63, Lund, Sweden Article History: Received 6 July 2018; Revised 20 December 2018; Accepted 21 December 2018 Byline: M. Ekholm [maria.ekholm@med.lu.se] (a,b,*), P.O. Bendahl (b), M. Ferno (b), B. Nordenskjold (c), O. Stal (c), L. Ryden (d,e)

Hepatoma -- Care and treatment, Antimitotic agents -- Product development, and Antineoplastic agents -- Product development

To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/S1470-2045(18)30351-6 Byline: Prof Andrew X Zhu, MD [azhu@mgh.harvard.edu] (a,b,*), Richard S Finn, MD (c), Julien Edeline, MD (d), Stephane Cattan, MD (e), Sadahisa Ogasawara, MD (f), Prof Daniel Palmer, PhD (g), Prof Chris Verslype, MD (h), Vittorina Zagonel, MD (i), Laetitia Fartoux, MD (j), Prof Arndt Vogel, MD (k), Debashis Sarker, PhD (l), Gontran Verset, MD (m), Stephen L Chan, MRCP (n), Jennifer Knox, MD (o), Bruno Daniele, MD (p), Andrea L Webber, PhD (q), Scot W Ebbinghaus, MD (q), Junshui Ma, PhD (q), Abby B Siegel, MD (q), Prof Ann-Lii Cheng, MD (r), Masatoshi Kudo, MD (s), Angela Alistar, Jamil Asselah, Jean-Frederic Blanc, Ivan Borbath, Timothy Cannon, Ki Chung, Allen Cohn, David P Cosgrove, Nevena Damjanov, Mukul Gupta, Yoshivasu Karino, Mark Karwal, Andreas Kaubisch, Robin Kelley, Jena-Luc Van Laethem, Timothy Larson, James Lee, Daneng Li, Atisha Manhas, Gulam Abbas Manji, Kazushi Numata, Benjamin Parsons, Andrew S. Paulson, Carmine Pinto, Robert Ramirez, Suresh Ratnam, Magnus Rizell, Olivier Rosmorduc, Yvonne Sada, Yutaka Sasaki, Per I Stal, Simone Strasser, Joerg Trojan, Gina Vaccaro, Hans Van Vlierberghe, Alan Weiss, Karl-Heinz Weiss, Tatsuya Yamashita Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0--1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11--26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc. Author Affiliation: (a) Department of Medicine, Harvard Medical School, Boston, MA, USA (b) Massachusetts General Hospital Cancer Center, Boston, MA, USA (c) Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA (d) Department of Medical Oncology, Centre Eugene Marquis, Rennes, France (e) Department of Medical Oncology and Gastroenterology, Hopital Claude Huriez, Centre Hospitalier Regional Universitaire de Lille, Lille, France (f) Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan (g) Department of Medical Oncology, University of Liverpool, Liverpool, UK (h) Department of Hepatology, University Hospital Gasthuisberg, Leuven, Leuven, Belgium (i) Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico (IOV-IRCCS), Padua, Italy (j) Department of Gastroenterology and Hepatology, Hopital Universitaire Pitie-SalpA*triere, Paris, France (k) Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule, Hannover, Germany (l) Department of Medical Oncology, King's College Hospital, London, UK (m) Gastrointestinal Oncology Unit, Hopital Erasme, Brussels, Belgium (n) Department of Clinical Oncology, State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong (o) Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada (p) Department of Oncology, Azienda Ospedaliera Gaetano Rummo, Benevento, Italy (q) Department of Global Clinical Development, Merck & Co, Kenilworth, NJ, USA (r) Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan (s) Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan * Correspondence to: Prof Andrew X Zhu, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA (footnote)[Dagger] Investigators listed in the

Orthopedic surgery -- Analysis, Immunohistochemistry -- Analysis, Myosin -- Analysis, and Muscle proteins -- Analysis

Genes -- Analysis, Genes -- Health aspects, Gene expression -- Analysis, and Gene expression -- Health aspects

Author(s): Helena Aguilar[sup.1], Ander Urruticoechea[sup.1,26], Pasi Halonen[sup.2], Kazuma Kiyotani[sup.3], Taisei Mushiroda[sup.3], Xavier Barril[sup.4,5], Jordi Serra-Musach[sup.1,6], Abul Islam[sup.7], Livia Caizzi[sup.8,9], Luciano Di Croce[sup.5,8,9], Ekaterina Nevedomskaya[sup.10], Wilbert Zwart[sup.10], Josefine Bostner[sup.11], Elin Karlsson[sup.11], [...]
Introduction Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor [alpha] (ER[alpha]) are among the most effective systemic treatments for ER[alpha]-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ER[alpha] transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process. Methods A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ER[alpha] was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. Results The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ER[alpha]. VAV3 was selectively reduced upon exposure to YC-1 or ER[alpha] depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10.sup.-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy. Conclusions This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Clinical trials -- Analysis

