PD-1 inhibition in congenital pigment synthesizing metastatic melanoma.

Pediatr Blood Cancer. 2017 Jul 04;:

Authors: Weyand AC, Mody RJ, Rabah RM, Opipari VP

Abstract
A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.

PMID: 28675691 [PubMed - as supplied by publisher]

Compound heterozygosity for loss-of-function GARS variants results in a multi-system developmental syndrome that includes severe growth retardation.

Hum Mutat. 2017 Jul 04;:

Authors: Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, Antonellis A

Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycyl-tRNA synthetase (GARS) is a bi-functional ARS that charges tRNA(Gly) in the cytoplasm and mitochondria. GARS variants have been associated with dominant Charcot-Marie-Tooth disease but have not been convincingly implicated in recessive phenotypes. Here we describe a patient from the NIH Undiagnosed Diseases Program with a multi-system, developmental phenotype. Whole-exome sequence analysis revealed that the patient is compound heterozygous for one frameshift (p.Glu83Ilefs*6) and one missense (p.Arg310Gln) GARS variant. Using in vitro and in vivo functional studies, we show that both GARS variants cause a loss-of-function effect: the frameshift variant results in depleted protein levels and the missense variant reduces GARS tRNA charging activity. In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARS-related recessive diseases, including features associated with variants in both cytoplasmic and mitochondrial ARSs; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants. This article is protected by copyright. All rights reserved.

PMID: 28675565 [PubMed - as supplied by publisher]

Epileptic Encephalopathies as Neurodegenerative Disorders.

Adv Neurobiol. 2017;15:295-315

Authors: Helbig I, von Deimling M, Marsh ED

Abstract
The epileptic encephalopathies are severe and often treatment-resistant conditions that are associated with a progressive disturbance of brain function, resulting in a broad range of neurological and non-neurological comorbidities. The concept of epileptic encephalopathies entails that the encephalopathy aspect of the overall condition is primarily driven by the epileptic activity of the disease, which often manifests as specific and pathological features on the electroencephalogram. Genetic factors in epileptic encephalopathies are increasingly recognized. As of 2016, more than 30 genes have been securely implicated as causative genes for genetic epileptic encephalopathies. Even though the traditional concept of epileptic encephalopathies entails that the progressive disturbance of brain dysfunction is primarily due to the abnormal hypersynchronous activity that underlies the seizure disorders, this strict concept rarely holds true for patients with identified genetic etiologies. More commonly, an underlying genetic etiology is thought to predispose both to the neurodevelopmental comorbidities and to the seizure phenotype with a complex interaction between both. In this chapter, we will elucidate to what extent neurodegeneration rather than epilepsy-related regression is a feature of the common epileptic encephalopathies, drawing parallels between two relatively separate fields of neurogenetic research.

PMID: 28674986 [PubMed - in process]

A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations.

J Am Soc Nephrol. 2017 Jul 03;:

Authors: Bongers EMHF, Shelton LM, Milatz S, Verkaart S, Bech AP, Schoots J, Cornelissen EAM, Bleich M, Hoenderop JGJ, Wetzels JFM, Lugtenberg D, Nijenhuis T

Abstract
Mice lacking distal tubular expression of CLDN10, the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.

PMID: 28674042 [PubMed - as supplied by publisher]

Brain involvement in Charcot-Marie-Tooth disease due to ganglioside-induced differentiation associated-protein 1 mutation.

Neuromuscul Disord. 2017 Jun 07;:

Authors: Al-Ghamdi F, Anselm I, Yang E, Ghosh PS

Abstract
Charcot-Marie-Tooth (CMT) due to ganglioside-induced differentiation associated-protein 1 (GDAP1) gene mutation can be inherited as an autosomal recessive (severe phenotype) or dominant (milder phenotype) disorder. GDAP1 protein, located in the outer mitochondrial membrane, is involved in the mitochondrial fission. Brain imaging abnormalities have not been reported in this condition. We described an 8-year-old boy who had an early onset autosomal recessive neuropathy. Whole exome sequencing revealed compound heterozygous mutations in the GDAP1 gene: c.313_313delA, p.Arg105Glufs*3 - a novel mutation (maternally inherited) and c.358C>T, pR120W - a known pathogenic mutation (paternally inherited). He had abnormal brain MRI findings since infancy localized to the middle cerebellar peduncles and cerebellar white matter with sparing of the supratentorial brain. We speculate that GDAP1 protein due to its widespread distribution and mitochondrial location is responsible for these imaging abnormalities. This report expands the spectrum of brain imaging abnormalities seen in different types of CMT.

