Exploration and analysis of drug modes of action through feature integration.

Mol Biosyst. 2017 Jan 31;13(2):425-431

Authors: Xin M, Fan J, Liu M, Jiang Z

Abstract
Identifying drug modes of action (MoA) is of paramount importance for having a good grasp of drug indications in clinical tests. Anticipating MoA can help to discover new uses for approved drugs. Here we first used a drug-set enrichment analysis method to discover significant biological activities in every mode of action category. Then, we proposed a new computational model, a probability ensemble approach based on Bayesian network theory, which integrated chemical, therapeutic, genomic and phenotypic properties of over a thousand of FDA approved drugs to assist with the prediction of MoA. 10-fold cross validation tests demonstrate that this method can achieve better performances than four other methods with the area under the receiver operating characteristic (ROC) curves. Finally, we further conducted a large-scale prediction for drug-MoA pairs. Using the Cardiovascular Agents category as an example, several predicted drug-MoA pairs were supported by literature resources.

PMID: 28092388 [PubMed - indexed for MEDLINE]

Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries.

Value Health. 2017 Jul - Aug;20(7):919-926

Authors: Nicod E, Berg Brigham K, Durand-Zaleski I, Kanavos P

Abstract
OBJECTIVES: To better understand the reasons for differences in reimbursement decisions for orphan drugs in four European countries that were not readily apparent from health technology assessment (HTA) reports and operating procedures.
METHODS: Semistructured interviews with representatives of HTA bodies in England, Scotland, Sweden, and France were conducted. An interview topic guide was developed on the basis of findings from a systematic comparison of HTA decisions for 10 orphan drugs. Qualitative thematic data analysis was applied to the interview transcripts using the framework approach.
RESULTS: Eight representatives from the four HTA bodies were interviewed between March and June 2015. Evidentiary requirements and approaches to dealing with imperfect or incomplete evidence were explored, including trial design and duration, study population and subgroups, comparators, and end points. Interviewees agreed that decisions regarding orphan drugs are made in a context of lower quality evidence, and the threshold of acceptable uncertainty varied by country. Some countries imposed higher evidentiary standards for greater clinical claims, which may be more challenging for orphan diseases. The acceptability of surrogate end points was not consistent across countries nor were the validation requirements. The most common social value judgments identified related to innovation, disease severity, and unmet need. Differences were seen in the way these concepts were defined and accounted for across countries.
CONCLUSIONS: Although agreement was seen in evidentiary requirements or preferences, there were subtle differences in the circumstances in which uncertain evidence may be considered acceptable, possibly explaining differences in HTA recommendations across countries.

PMID: 28712621 [PubMed - indexed for MEDLINE]

Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.

Value Health. 2017 Jul - Aug;20(7):838-855

Authors: Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L

Abstract
BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals.
OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials.
GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use.
CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

PMID: 28712612 [PubMed - indexed for MEDLINE]

Molecular oncogenesis of chondrosarcoma: impact for targeted treatment.

Curr Opin Oncol. 2016 Jul;28(4):314-22

Authors: Speetjens FM, de Jong Y, Gelderblom H, Bovée JV

Abstract
PURPOSE OF REVIEW: The prognosis of patients with unresectable or metastatic chondrosarcoma of the bone is poor. Chondrosarcomas are in general resistant to chemotherapy and radiotherapy. This review discusses recent developments in the characterization of molecular pathways involved in the oncogenesis of chondrosarcoma that should be explored to improve prognosis of patients with advanced chondrosarcoma.
RECENT FINDINGS: The different oncogenic pathways for chondrosarcoma have become better defined. These include alterations in pathways such as isocitrate dehydrogenase mutation, hedgehog signalling, the retinoblastoma protein and p53 pathways, apoptosis and survival mechanisms, and several tyrosine kinases. These specific alterations can be employed for use in clinical interventions in advanced chondrosarcoma.
SUMMARY: As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.

PMID: 27166664 [PubMed - indexed for MEDLINE]

Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma.

