Safety assessment of sorafenib in Chinese patients with unresectable hepatocellular carcinoma: subgroup analysis of the GIDEON study.

BMC Cancer. 2018 Mar 02;18(1):247

Authors: Ye SL, Yang J, Bie P, Zhang S, Chen X, Liu F, Liu L, Zhou J, Dou K, Hao C, Shao G, Xia Q, Chen Y, Yang J, Deng X, Liu Y, Yuan Y, Fu Z, Nakajima K, Lv Z

Abstract
BACKGROUND: This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients.
METHODS: A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0.
RESULTS: Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug-related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib.
CONCLUSION: Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation.
TRIAL REGISTRATION: ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008.

PMID: 29499662 [PubMed - in process]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

36 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Leaks during multiple-breath washout: characterisation and influence on outcomes.

ERJ Open Res. 2018 Jan;4(1):

Authors: Lenherr N, Ramsey KA, Jost K, Hornwall L, Singer F, Yammine S, Latzin P

Abstract
Nitrogen multiple-breath washout (N2MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N2MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N2MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different "red flags", i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N2MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise.

PMID: 29497618 [PubMed]

Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons.

ERJ Open Res. 2018 Jan;4(1):

Authors: Pranke I, Bidou L, Martin N, Blanchet S, Hatton A, Karri S, Cornu D, Costes B, Chevalier B, Tondelier D, Girodon E, Coupet M, Edelman A, Fanen P, Namy O, Sermet-Gaudelus I, Hinzpeter A

Abstract
Premature termination codons (PTCs) are generally associated with severe forms of genetic diseases. Readthrough of in-frame PTCs using small molecules is a promising therapeutic approach. Nonetheless, the outcome of preclinical studies has been low and variable. Treatment efficacy depends on: 1) the level of drug-induced readthrough, 2) the amount of target transcripts, and 3) the activity of the recoded protein. The aim of the present study was to identify, in the cystic fibrosis transmembrane conductance regulator (CFTR) model, recoded channels from readthrough therapy that may be enhanced using CFTR modulators. First, drug-induced readthrough of 15 PTCs was measured using a dual reporter system under basal conditions and in response to gentamicin and negamycin. Secondly, exon skipping associated with these PTCs was evaluated with a minigene system. Finally, incorporated amino acids were identified by mass spectrometry and the function of the predicted recoded CFTR channels corresponding to these 15 PTCs was measured. Nonfunctional channels were subjected to CFTR-directed ivacaftor-lumacaftor treatments. The results demonstrated that CFTR modulators increased activity of recoded channels, which could also be confirmed in cells derived from a patient. In conclusion, this work will provide a framework to adapt treatments to the patient's genotype by identifying the most efficient molecule for each PTC and the recoded channels needing co-therapies to rescue channel function.

PMID: 29497617 [PubMed]

From gene networks to drugs: systems pharmacology approaches for AUD.

Psychopharmacology (Berl). 2018 Mar 01;:

Authors: Ferguson LB, Harris RA, Mayfield RD

Abstract
The alcohol research field has amassed an impressive number of gene expression datasets spanning key brain areas for addiction, species (humans as well as multiple animal models), and stages in the addiction cycle (binge/intoxication, withdrawal/negative effect, and preoccupation/anticipation). These data have improved our understanding of the molecular adaptations that eventually lead to dysregulation of brain function and the chronic, relapsing disorder of addiction. Identification of new medications to treat alcohol use disorder (AUD) will likely benefit from the integration of genetic, genomic, and behavioral information included in these important datasets. Systems pharmacology considers drug effects as the outcome of the complex network of interactions a drug has rather than a single drug-molecule interaction. Computational strategies based on this principle that integrate gene expression signatures of pharmaceuticals and disease states have shown promise for identifying treatments that ameliorate disease symptoms (called in silico gene mapping or connectivity mapping). In this review, we suggest that gene expression profiling for in silico mapping is critical to improve drug repurposing and discovery for AUD and other psychiatric illnesses. We highlight studies that successfully apply gene mapping computational approaches to identify or repurpose pharmaceutical treatments for psychiatric illnesses. Furthermore, we address important challenges that must be overcome to maximize the potential of these strategies to translate to the clinic and improve healthcare outcomes.

PMID: 29497781 [PubMed - as supplied by publisher]

Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia.

Am J Psychiatry. 2018 Mar 02;:appiajp201717040410

Authors: Kauppi K, Rosenthal SB, Lo MT, Sanyal N, Jiang M, Abagyan R, McEvoy LK, Andreassen OA, Chen CH

Abstract
OBJECTIVE: Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product.
METHOD: The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328).
RESULTS: Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms.
CONCLUSIONS: The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.

PMID: 29495895 [PubMed - as supplied by publisher]

Ontology-Based Method for Fault Diagnosis of Loaders.

