Targeted exome sequencing of Korean triple-negative breast cancer reveals homozygous deletions associated with poor prognosis of adjuvant chemotherapy-treated patients.

Oncotarget. 2017 Jun 27;:

Authors: Jeong HM, Kim RN, Kwon MJ, Oh E, Han J, Lee SK, Choi JS, Park S, Nam SJ, Gong GY, Nam JW, Choi DH, Lee H, Nam BH, Choi YL, Shin YK

Abstract
Triple-negative breast cancer is characterized by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is associated with a poorer outcome than other subtypes of breast cancer. Moreover, there are no accurate prognostic genes or effective therapeutic targets, thereby necessitating continued intensive investigation. This study analyzed the genetic mutation landscape in 70 patients with triple-negative breast cancer by targeted exome sequencing of tumor and matched normal samples. Sequencing showed that more than 50% of these patients had deleterious mutations and homozygous deletions of DNA repair genes, such as ATM, BRCA1, BRCA2, WRN, and CHEK2. These findings suggested that a large number of patients with triple-negative breast cancer have impaired DNA repair function and that therefore a poly ADP-ribose polymerase inhibitor may be an effective drug in the treatment of this disease. Notably, homozygous deletion of three genes, EPHA5, MITF, and ACSL3, was significantly associated with an increased risk of recurrence or distant metastasis in adjuvant chemotherapy-treated patients.

PMID: 28679863 [PubMed - as supplied by publisher]

An unusual genomic variant of pancreatic ductal adenocarcinoma with an indolent clinical course.

Cold Spring Harb Mol Case Stud. 2017 Jul;3(4):

Authors: Kohutek ZA, Rosati LM, Hong J, Poling J, Attiyeh MA, Makohon-Moore A, Herman JM, Iacobuzio-Donahue CA

Abstract
We describe an 85-yr-old male of Ashkenazi Jewish descent with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA). The patient underwent a modified course of gemcitabine and stereotactic body radiation therapy and survived for 42 mo with a stable pancreatic head mass and no evidence of metastatic disease before death due to complications from a stroke. Whole-exome sequencing of his tumor revealed a simple genome landscape with no evidence of mutations, copy-number changes, or structural alterations in genes most commonly associated with PDA (i.e., KRAS, CDKN2A, TP53, or SMAD4). An analysis of his germline DNA revealed no pathogenic variants of significance. Whole-exome and whole-genome sequencing identified a somatic mutation of RNF213 and an inversion/deletion of CTNNA2 as the genetic basis of his PDA. Although PDA is classically characterized by a predictable set of mutations, these data suggest that alternate genetic paths to PDA may exist, which can be associated with a more indolent clinical course.

PMID: 28679692 [PubMed - in process]

Risk Prediction Modeling on Family-Based Sequencing Data Using a Random Field Method.

Genetics. 2017 Jul 05;:

Authors: Wen Y, Burt A, Lu Q

Abstract
Family-based design is one of the most popular designs in genetic studies and has many unique features for risk prediction research. It is more robust against genetic heterogeneity, and the relatedness among family members can be informative for predicting individuals' risk for disease with polygenic and shared environmental components of risk. Despite these strengths, family-based designs have been used infrequently in current risk prediction studies, and their related statistical methods have been much less developed. In this paper, we developed a generalized random field (GRF) method for family-based risk prediction modeling on sequencing data. In GRF, subjects' phenotypes are viewed as stochastic realizations of a random field on a space, and a subject's phenotype is predicted by adjacent subjects, where adjacencies between subjects are determined by their genetic and within-family similarities. Different from existing methods that adjust for familiar correlations, the GRF utilizes this information to form surrogates to further improve prediction accuracy. It also uses within-family information to capture predictors (e.g., rare mutations) that are homogenous in families. Through simulations, we have demonstrated that the GRF method attained better performance than an existing method by considering additional information from family members and accounting for genetic heterogeneity. We further provided practical recommendations for designing family-based risk prediction studies. Finally, we illustrated the GRF method with an application to a whole-genome exome dataset from the Michigan State University Twin Registry study.

PMID: 28679544 [PubMed - as supplied by publisher]

Genetic investigations of the epileptic encephalopathies: Recent advances.