J Allergy Clin Immunol. 2017 Jul 20;:

Authors: Burbank AJ, Duran CG, Pan Y, Burns P, Jones S, Jiang Q, Yang C, Jenkins S, Wells H, Alexis N, Kesimer M, Bennett WD, Zhou H, Peden DB, Hernandez ML

Abstract
BACKGROUND: We and others have shown that the gamma tocopherol (γT) isoform of vitamin E has multiple anti-inflammatory and antioxidant actions and that γT supplementation reduces eosinophilic and endotoxin (LPS)-induced neutrophilic airway inflammation in animal models and healthy human volunteers.
OBJECTIVE: To determine if γT supplementation reduces eosinophilic airway inflammation and acute neutrophilic response to inhaled LPS challenge in volunteers with asthma.
METHODS: Participants with mild asthma were enrolled in a double-blinded, placebo controlled crossover study to assess the effect of 1200 mg of γT daily for 14 days on sputum eosinophils, mucins and cytokines. We also assessed the effect on acute inflammatory response to inhaled LPS challenge following γT treatment, focusing on changes in sputum neutrophilia, mucins and cytokines. Mucociliary clearance was measured using gamma scintigraphy.
RESULTS: Fifteen subjects with mild asthma completed both arms of the study. Compared to placebo, γT notably reduced pre-LPS challenge sputum eosinophils and mucins, including MUC5AC, and reduced LPS-induced airway neutrophil recruitment 6 and 24-hours after challenge. Mucociliary clearance was slowed 4-hours post-challenge in the placebo group but not in the γT treatment group. Total sputum mucins (but not MUC5AC) were reduced at 24-hours post-challenge during γT treatment compared to placebo.
CONCLUSION: γT supplementation for 14 days reduced inflammatory features of asthma, including sputum eosinophils and mucins, as well as acute airway response to inhaled LPS challenge when compared to placebo. Larger scale clinical trials are needed to assess the efficacy of γT supplements as a complementary or steroid-sparing treatment for asthma.

PMID: 28736267 [PubMed - as supplied by publisher]

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.

Thorax. 2016 Dec;71(12):1110-1118

Authors: McDonnell MJ, Aliberti S, Goeminne PC, Dimakou K, Zucchetti SC, Davidson J, Ward C, Laffey JG, Finch S, Pesci A, Dupont LJ, Fardon TC, Skrbic D, Obradovic D, Cowman S, Loebinger MR, Rutherford RM, De Soyza A, Chalmers JD

Abstract
INTRODUCTION: Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality.
METHODS: We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies.
RESULTS: The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline.
CONCLUSION: The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

PMID: 27516225 [PubMed - indexed for MEDLINE]

Thermal unfolding simulations of NBD1 domain variants reveal structural motifs associated with the impaired folding of F508del-CFTR.

Mol Biosyst. 2016 Aug 16;12(9):2834-48

Authors: Estácio SG, Martiniano HF, Faísca PF

Abstract
We employed high-temperature classical molecular dynamics (MD) simulations to investigate the unfolding process of the wild-type (WT) and F508del-NBD1 domains of CFTR protein, with and without second-site mutations. To rationalize the in vitro behavior of F508del-NBD1, namely its lower folding yield and higher aggregation propensity, we focused our analysis of the MD data on the existence of intermediate states with aggregation potential and/or stabilized by a significant number of non-native interactions (i.e. misfolded states). We find that the deletion of phenylalanine 508 is able to forcefully reshape the conformational space of the NBD1 domain to the extent that it uniquely populates intermediate states whose structural traits provide important insights into the molecular events that underlie the impaired folding of F508del-NBD1. In particular, our simulations predict the formation of a misfolded intermediate whose population is highly enhanced by deletion of residue 508. The stabilization of this intermediate is a direct consequence of the enhanced non-native coupling between various key regions of the α-helical subdomain and ATP-binding subdomain; it is singularly characterized by a set of non-native interactions within the ATP-binding subdomain and between that domain and the α-helical subdomain region. The formation of this intermediate is not blocked by second-site suppressor mutations which indicates a limited role of the latter in correcting the rather complex folding process of the CFTR protein missing residue 508.

PMID: 27354240 [PubMed - indexed for MEDLINE]

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality.

PLoS One. 2016;11(6):e0157523

Authors: Jensen R, Stanojevic S, Klingel M, Pizarro ME, Hall GL, Ramsey K, Foong R, Saunders C, Robinson PD, Webster H, Hardaker K, Kane M, Ratjen F

Abstract
BACKGROUND: Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria.
METHODS: 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic).
RESULTS: Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53-0.83%) to (κ 0.73-0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis.
CONCLUSIONS: The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.

PMID: 27304432 [PubMed - indexed for MEDLINE]

The evolving genetic risk for sporadic ALS.

Neurology. 2017 Jul 18;89(3):226-233

Authors: Gibson SB, Downie JM, Tsetsou S, Feusier JE, Figueroa KP, Bromberg MB, Jorde LB, Pulst SM

Abstract
OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.
METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.
RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.
CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.