PMID: 28673555 [PubMed - as supplied by publisher]

Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

Regul Toxicol Pharmacol. 2016 Nov;81:341-352

Authors: Karwasra R, Kalra P, Nag TC, Gupta YK, Singh S, Panwar A

Abstract
Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

PMID: 27667768 [PubMed - indexed for MEDLINE]

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Evolution and multiple roles of the Pancrustacea specific transcription factor zelda in insects.

PLoS Genet. 2017 Jul 03;13(7):e1006868

Authors: Ribeiro L, Tobias-Santos V, Santos D, Antunes F, Feltran G, de Souza Menezes J, Aravind L, Venancio TM, Nunes da Fonseca R

Abstract
Gene regulatory networks (GRNs) evolve as a result of the coevolutionary processes acting on transcription factors (TFs) and the cis-regulatory modules they bind. The zinc-finger TF zelda (zld) is essential for the maternal-to-zygotic transition (MZT) in Drosophila melanogaster, where it directly binds over thousand cis-regulatory modules to regulate chromatin accessibility. D. melanogaster displays a long germ type of embryonic development, where all segments are simultaneously generated along the whole egg. However, it remains unclear if zld is also involved in the MZT of short-germ insects (including those from basal lineages) or in other biological processes. Here we show that zld is an innovation of the Pancrustacea lineage, being absent in more distant arthropods (e.g. chelicerates) and other organisms. To better understand zld´s ancestral function, we thoroughly investigated its roles in a short-germ beetle, Tribolium castaneum, using molecular biology and computational approaches. Our results demonstrate roles for zld not only during the MZT, but also in posterior segmentation and patterning of imaginal disc derived structures. Further, we also demonstrate that zld is critical for posterior segmentation in the hemipteran Rhodnius prolixus, indicating this function predates the origin of holometabolous insects and was subsequently lost in long-germ insects. Our results unveil new roles of zld in different biological contexts and suggest that changes in expression of zld (and probably other major TFs) are critical in the evolution of insect GRNs.

PMID: 28671979 [PubMed - as supplied by publisher]

Raising Awareness Among Healthcare Providers about Epidermolysis Bullosa and Advancing Toward a Cure.

J Clin Aesthet Dermatol. 2017 May;10(5):36-48

Authors: Tabor A, Pergolizzi JV, Marti G, Harmon J, Cohen B, Lequang JA

Abstract
Objective: Epidermolysis bullosa (EB) is an orphan disease that affects about half a million people worldwide, but may not be familiar to all clinicians. The authors' goal was to present a short description of this condition and current research in the form of a narrative review. Methods: The authors reviewed the literature on epidermolysis bullosa in order to describe the condition and current genetic research. Results: There are at least 31 subtypes of EB, including junctional EB, dystrophic EB, and Kindler syndrome. Genetic research is crucial in finding strategies to manage and possibly cure EB, which is often undiagnosed or misdiagnosed. EB may present in newborns and may persist over the course of a lifetime. Serious complications can occur with EB, including chronic blisters, wounds, ulcers, pruritus, clubbing of hands and feet, and amputations. Pain is frequently reported. About 80 percent of patients with recessive dystrophic EB will succumb to squamous cell carcinoma by age 55. Promising directions for future research include genome editing, gene therapy, and cell-based therapies. Conclusion: Our growing understanding of genetics and cell therapies may lead to promising therapeutic advances to treat this challenging condition.

PMID: 28670357 [PubMed - in process]

Warfarin Pharmacogenomics in Diverse Populations.

Pharmacotherapy. 2017 Jul 03;:

Authors: Kaye JB, Schultz LE, Steiner HE, Kittles RA, Cavallari LH, Karnes JH

Abstract
Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African-Americans (AAs) and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies and effects of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence with warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. This article is protected by copyright. All rights reserved.

PMID: 28672100 [PubMed - as supplied by publisher]

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

Pharmacotherapy. 2017 Jul 03;:

Authors: Maxwell WD, Ramsey LB, Johnson SG, Moore KG, Shtutman M, Schoonover JH, Kawaguchi-Suzuki M

Abstract
Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. A summary of the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy is provided. This article is protected by copyright. All rights reserved.

PMID: 28672099 [PubMed - as supplied by publisher]

Collaborative counseling considerations for pharmacogenomic tests.

