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Penrose S.D.,A Charles River Company | Stott A.J.,A Charles River Company | Breccia P.,A Charles River Company | Haughan A.F.,A Charles River Company | And 3 more authors.
Organic Letters | Year: 2015

Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter-and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center. © 2015 American Chemical Society.


Lu X.-H.,University of California at Los Angeles | Mattis V.B.,Cedars Sinai Medical Center | Wang N.,University of California at Los Angeles | Al-Ramahi I.,Baylor College of Medicine | And 18 more authors.
Science translational medicine | Year: 2014

Age-related neurodegenerative disorders including Alzheimer's disease and Huntington's disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been demonstrated in Alzheimer's disease and in mouse models of other neurodegenerative diseases. We show that ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown protected from toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models. By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full-length human mHTT, we show that genetic reduction of Atm gene dosage by one copy ameliorated multiple behavioral deficits and partially improved neuropathology. Small-molecule ATM inhibitors reduced mHTT-induced death of rat striatal neurons and induced pluripotent stem cells derived from HD patients. Our study provides converging genetic and pharmacological evidence that reduction of ATM signaling could ameliorate mHTT toxicity in cellular and animal models of HD, suggesting that ATM may be a useful therapeutic target for HD. Copyright © 2014, American Association for the Advancement of Science.


PubMed | College Park, Ishihara Sangyo Kaisha Ltd., Food Safety Commission, Takeda Pharmaceutical and 15 more.
Type: Journal Article | Journal: Toxicologic pathology | Year: 2016

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.


PubMed | Food Safety Commission of Japan, Charles River Laboratories, Pfizer, Covance and 7 more.
Type: Journal Article | Journal: Toxicologic pathology | Year: 2016

Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.


PubMed | Janssen Pharmaceutical and a Charles River Company
Type: | Journal: Reproductive toxicology (Elmsford, N.Y.) | Year: 2016

For pediatric indications requiring juvenile toxicity testing, the rat is the preferred species. However, for some drugs it might not be an appropriate model or regulatory agencies may also request a non-rodent species. Due to the relatively recent use of Gttingen minipigs, little background data are available. This shortage of historical data can raise concerns with respect to interpretation, thus potentially discouraging investigators. This article presents background data from 82 piglets collected at different ages. The data described show the normal variations and changes which are important in the interpretations of these studies. Age-related changes were observed for several cardiac and clinical pathology parameters and in the haematopoietic tissues. Therefore, all pigs were not considered equal. It can be concluded that these data can be used as guidance, to support the concurrent study control data but cannot completely replace them.


PubMed | a Charles River company, Case Western Reserve University and Charles River Nederland BV
Type: Journal Article | Journal: Nature chemical biology | Year: 2016

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.


PubMed | Envigo, CiToxLAB Scantox A S, A Charles River Company Lyon, Ellegaard Gottingen Minipigs A S and 2 more.
Type: | Journal: Reproductive toxicology (Elmsford, N.Y.) | Year: 2016

Knowledge of the incidence of spontaneous congenital abnormalities is critical for the accurate interpretation of findings in teratogenicity studies in any species. In this paper, results of the examination of 1739 neonatal Gttingen Minipigs are presented. Over the 2-year period under consideration, the incidence of external and visceral malformations was less than 0.2 and 0.1%, respectively. The most common external malformations were syndactyly, limb hyperflexion, domed head and scoliosis. The most common internal malformations were undescended testes, ventricular septal defect, diaphragmatic hernia and atrial septal defects. Pentadactyly and variation in the aortic archs bifurcation (absent truncus bicaroticus) were the most common variations. These data will help support the use of the Gttingen Minipig as a non-rodent species in embryofetal development studies where concerns persist about the availability of background data.


Howroyd P.C.,A Charles River Company | Peter B.,A Charles River Company | De Rijk E.,A Charles River Company
Toxicologic Pathology | Year: 2016

It is important to know whether the animals used in toxicology studies are sexually mature. As minipigs are being used increasingly in toxicity studies, we reviewed published data on the age of sexual maturity in the minipig. Maturity in females was assessed on the basis either of normal cycles of progesterone secretion or of the histological presence of corpora lutea and, in males, was assessed on the histological appearance of the seminiferous tubules and epididymides. In female Göttingen minipigs, the first progesterone peak was at 3.7 to 4.2 or 6.1 to 6.5 months of age. These animals were in the presence of a boar. In female Göttingen minipigs in toxicology studies, which were not in the presence of a boar, at least 1 corpus luteum in the ovaries was present in only 50% of the females by 6.5 months of age, while all were mature by 7.7 months of age. Histological maturity in the male Yucatan minipig is reported to be attained at about 4.4 months old, but in male Göttingen minipigs at about 2 months old, although the definition of maturity may have been different in the 2 studies. © 2016 Society of Toxicologic Pathology.


PubMed | A Charles River Company and Astrazeneca
Type: Journal Article | Journal: British journal of pharmacology | Year: 2016

Neutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model.Rats were treated with a DPP1 inhibitor twice daily for up to 14days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response.Maximum NSP inhibition was achieved after 8days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4-6days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20days in human.Following inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.


PubMed | A Charles River Company
Type: Journal Article | Journal: Toxicologic pathology | Year: 2016

It is important to know whether the animals used in toxicology studies are sexually mature. As minipigs are being used increasingly in toxicity studies, we reviewed published data on the age of sexual maturity in the minipig. Maturity in females was assessed on the basis either of normal cycles of progesterone secretion or of the histological presence of corpora lutea and, in males, was assessed on the histological appearance of the seminiferous tubules and epididymides. In female Gttingen minipigs, the first progesterone peak was at 3.7 to 4.2 or 6.1 to 6.5 months of age. These animals were in the presence of a boar. In female Gttingen minipigs in toxicology studies, which were not in the presence of a boar, at least 1 corpus luteum in the ovaries was present in only 50% of the females by 6.5 months of age, while all were mature by 7.7 months of age. Histological maturity in the male Yucatan minipig is reported to be attained at about 4.4 months old, but in male Gttingen minipigs at about 2 months old, although the definition of maturity may have been different in the 2 studies.

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