PMID: 28642336 [PubMed - indexed for MEDLINE]

Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report.

BMC Med Genet. 2017 Jun 15;18(1):68

Authors: Bastaki F, Nair P, Mohamed M, Malik EM, Helmi M, Al-Ali MT, Hamzeh AR

Abstract
BACKGROUND: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor.
CASE PRESENTATION: This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay.
CONCLUSIONS: Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings.

PMID: 28619046 [PubMed - indexed for MEDLINE]

Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation.

Cancer Lett. 2016 Dec 01;383(1):106-114

Authors: Hayes TF, Benaich N, Goldie SJ, Sipilä K, Ames-Draycott A, Cai W, Yin G, Watt FM

Abstract
Oral squamous cell carcinoma (OSCC) is genetically highly heterogeneous, which contributes to the challenges of treatment. To create an in vitro model that accurately reflects this heterogeneity, we generated a panel of HPV-negative OSCC cell lines. By whole exome sequencing of the lines and matched patient blood samples, we demonstrate that the mutational spectrum of the lines is representative of primary OSCC in The Cancer Genome Atlas. We show that loss of function mutations in FAT1 (an atypical cadherin) and CASP8 (Caspase 8) frequently occur in the same tumour. OSCC cells with inactivating FAT1 mutations exhibited reduced intercellular adhesion. Knockdown of FAT1 and CASP8 individually or in combination in OSCC cells led to increased cell migration and clonal growth, resistance to Staurosporine-induced apoptosis and, in some cases, increased terminal differentiation. The OSCC lines thus represent a valuable resource for elucidating the impact of different mutations on tumour behaviour.

PMID: 27693639 [PubMed - indexed for MEDLINE]

Semiconductor Whole Exome Sequencing for the Identification of Genetic Variants in Colombian Patients Clinically Diagnosed with Long QT Syndrome.

Mol Diagn Ther. 2016 Aug;20(4):353-62

Authors: Burgos M, Arenas A, Cabrera R

Abstract
BACKGROUND AND OBJECTIVE: Inherited long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of QT interval and the risk of syncope, cardiac arrest, and sudden cardiac death. Genetic diagnosis of LQTS is critical in medical practice as results can guide adequate management of patients and distinguish phenocopies such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, extensive screening of large genomic regions is required in order to reliably identify genetic causes. Semiconductor whole exome sequencing (WES) is a promising approach for the identification of variants in the coding regions of most human genes.
METHODS: DNA samples from 21 Colombian patients clinically diagnosed with LQTS were enriched for coding regions using multiplex polymerase chain reaction (PCR) and subjected to WES using a semiconductor sequencer.
RESULTS: Semiconductor WES showed mean coverage of 93.6 % for all coding regions relevant to LQTS at >10× depth with high intra- and inter-assay depth heterogeneity. Fifteen variants were detected in 12 patients in genes associated with LQTS. Three variants were identified in three patients in genes associated with CPVT. Co-segregation analysis was performed when possible. All variants were analyzed with two pathogenicity prediction algorithms. The overall prevalence of LQTS and CPVT variants in our cohort was 71.4 %. All LQTS variants previously identified through commercial genetic testing were identified.
CONCLUSION: Standardized WES assays can be easily implemented, often at a lower cost than sequencing panels. Our results show that WES can identify LQTS-causing mutations and permits differential diagnosis of related conditions in a real-world clinical setting. However, high heterogeneity in sequencing depth and low coverage in the most relevant genes is expected to be associated with reduced analytical sensitivity.

PMID: 27251404 [PubMed - indexed for MEDLINE]

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

Eur J Hum Genet. 2016 Aug;24(8):1145-53

Authors: Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, Santen GW, van den Maagdenberg AM, Peeters-Scholte CM, Kuenen S, Verstreken P, Pfundt R, Yntema HG, de Vries PF, Veltman JA, Hoischen A, Gilissen C, de Vries BB, Schenck A, Kleefstra T, Vissers LE

Abstract
Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

PMID: 26757981 [PubMed - indexed for MEDLINE]

Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.

Eur J Hum Genet. 2016 Aug;24(8):1223-7

Authors: Ansar M, Jan A, Santos-Cortez RL, Wang X, Suliman M, Acharya A, Habib R, Abbe I, Ali G, Lee K, Smith JD, University of Washington Center for Mendelian Genomics, Nickerson DA, Shendure J, Bamshad MJ, Ahmad W, Leal SM

Abstract
Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

PMID: 26695873 [PubMed - indexed for MEDLINE]

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene.