Summary Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2--F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement ([greater than or equal to]1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2--F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1--F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2--F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0*045), and 71 (23%) in the obeticholic acid 25 mg group (p=0*0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0*18], and 36 [12%] in the obeticholic acid 25 mg group [p=0*13]). In the safety population (1968 patients with fibrosis stages F1--F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. Funding Intercept Pharmaceuticals. Author Affiliation: (a) Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA (b) Sorbonne Universite, Assistance Publique-Hopitaux de Paris, Hopital Pitie--Salpetriere, Institute for Cardiometabolism and Nutrition, Paris, France (c) NAFLD Rsearch Center, University of California San Diego, San Diego, CA, USA (d) Feinberg School of Medicine, Northwestern University, Chicago, IL, USA (e) The Newcastle Liver Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (f) Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK (g) Service d'Anatomie Pathologique, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Paris, France (h) Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany (i) St Josef-Krankenhaus Kupferdreh, Essen, Germany (j) National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK (k) Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK (l) Institute of Translational & Stratified Medicine, University of Plymouth and University Hospitals Plymouth NHS Trust, Plymouth, UK (m) Fresno Clinical Research Center, Fresno, CA, USA (n) Baylor Health, Liver Consultants of Texas, Dallas, TX, USA (o) Arkansas Gastroenterology, North Little Rock, AR, USA (p) Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA (q) Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, USA (r) Swedish Liver Center, Seattle, WA, USA (s) Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada (t) HIFIH Laboratory, UPRES EA3859, SFR 4208, Angers University, Angers, France (u) Hepato-Gastroenterology Department, Angers University Hospital, Angers, France (v) Hepato-gastroenterology, CHU Lille, Lille, France (w) Department of Medical Sciences, University of Turin, Turin, Italy (x) Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna, Bologna, Italy (y) Department of Gastroenterology, Hospital Universitario La Paz, Madrid, Spain (z) Clinica Universitaria de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (aa) Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain (ab) Institut D'investigacions Biomediques August Pi I Sunyer, Barcelona, Spain (ac) Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Barcelona, Spain (ad) New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand (ae) The Gastrounit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (af) University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland (ag) Intercept Pharmaceuticals, San Diego, CA, USA (ah) Pinnacle Clinical Research Center, San Antonio, TX, USA (ai) Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA * Correspondence to: Prof Arun J Sanyal, Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA 23298, USA (footnote)* Joint first authors (footnote)[Dagger] Joint senior authors Byline: Zobair M Younossi, MD (a), Vlad Ratziu, MD (b), Rohit Loomba, MD (c), Mary Rinella, MD (d), Quentin M Anstee, MD (e,f), Zachary Goodman, MD (a), Pierre Bedossa, MD (g), Andreas Geier, MD (h), Susanne Beckebaum, MD (i), Philip N Newsome, MD (j,k), David Sheridan, MD (l), Muhammad Y Sheikh, MD (m), James Trotter, MD (n), Whitfield Knapple, MD (o), Eric Lawitz, MD (p), Manal F Abdelmalek, MD (q), Prof Kris V Kowdley, MD (r), Aldo J Montano-Loza, MD (s), Jerome Boursier, MD (t,u), Philippe Mathurin, MD (v), Elisabetta Bugianesi, MD (w), Giuseppe Mazzella, MD (x), Antonio Olveira, MD (y), Helena Cortez-Pinto, MD (z), Isabel Graupera, MD (aa,ab,ac), David Orr, MD (ad), Lise Lotte Gluud, MD (ae), Jean-Francois Dufour, MD (af), David Shapiro, MD (ag), Jason Campagna, MD (ag), Luna Zaru, PhD (ag), Leigh MacConell, PhD (ag), Reshma Shringarpure, PhD (ag), Stephen Harrison, MD (ah,[Dagger]), Prof Arun J Sanyal, MD [arun.sanyal@vcuhealth.org] (ai,[Dagger]), Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Susanne Beckebaum, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, Jerome Boursier, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Elisabetta Bugianesi, Cindy Cai, Jose Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrion, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Kathleen Corey, Lynsey Corless, Helena Cortez-Pinto, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Jean-Francois Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Andreas Geier, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Lise Lotte Gluud, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Stephen Harrison, Marek Hartleb, Tarek Hassanein, Dieter Haussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Whitfield Knapple, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Damien Labarriere, Michelle Lai, Pietro Lampertico, Eric Lawitz, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Rohit Loomba, Yoav Lurie, Guilherme Macedo, Mihaly Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Philippe Mathurin, Marlyn Mayo, Giuseppe Mazzella, Mark McCullen, William McLaughlin, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Muller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Antonio Olveira, Hans Orlent, David Orr, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Merle Uta, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Vlad Ratziu, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Andres Riera, Mary Rinella, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jorn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, David Sheridan, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Michael Trauner, Christian Trautwein, James Trotter, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin

Breast cancer -- Drug therapy, Tamoxifen -- Dosage and administration, Menopause -- Physiological aspects, Cancer -- Adjuvant treatment, and Cancer -- Usage

Company growth, Dextrose -- Physiological aspects, Dextrose -- Growth, Glucose -- Physiological aspects, Glucose -- Growth, Pancreatic beta cells -- Physiological aspects, Pancreatic beta cells -- Growth, Insulin -- Physiological aspects, Insulin -- Growth, Trihalomethanes -- Physiological aspects, and Trihalomethanes -- Growth

Water chlorination results in the formation of trihalomethanes (THMs) including chloroform. In human studies, fetal growth restriction has been associated with exposure to THMs during pregnancy and impaired fetal growth has been associated with an increased risk of type 2 diabetes. Therefore, the objective of this study was to determine the effect of in utero and lactational exposure to chloroform on birthweight and postnatal indicators of type 2 diabetes. Female Wistar rats were given chloroform (0 Aug/L, 75 Aug/L) in their drinking water for 2 wk prior to mating until parturition (in utero exposure only) or until weaning (in utero + lactational exposure). At postnatal d 1 (PND1) pups of dams exposed to chloroform had significantly higher serum glucose levels and lower insulin levels, but this effect was not due to [beta]-cell depletion in the neonatal pancreas. Glucose homeostasis in response to a glucose challenge was not changed by chloroform treatment. Chloroform exposure did not affect birthweight however, offspring of dams exposed to chloroform had significantly impaired postnatal growth. Although fetal and neonatal exposure to chloroform did not elicit physiological changes associated with the onset of type 2 diabetes, there were physiological changes resulting in impaired postnatal growth.