Sensors (Basel). 2018 Feb 28;18(3):

Authors: Xu F, Liu X, Chen W, Zhou C, Cao B

Abstract
This paper proposes an ontology-based fault diagnosis method which overcomes the difficulty of understanding complex fault diagnosis knowledge of loaders and offers a universal approach for fault diagnosis of all loaders. This method contains the following components: (1) An ontology-based fault diagnosis model is proposed to achieve the integrating, sharing and reusing of fault diagnosis knowledge for loaders; (2) combined with ontology, CBR (case-based reasoning) is introduced to realize effective and accurate fault diagnoses following four steps (feature selection, case-retrieval, case-matching and case-updating); and (3) in order to cover the shortages of the CBR method due to the lack of concerned cases, ontology based RBR (rule-based reasoning) is put forward through building SWRL (Semantic Web Rule Language) rules. An application program is also developed to implement the above methods to assist in finding the fault causes, fault locations and maintenance measures of loaders. In addition, the program is validated through analyzing a case study.

PMID: 29495646 [PubMed - in process]

Understanding Nomophobia: Structural Equation Modeling and Semantic Network Analysis of Smartphone Separation Anxiety.

Cyberpsychol Behav Soc Netw. 2017 Jul;20(7):419-427

Authors: Han S, Kim KJ, Kim JH

Abstract
This study explicates nomophobia by developing a research model that identifies several determinants of smartphone separation anxiety and by conducting semantic network analyses on smartphone users' verbal descriptions of the meaning of their smartphones. Structural equation modeling of the proposed model indicates that personal memories evoked by smartphones encourage users to extend their identity onto their devices. When users perceive smartphones as their extended selves, they are more likely to get attached to the devices, which, in turn, leads to nomophobia by heightening the phone proximity-seeking tendency. This finding is also supplemented by the results of the semantic network analyses revealing that the words related to memory, self, and proximity-seeking are indeed more frequently used in the high, compared with low, nomophobia group.

PMID: 28650222 [PubMed - indexed for MEDLINE]

Synthesis, structural and antimicrobial studies of type II topoisomerase-targeted copper(II) complexes of 1,3-disubstituted thiourea ligands.

J Inorg Biochem. 2018 Jan 16;182:61-70

Authors: Bielenica A, Drzewiecka-Antonik A, Rejmak P, Stefańska J, Koliński M, Kmiecik S, Lesyng B, Włodarczyk M, Pietrzyk P, Struga M

Abstract
A series of Cu(II) complexes of 3-(trifluoromethyl)phenylthiourea derivatives was synthesized. Their structural properties were investigated by spectroscopic techniques (infrared and electron paramagnetic resonance), as well as molecular modeling. All studied coordination compounds are mononuclear complexes containing two chelating ligands bonded to the metal cation via S and deprotonated N atoms. The new chelates were evaluated for their antimicrobial potency. The complex of 1-(3,4-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (3) presented the highest activity against Gram-positive pathogens, even stronger than the activity of its non-complexed counterpart and the reference drug. The compound also prevented the biofilm formation of methicillin-resistant and standard strains of staphylococcal cocci. The title derivatives were found to be effective inhibitors of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. The binding modes of the ligand L3 with DNA gyrase and topoisomerase IV were presented.

PMID: 29499458 [PubMed - as supplied by publisher]

Precision medicine in diabetes prevention, classification and management.

J Diabetes Investig. 2018 Mar 02;:

Authors: Xie F, Chan JCN, Ma RCW

Abstract
Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding in the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In this review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. While major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are needed to translate these findings into practice by incorporating genetic information into risk prediction model for prioritization of treatment strategies as well as using multi-omic analysis to discover novel drug targets with companion diagnostics. Further research is also needed to ensure appropriate use of these information to empower individuals and healthcare professionals to make personalized decision for achieving optimal outcome. This article is protected by copyright. All rights reserved.

PMID: 29499103 [PubMed - as supplied by publisher]

Pharmacogenomics and the Placebo Response.

ACS Chem Neurosci. 2018 Mar 02;:

Authors: Hall KT, Loscalzo J, Kaptchuk T

Abstract
There is perhaps no more important time in the history of placebos to consider their role in clinical trials and in medicine. Increasingly well-designed pharmaceutical and academic clinical trials testing promising and established drug and surgical interventions have failed to "beat" the placebo response. The collateral damage resulting from these failures is staggering; novel treatments, many with compelling mechanisms of action and promising Phase 2 trial results, never reach the patient, adversely affecting small and large pharma alike. Recent evidence suggests that variability in placebo response may be attributed in part to genetic variation. Thus, having a better understanding of the genomic underpinnings of the placebo response, the "placebome", may pave the way to innovatively and more effectively use placebos in drug development.

PMID: 29498823 [PubMed - as supplied by publisher]

Pharmacogenetics of Dopamine β-Hydroxylase in cocaine dependence therapy with doxazosin.