Eur J Hum Genet. 2016 Aug;24(8):1206-10

Authors: Girisha KM, Kortüm F, Shah H, Alawi M, Dalal A, Bhavani GS, Kutsche K

Abstract
We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T>A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations.

PMID: 26669664 [PubMed - indexed for MEDLINE]

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2).

Eur J Hum Genet. 2016 Aug;24(8):1154-9

Authors: Guissart C, Drouot N, Oncel I, Leheup B, Gershoni-Barush R, Muller J, Ferdinandusse S, Larrieu L, Anheim M, Arslan EA, Claustres M, Tranchant C, Topaloglu H, Koenig M

Abstract
Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21-p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown-Vialleto-Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.

PMID: 26669662 [PubMed - indexed for MEDLINE]

Ovarian cancer survivors' acceptance of treatment side effects evolves as goals of care change over the cancer continuum.

Gynecol Oncol. 2017 Aug;146(2):386-391

Authors: Frey MK, Ellis AE, Koontz LM, Shyne S, Klingenberg B, Fields JC, Chern JY, Blank SV

Abstract
OBJECTIVES: Women with ovarian cancer can have long overall survival and goals of treatment change over time from cure to remission to stable disease. We sought to determine whether survivors' acceptance of treatment side effects also changes over the disease continuum.
METHODS: Women with ovarian cancer completed an online survey focusing on survivors' goals and priorities. The survey was distributed through survivor networks and social media.
RESULTS: Four hundred and thirty-four women visited the survey website and 328 (76%) completed the survey. Among participants, 141 (43%) identified themselves as having ever recurred, 119 (36%) were undergoing treatment at the time of survey completion and 86 (26%) had received four or more chemotherapy regimens. Respondents' goals of care were cure for 115 women (35%), remission for 156 (48%) and stable disease for 56 (17%). When asked what was most meaningful, 148 women (45%) reported overall survival, 135 (41%) reported quality of life and 40 (12%) reported progression-free survival. >50% of survivors were willing to tolerate the following symptoms for the goal of cure: fatigue (283, 86%), alopecia (281, 86%), diarrhea (232, 71%), constipation (227, 69%), neuropathy (218, 66%), arthralgia (210, 64%), sexual side effects (201, 61%), reflux symptoms (188, 57%), memory loss (180, 55%), nausea/vomiting (180, 55%), hospitalization for treatment side effects (179, 55%) and pain (169, 52%). The rates of tolerance for most symptoms decreased significantly as the goal of treatment changed from cure to remission to stable disease.
CONCLUSIONS: Women with ovarian cancer willingly accept many treatment side effects when the goal of treatment is cure, however become less accepting when the goal is remission and even less so when the goal is stable disease. Physicians and survivors must carefully consider treatment toxicities and quality of life effects when selecting drugs for patients with incurable disease.

PMID: 28602549 [PubMed - indexed for MEDLINE]

A systematic review of patient values, preferences and expectations for the treatment of recurrent ovarian cancer.

Gynecol Oncol. 2017 Aug;146(2):392-398

Authors: PEBC’s Ovarian Oncology Guidelines Group

Abstract
BACKGROUND AND OBJECTIVES: It is our belief that patient preference should play a significant role in disease management of recurrent ovarian cancer. Since cure is seldom an endpoint in this circumstance, patients' attitudes toward the risks and benefits of chemotherapy versus palliation are relevant.
METHODS: Medline, Embase, CINAHL and PsycINFO from were searched from January 1, 2000 to December 13, 2016 for studies of values, preferences or expectations of women with platinum-sensitive recurrent or refractory ovarian cancer.
RESULTS: Ten studies representing five countries met inclusion criteria. Although there was regional variation in preference for palliation over treatment, certain themes emerged. 1) Patients, even in the context of counselling overestimated the curative capability of chemotherapy. In one study 92% of patients had high expectations of healing after completing an expectation of treatment checklist. Another study observed that patients are often overwhelmed by information provided at diagnosis and there can be a discrepancy between what patients report to have heard and what the clinicians said. 2) Patients who had previously tolerated chemotherapy well were more likely to be accepting of the side-effects of chemotherapy. 3) Patients were more willing to accept chemotherapy and the related side effects when treatment was of curative intent or when overall survival was increased. 4) Patients valued both overall and progression free survival. 5) A significant minority (24%) consistently chose treatment over palliation. 6) Patients were more willing to accept the side effects of chemotherapy than were their health care providers.
CONCLUSIONS: These findings, in aggregate, highlight the importance of communication with patients regarding prognosis, adverse effects and symptom management to help negotiate the decision making process. Chemotherapy in the recurrent setting should be managed on a case by case basis, combining both medical constraints and consideration to patient preferences.