Prog Brain Res. 2016;226:35-60

Authors: Myers CT, Mefford HC

Abstract
The epileptic encephalopathies (EEs) are a group of epilepsy syndromes characterized by multiple seizure types, abundant epileptiform activity, and developmental delay or regression. Advances in genomic technologies over the past decade have accelerated our understanding of the genetic etiology of EE, which is largely due to de novo mutations. Chromosome microarrays to detect copy number variants identify a genomic cause in at least 5-10% of cases. Next-generation sequencing in the form of gene panels or whole exome sequencing have highlighted the role of de novo sequence changes and revealed extensive genetic heterogeneity. The novel gene discoveries in EE implicate diverse cellular pathways including chromatin remodeling, transcriptional regulation, and mTOR regulation in the etiology of epilepsy, highlighting new targets for potential therapeutic intervention. In this chapter, we discuss the rapid pace of gene discovery in EE facilitated by genomic technologies and highlight several novel genes and potential therapies.

PMID: 27323938 [PubMed - indexed for MEDLINE]

Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.

PLoS One. 2016;11(5):e0154827

Authors: Okuda H, Noguchi A, Kobayashi H, Kondo D, Harada KH, Youssefian S, Shioi H, Kabata R, Domon Y, Kubota K, Kitano Y, Takayama Y, Hitomi T, Ohno K, Saito Y, Asano T, Tominaga M, Takahashi T, Koizumi A

Abstract
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.

PMID: 27224030 [PubMed - indexed for MEDLINE]

Levodopa dose maintenance or reduction in patients with Parkinson's disease transitioning to levodopa/carbidopa/entacapone.

Neurol India. 2017 Jul-Aug;65(4):746-751

Authors: Park J, Kim Y, Youn J, Lee PH, Sohn YH, Koh SB, Lee JY, Baik JS, Cho JW

Abstract
BACKGROUND: Levodopa bioavailability is enhanced by adding entacapone. However, the optimal dose of levodopa while transitioning to levodopa/carbidopa/entacapone (LCE) in Parkinson's disease (PD) during the wearing-off period is unclear.
AIMS: The relative therapeutic efficacy and safety of different doses of levodopa were assessed when transitioning to the LCE combination for optimizing combined levodopa therapy.
MATERIALS AND METHODS: A randomized, multicenter, double-arm, open-label study was conducted in Korea. The patients were randomly assigned to either a maintained levodopa dose (Group 1, n = 66) or a reduced levodopa dose by 15-25% (Group 2, n = 41). Treatment efficacy, safety, and tolerability were assessed during an 8-week treatment period.
RESULTS: Eighty of the 107 (74.8%) participants completed the study (Group 1, n = 50; Group 2, n = 30). The patients' global impression of a change in scores indicated significant benefits of maintaining the levodopa dose (Group 1) compared to reducing the dose (Group 2). Although changes in the unified Parkinson's disease rating scale (UPDRS) scores, Hoehn and Yahr (H and Y) stages, and duration of ON, OFF and dyskinesia were not statistically different between the groups, an increased ON time and a reduced OFF time occurred in both the groups after LCE administration. Twenty-four participants (26.7%) experienced adverse events and 15 of them did not complete the study in the safety population (Group 1, n = 57; Group 2, n = 38). Significant drug-related withdrawal caused troublesome dyskinesia and aggravation of Parkinsonism in both Group 1 and Group 2, respectively.
CONCLUSIONS: Direct transitioning to LCE, without levodopa dose reduction, is recommended in Asian patients with PD and wearing-off.

PMID: 28681744 [PubMed - in process]

Amenamevir, a novel helicase-primase inhibitor, for treatment of herpes zoster: A randomized, double-blind, valaciclovir-controlled phase 3 study.

J Dermatol. 2017 Jul 05;:

Authors: Kawashima M, Nemoto O, Honda M, Watanabe D, Nakayama J, Imafuku S, Kato T, Katsuramaki T, study investigators

Abstract
Amenamevir is a potent helicase-primase inhibitor and a novel class of antiviral agent other than nucleoside compounds, such as aciclovir, valaciclovir and famciclovir. This study is the first randomized, double-blind, valaciclovir-controlled phase 3 study to evaluate the efficacy and safety of amenamevir in Japanese patients with herpes zoster when treated within 72 h after onset of rash. A total of 751 patients were randomly assigned to receive either amenamevir 400 mg or 200 mg p.o. once daily or valaciclovir 1000 mg three times daily (daily dose, 3000 mg) for 7 days. The primary efficacy end-point was the proportion of cessation of new lesion formation by day 4 ("day 4 cessation proportion"). The day 4 cessation proportions for amenamevir 400 and 200 mg and valaciclovir were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively. Non-inferiority of amenamevir 400 mg to valaciclovir was confirmed by a closed testing procedure. Days to cessation of new lesion formation, complete crusting, healing, pain resolution and virus disappearance were evaluated as secondary end-points. No significant differences were observed in any of the treatment groups. Amenamevir 400 and 200 mg were well tolerated as well as valaciclovir. The proportions of patients who experienced drug-related adverse events were 10.0% (25/249), 10.7% (27/252) and 12.0% (30/249) with amenamevir 400 and 200 mg and valaciclovir, respectively. In conclusion, amenamevir 400 mg appears to be effective and well tolerated for treatment of herpes zoster in immunocompetent Japanese patients.

