Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

An Integrative Model of Inter- and Intragenerational Preconception Processes Influencing Birthweight in the United States

Social inequalities in birth weight are an important population health concern as low birth weight is one mechanism through which inequalities are reproduced across generations. Yet we don’t understand what causes adverse birth outcomes. This study draws together theoretic and empiric findings from disparate disciplines—sociology, economics, public health, and behavior genetics—to develop a new integrative intra- and inter-generational model of preconception processes influencing birth weight. This model is empirically tested using structural equation modeling and population-level data containing linked mother-daughter pairs from the National Longitudinal Survey of Youth (NLSY79) and the Children of the NLSY79 (N=1,580 mother-daughter pairs). Results reveal that birth weight is shaped by preconception factors dating back to women’s early life experiences as well as conditions dating back three generations, via integrative intra- and inter-generational processes. These processes reveal specific mechanisms through which social inequality can transmit from mothers to children via birth weight

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty

Context The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. Objective This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Methods We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. Results MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). Conclusion We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.Fil: Duckett, Katie. Addenbrooke’s Hospital; Reino UnidoFil: Williamson, Alice. Addenbrooke’s Hospital; Reino UnidoFil: Kincaid, John W. R.. Addenbrooke’s Hospital; Reino UnidoFil: Rainbow, Kara. Addenbrooke’s Hospital; Reino UnidoFil: Corbin, Laura J.. University of Bristol; Reino UnidoFil: Martin, Hilary C.. Wellcome Sanger Institute; Reino UnidoFil: Eberhardt, Ruth Y.. Wellcome Sanger Institute; Reino UnidoFil: Huang, Qin Qin. Wellcome Sanger Institute; Reino UnidoFil: Hurles, Matthew E.. Wellcome Sanger Institute; Reino UnidoFil: He, Wen. Boston Children’s Hospital; Estados UnidosFil: Brauner, Raja. Umr - S1134 Biologie Integree Du Globule Rouge ; Universite de Paris;Fil: Delaney, Angela. St. Jude Children’s Research Hospital; Estados UnidosFil: Dunkel, Leo. Barts & the London Medical School; Reino UnidoFil: Grinspon, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Hall, Janet E. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Hirschhorn, Joel N.. Public Health Service. National Institute Of Health; Estados UnidosFil: Howard, Sasha R.. Queen Mary University of London; Reino UnidoFil: Latronico, Ana C.. No especifíca;Fil: Jorge, Alexander A. L.. No especifíca;Fil: McElreavey, Ken. Universite de Paris; FranciaFil: Mericq, Verónica. Universidad de Chile; ChileFil: Merino, Paulina M.. Universidad de Chile; ChileFil: Palmert, Mark R.. University of Toronto; CanadáFil: Plummer, Lacey. Massachusetts General Hospital Harvard; Estados UnidosFil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Rezende, Raíssa C.. No especifíca;Fil: Seminara, Stephanie B.. Massachusetts General Hospital Harvard; Estados UnidosFil: Salnikov, Kathryn. Massachusetts General Hospital Harvard; Estados UnidosFil: Banerjee, Indraneel. Royal Manchester Children’s Hospital; Reino UnidoFil: Lam, Brian Y. H.. Wellcome-MRC Institute of Metabolic Science; Reino UnidoFil: Perry, John R. B.. Wellcome-MRC Institute of Metabolic Science; Reino UnidoFil: Timpson, Nicholas J.. University of Bristol; Reino UnidoFil: Clayton, Peter. Royal Manchester Children’s Hospital; Reino UnidoFil: Chan, Yee Ming. Boston Children’s Hospital; Estados UnidosFil: Ong, Ken K.. University of Cambridge; Estados UnidosFil: O’Rahilly, Stephen. University of Cambridge; Estados Unido

Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: To determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). DESIGN, SETTING AND PARTICIPANTS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07). CONCLUSIONS: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype

The Children's Oncology Group Radiation Oncology Discipline: 15 Years of Contributions to the Treatment of Childhood Cancer

Our aim was to review the advances in radiation therapy for the management of pediatric cancers made by the Children's Oncology Group (COG) radiation oncology discipline since its inception in 2000. The various radiation oncology disease site leaders reviewed the contributions and advances in pediatric oncology made through the work of the COG. They have presented outcomes of relevant studies and summarized current treatment policies developed by consensus from experts in the field. The indications and techniques for pediatric radiation therapy have evolved considerably over the years for virtually all pediatric tumor types, resulting in improved cure rates together with the potential for decreased treatment-related morbidity and mortality. The COG radiation oncology discipline has made significant contributions toward the treatment of childhood cancer. Our discipline is committed to continuing research to refine and modernize the use of radiation therapy in current and future protocols with the goal of further improving the cure rates and quality of life of children with cancer