PMID: 28601379 [PubMed - indexed for MEDLINE]

ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish.

Int J Mol Sci. 2017 Apr 19;18(4):

Authors: Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T, D'Amico D, Terriente J

Abstract
Toxicity is one of the major attrition causes during the drug development process. In that line, cardio-, neuro-, and hepatotoxicities are among the main reasons behind the retirement of drugs in clinical phases and post market withdrawal. Zebrafish exploitation in high-throughput drug screening is becoming an important tool to assess the toxicity and efficacy of novel drugs. This animal model has, from early developmental stages, fully functional organs from a physiological point of view. Thus, drug-induced organ-toxicity can be detected in larval stages, allowing a high predictive power on possible human drug-induced liabilities. Hence, zebrafish can bridge the gap between preclinical in vitro safety assays and rodent models in a fast and cost-effective manner. ZeGlobalTox is an innovative assay that sequentially integrates in vivo cardio-, neuro-, and hepatotoxicity assessment in the same animal, thus impacting strongly in the 3Rs principles. It Reduces, by up to a third, the number of animals required to assess toxicity in those organs. It Refines the drug toxicity evaluation through novel physiological parameters. Finally, it might allow the Replacement of classical species, such as rodents and larger mammals, thanks to its high predictivity (Specificity: 89%, Sensitivity: 68% and Accuracy: 78%).

PMID: 28422076 [PubMed - indexed for MEDLINE]

Guided Imagery And Progressive Muscle Relaxation as a Cluster of Symptoms Management Intervention in Patients Receiving Chemotherapy: A Randomized Control Trial.

PLoS One. 2016;11(6):e0156911

Authors: Charalambous A, Giannakopoulou M, Bozas E, Marcou Y, Kitsios P, Paikousis L

Abstract
OBJECTIVE: Patients receiving chemotherapy often experience many different symptoms that can be difficult to alleviate and ultimately negatively influence their quality of life. Such symptoms include pain, fatigue, nausea, vomiting and retching, anxiety and depression. There is a gap in the relevant literature on the effectiveness of cognitive-behavioural and relaxation techniques in symptom clusters. The study reflects this gap in the literature and aimed to test the effectiveness of Guided Imagery (GI) and Progressive Muscle Relaxation (PMR) on a cluster of symptoms experienced by patients undergoing chemotherapy.
METHODS: This was a randomized control trial with 208 patients equally assigned either in the intervention or the control group. Measurements in both groups were collected at baseline and at completion of intervention (4 weeks). Patients were assessed for pain, fatigue, nausea, vomiting and retching, anxiety and depression. The overall management of the cluster was also assessed based on the patients' self-reported health related quality of life-HRQoL. Chi-square tests (X2), independent T-tests and Linear Mixed Models were calculated.
RESULTS: Patients in the intervention group experienced lower levels of Fatigue (p<0.0.0225), and Pain (p = 0.0003) compared to those in the control group and experienced better HRQoL (p<0.0001) [PRE-POST:
INTERVENTION: Pain 4.2(2.5) - 2.5(1.6), Fatigue 27.6(4.1) - 19.3(4.1), HRQoL 54.9(22.7) - 64.5(23), CONTROL: Pain 3.5(1.7) - 4.8(1.5), Fatigue 28.7(4.1) - 32.5(3.8), HRQoL 51.9(22.3)- 41.2(24.1)]. Nausea, vomiting and retching occurred significantly less often in the intervention group [pre-post: 25.4(5.9)- 20.6(5.6) compared to the control group (17.8(6.5)- 22.7(5.3) (F = 58.50 p<0.0001). More patients in the control group (pre:n = 33-post:n = 47) were found to be moderately depressed compared to those in the intervention group (pre:n = 35-post:n = 15) (X2 = 5.93; p = 0.02).
CONCLUSION: This study provided evidence that the combination of GI and PMR can be effective in the management of a cluster of symptoms in cancer patients receiving chemotherapy. These techniques can complement existing management measures to achieve a comprehensive management of this symptom cluster and increase patients HRQoL.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01275872.

PMID: 27341675 [PubMed - indexed for MEDLINE]