PMID: 28681394 [PubMed - as supplied by publisher]

Efficacy and Safety Results of the Afatinib Expanded Access Program.

Oncol Ther. 2017;5(1):103-110

Authors: Kim ES, Halmos B, Kohut IF, Patel T, Rostorfer RD, Spira AI, Cseh A, McKay J, Wallenstein G, Mileham KF

Abstract
INTRODUCTION: Afatinib is an oral, irreversible ErbB family blocker approved for first-line treatment of metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The expanded access program (EAP) allowed early access to afatinib and provided additional data on its safety, tolerability, and efficacy.
METHODS: The afatinib EAP was an open-label, multicenter, single-arm program in the United States that treated and followed patients with locally advanced or metastatic NSCLC harboring EGFR mutations. Afatinib 40 mg was administered orally once daily until discontinuation due to disease progression, adverse events (AEs), or transition to commercially available drug.
RESULTS: Three hundred twenty-two patients received ≥1 dose of afatinib. Most patients had received prior therapies. Drug-related AEs occurred in 89.4% of patients, including 7.8% with serious AEs. The most common afatinib-related AEs (all grades) were diarrhea (77.0%) and rash (36.0%). Dose reductions occurred in 31.1% of patients. Discontinuation rates due to diarrhea (1.6%) or rash/acne (0.3%) were low. Efficacy data were collected and analyzed when available, with 17.1% and 69.9% of patients achieving objective response and disease control, respectively, in this highly pretreated population.
CONCLUSIONS: No additional or unexpected safety concerns were revealed, and afatinib demonstrated antitumor activity in a heavily pretreated NSCLC patient population in a routine clinical setting.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01649284.
FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.

PMID: 28680960 [PubMed - in process]

Recommendations for the use of oral treprostinil in clinical practice: a Delphi consensus project pulmonary circulation.

Pulm Circ. 2017 Mar;7(1):167-174

Authors: Rahaghi FF, Feldman JP, Allen RP, Tapson V, Safdar Z, Balasubramanian VP, Shapiro S, Mathier MA, Elwing JM, Chakinala MM, White RJ

Abstract
Oral treprostinil was recently labeled for treatment of pulmonary arterial hypertension. Similar to the period immediately after parenteral treprostinil was approved, there is a significant knowledge gap for practicing physicians who might prescribe oral treprostinil. Despite its oral route of delivery, use of the drug is challenging because of the requirement for careful titration and management of drug-related adverse effects. We aimed to create a consensus document combining available evidence with expert opinion to provide guidance for use of oral treprostinil. Following a methodology commonly used in business and social sciences (the 'Delphi Process'), two investigators from the oral treprostinil (Freedom) studies created a series of statements based on available evidence and the package insert. The set of 'best practice' statements was circulated to nine other Freedom trial investigators. Their comments were incorporated into the document as new line items for further vote and comment. The subsequent document was put to vote line by line (scale of -5 to +5) and a final statement was drafted. Consensus recommendations include initial therapy with 0.125 mg for treatment naÿ patients, three times daily dosing, aggressive use of antidiarrheal medication, and a strong preference for use of the drug in combination with other approved PAH therapies. This process was particularly valuable in providing guidance for the management of adverse events (where essentially no data is available). The Delphi process was useful to codify investigator experience and subsequently develop investigator consensus about practical issues for physicians who may wish to prescribe oral treprostinil.

PMID: 28680576 [PubMed - in process]

[Optimization of the solid-phase extraction procedure for the screening of the medicinal and narcotic substances in the blood by gas chromatography with mass-spectrometric detection].

Sud Med Ekspert. 2017;60(1):29-35

Authors: Kataev SS, Dvorskaya ON, Krokhin IP

Abstract
This paper was designed to describe the application of the method for solid-phase extraction of the medicinal and narcotic substances having different physicochemical composition by gas chromatography with mass-spectrometric detection (GC-MS) for the purpose of their screening in the blood. The solid-phase extraction technique was optimized by means of the Box-Behnken modeling with the evaluation of the influence on the effectiveness of extraction of various factors including pH of the buffer solution, eluent composition, the type and the volume of the solutions used to wash the sorbent.