Addict Biol. 2018 Mar 02;:

Authors: Zhang X, Nielsen DA, Domingo CB, Shorter DI, Nielsen EM, Kosten TR

Abstract
The α1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine β-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DβH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DβH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DβH levels from the DBH CC genotype and 27 with lower DβH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DβH and NE levels, as compared with no net reduction in the CC genotype group with normal DβH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

PMID: 29498170 [PubMed - as supplied by publisher]

Navigating Transporter Sciences in Pharmacokinetics Characterization Using Extended Clearance Classification System (ECCS).

Drug Metab Dispos. 2018 Mar 01;:

Authors: El-Kattan AF, Varma MVS

Abstract
Membrane transporters play an important role in the absorption, distribution, clearance and elimination (ADCE) of the drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion proteins (MATEs), P-glycoprotein and breast cancer resistance protein (BCRP) are suggested to be of clinical relevance. An early understanding of transporters role in the drug disposition and clearance allows reliable prediction/evaluation of the pharmacokinetic changes due to drug-drug interactions (DDIs) or genetic polymorphisms. We recently proposed extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization permeability and molecular weight) to predict predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A, 4 and certain class 3B drugs are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2 and MATEs could contribute to their active renal secretion. Intestinal efflux and uptake transporters largely influence the oral pharmacokinetics of class 3A, 3B and 4 drugs. We discuss the paradigm of applying ECCS framework in mapping the role of clinically relevant drug transporters in early discovery and development; and thereby, implementing the right strategy to allow optimization of drug exposure and evaluation of clinical risk due to DDIs and pharmacogenomics.

PMID: 29496721 [PubMed - as supplied by publisher]

Lung Disease and Genomics.

AACN Adv Crit Care. 2018;29(1):74-83

Authors: Wysocki K

Abstract
Research and application of genomic medicine in lung disease during the past century has clarified our understanding and focus on specific phenotypes, helping clinicians tailor treatment for individual patients. Cystic fibrosis and lung cancer have been researched extensively; specific genotypes have been instrumental in precision medicine to treat these lung diseases. Asthma and chronic obstructive pulmonary disease are more complex and heterogeneous in their pathogenesis, genotypic profile, and phenotypic expression, making treatment more difficult with increasing disease severity. This article focuses on the evolving state of the science of precision medicine in lung cancer, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The body of knowledge in lung disease is growing related to pharmacogenomics, clinical guidelines, genome editing, and approaches to genomic health that will guide clinical treatment options, reduce risk, and promote health.

PMID: 29496715 [PubMed - in process]

Pharmacogenomics in Critical Care.

AACN Adv Crit Care. 2018;29(1):36-42

Authors: Cheek D, Howington L

Abstract
Since the successful completion of the Human Genome Project in 2003, extensive genomic research has continued to alter pathophysiology at the molecular level. This research includes investigation of the specific receptors and metabolizing enzymes in drug pharmacodynamics and pharmacokinetics, specifically the cytochrome P450 system located primarily in the liver. In this article, pharmacogenomics and the role of the cytochrome P450 system in metabolism of various drugs are discussed. Specifically, drugs that are used in the critical care setting and are of clinical significance to the bedside critical care nurse are examined.

PMID: 29496712 [PubMed - in process]

Genomics and Precision Medicine: Implications for Critical Care.

AACN Adv Crit Care. 2018;29(1):28-35

Authors: Kessler C

Abstract
A new paradigm for disease diagnosis and treatment is emerging that will bring about changes in health care delivery in and out of the hospital setting. Over the past several decades, genomic medicine has been one of the fastest growing fields in acute and chronic health care. This quick growth has created a lag in genomics knowledge and preparation among nurses and health care providers. Genomic medicine may lead to more precise evaluation, diagnosis, and management of selected acute care conditions. This article reviews the current state of genetic and genomics science and looks at the expanding field of genomic medicine's integration into precision medicine. The aim of this article is to raise awareness and spark further inquiry to the remarkable field of genomics and precision medicine.

PMID: 29496711 [PubMed - in process]

CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification.

Ann Oncol. 2017 May 01;28(5):1032-1035

Authors: Pilati C, Taieb J, Balogoun R, Marisa L, de Reyniès A, Laurent-Puig P

Abstract
Background: Caudal-type homeobox transcription factor 2 (CDX2) is involved in colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in patients with stage II or III CC.
Patients and methods: We analyzed CDX2 expression in a series of 469 CC typed for the new international consensus molecular subtype (CMS) classification, and we confirmed results in a series of 90 CC.
Results: Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer. Although CDX2 expression was a globally independent prognostic factor, loss of CDX2 expression is not associated with a worse prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both relapse free and overall survival. Similarly, lack of CDX2 expression was a bad prognostic factor in MSS patients, but not in MSI.
Conclusions: Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis.

PMID: 28328000 [PubMed - indexed for MEDLINE]