PMID: 28252615 [PubMed - indexed for MEDLINE]

[The distribution of amlodipine in the organism of the warm-blooded animals].

Sud Med Ekspert. 2017;60(1):23-28

Authors: Shormanov VK, Kvachakhiya LL

Abstract
The objective of the present study was to elucidate the specific features of amlodipine distribution in the organism of the warm-blooded animals (rats) following a single intragastric administration of the poisonous substance at a dose of 686 mg/kg b/w/ (LD50). Amlodipine was isolated from the blood and various organs of the animals by means of acetone extraction and purified on the silica gel column (100/160 mcm) with the elution by an ethanol-hexane (7:3) mixture. The identification and the quantitative measurement of amlodipine were performed with the use of the TLC, GC-M, and UV-spectrophotometry. The study has shown that unmetabolized amlodipine was present in large amounts in the internal organs and blood of the poisoned animals. The principal organs of its accumulation were the stomach, kidneys, and blood.

PMID: 28252614 [PubMed - indexed for MEDLINE]

[Polypragmasy: A clinical pharmacologist's view].

Ter Arkh. 2016;88(12):94-102

Authors: Sychev DA, Otdelеnov VA, Krasnova NM, Ilyina ES

Abstract
In the modern world, there is a rapid advance in the design and clinical introduction of a huge number of drugs that are able to cure a patient or to improve his/her health status on the one hand and to cause significant harm to his/her health on the other. Polypragmasy is the desire to enhance the efficiency of treatment and to help the patient recover from all developed diseases inevitably leads to the use of a large number of medications. At the present time, polypragmasy as a result of iatrogenia is a serious public health problem, as it is clinically manifested by a reduction in the effectiveness of pharmacotherapy, by the development of severe adverse drug reactions, and by a considerable increase in healthcare expenditures. The reason for the simultaneous prescription of multiple drugs may be comorbidity (multimorbidity), the availability of drugs, as well as clinical guidelines, manuals of professional medical associations, treatment standards that contain recommendations for using combination therapy with more than 5 drugs for only one disease in some cases, the efficiency of which corresponds to a high level of evidence. Currently, the fight against polypragmasy is one of the important tasks in rendering medical care to elderly and senile patients since it is a major risk factor of adverse drug reactions in this category of people. To minimize polypragmasy in elderly patients, it is necessary to use current methods for analyzing each prescription of a drug (the index of rational drug prescribing; an anticholinergic burden scale) and those for optimizing pharmacotherapy with the use of restrictive lists (Beers criteria, STOPP/START criteria) that will be able to reduce the number of errors in the administration of drugs and to maximize the efficiency and safety of pharmacotherapy.

PMID: 28139567 [PubMed - indexed for MEDLINE]

Violences et thérapeutiques 2/2.

Rev Infirm. 2017 Jan;66(227):45-46

Authors: Roynard P, Castel C, Lebain P, Roupie É, Saint-Lorant G

PMID: 28048997 [PubMed - indexed for MEDLINE]

Hospitalisation Resulting from Medicine-Related Problems in Adult Patients with Cardiovascular Diseases and Diabetes in the United Kingdom and Saudi Arabia.

Int J Environ Res Public Health. 2016 May 09;13(5):

Authors: Al Hamid A, Aslanpour Z, Aljadhey H, Ghaleb M

Abstract
Cardiovascular diseases (CVDs) and diabetes (DM) are two interrelated conditions that have a heavy morbidity and mortality burden worldwide. Patients with the two conditions usually take multiple medicines and thus are more susceptible to medicine-related problems (MRPs). MRPs can occur at any stage of the treatment process and in many cases can lead to unplanned hospitalisations. The aim of the study was to determine the prevalence of hospitalisation resulting from MRPs in adult patients with CVDs and/or DM and to identify the main causes, risk factors, and medicine classes involved. A retrospective study included 300 adult patients from two hospitals, one in the United Kingdom and one in Saudi Arabia. To identify MRPs, medical records were reviewed for demographic data, clinical data, laboratory assay, and prescription records. A total of 197 (65.7%) patients had MRPs, of which less than 10% were severe. The main problems were lack of treatment effectiveness and adverse drug reactions. Moreover, polypharmacy and patient non-adherence were the main risk factors contributing to MRPs. The main medicine classes associated with MRPs were insulin and antihypertensive medicines. Further research should address the pharmaceutical care processes employed in treating CVDs and DM, and to empower patients/healthcare providers in tackling MRPs.

PMID: 27171100 [PubMed - indexed for MEDLINE]

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