Pharmacotherapy. 2017 Jul 03;:

Authors: Zierhut HA, Campbell CA, Mitchell AG, Lemke AA, Mills R, Bishop JR

Abstract
Increased use of pharmacogenomic (PGx) testing in the clinical setting has revealed a number of challenges to the provision of this service. PGx is an important component of precision medicine which brings together the fields of genetics and clinical pharmacology. A model that incorporates a multi-disciplinary approach to implementation and information delivery may be the most beneficial to patients and providers. In this review, translational considerations in the provision of PGx testing and counseling services are described. Specifically, the selection of PGx tests, the provision of patient education and counseling, and examples of PGx service delivery models that incorporate counseling by pharmacists and genetic counselors are reported. Examples of ancillary risks associated with PGx testing, testing of children, and familial implications of testing are reviewed. Through multi-specialty partnerships, including genetic counselors and pharmacists, implementation obstacles to PGx testing can be overcome to provide quality, precision medicine to patients. This article is protected by copyright. All rights reserved.

PMID: 28672074 [PubMed - as supplied by publisher]

A genome-wide association study suggested that the mitogen-activated protein kinase 14 gene (MAPK14) is associated with diabetic foot ulcer.

Br J Dermatol. 2017 Jul 03;:

Authors: Meng W, Veluchamy A, Hébert HL, Campbell A, Colhoun HM, Palmer CNA

Abstract
BACKGROUND: Diabetic foot ulcer (DFU) is a devastating complication of diabetes.
OBJECTIVES: We aimed to identify genetic contributors of DFU based on a genome-wide association study approach using a Scottish diabetic cohort.
METHODS: A genome-wide association approach was applied. A case was defined as a diabetic patient (type 1 or type 2) who had ever been recorded in the linked e-health records as having a foot ulcer (current or previous) in at least one foot as well as a positive result of the monofilament test in the longitudinal e-health records. A control in this study was defined as a diabetic individual (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot in the linked e-health records and the monofilament test results of any foot was once recorded to be positive in the longitudinal e-health records.
RESULTS: We have 699 DFU cases and 2,695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The lowest P value of rs80028505 (Chr6p21.31) in the MAPK14 gene was 2.45x10(-8) . The narrow-sense heritability of this phenotype is 0.06.
CONCLUSIONS: We suggest that the MAPK14 gene is associated with DFU. This article is protected by copyright. All rights reserved.

PMID: 28672053 [PubMed - as supplied by publisher]

Genetic variants of the kynurenine-3-monooxygenase and postpartum depressive symptoms after cesarean section in Chinese women.

J Affect Disord. 2017 Jun;215:94-101

Authors: Wang SY, Duan KM, Tan XF, Yin JY, Mao XY, Zheng W, Wang CY, Yang M, Peng C, Zhou HH, Liu ZQ

Abstract
BACKGROUND: New conceptualizations of depression have emphasized the role of the kynurenine pathway (KP) in the pathogenesis of postpartum depressive symptoms (PDS). Kynurenine 3-monooxygenase (KMO) is a rate-limiting enzyme of the KP, where it catalyzes the conversion of kynurenine (KYN) to 3-hydroxykynurenine (3-HK). Previous work indicates that KMO is closely linked to the pathophysiology of depressive disorders. The purpose of this study is to investigate whether variations in the KMO gene affect PDS development after cesarean section.
METHODS: A total of 710 Chinese women receiving cesarean section were enrolled in this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Subsequently, 24 women with PDS and 48 matched women without PDS were randomly selected for investigation of perinatal serum concentrations of KYN, 3-HK and the 3-HK/KYN ratio. The 3-HK/KYN ratio indicates the activity of KMO. In addition, 6 single nucleotide polymorphisms of the KMO gene were examined. Following this genotyping, 36 puerperant women carrying the KMO rs1053230 AG genotype and 72 matched puerperant women carrying the KMO rs1053230 GG genotype were selected for comparisons of KYN, 3-HK and 3-HK/KYN ratio levels.
RESULTS: The results show the incidence of PDS in the Chinese population to be 7.3%, with PDS characterized by increased serum 3-HK concentration and 3-HK/KYN ratio, versus matched postpartum women without PDS (P<0.05). Furthermore, polymorphisms of KMO rs1053230 are significantly associated with the incidence of PDS (P<0.05). The serum concentrations of 3-HK and the 3-HK/KYN ratio in postpartum women carrying the KMO rs1053230 AG genotype are significantly higher than those in matched postpartum women carrying the KMO rs1053230 GG genotype.
CONCLUSIONS: The presented data highlight the contribution of alterations in the KP to the pathogenesis of postpartum depression. Heightened KMO activity, including as arising from KMO rs1053230 G/A genetic variations, are indicated as one possible mechanism driving the biological underpinnings of PDS.

PMID: 28319697 [PubMed - indexed for MEDLINE]

Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach.

PLoS One. 2016;11(12):e0166207

Authors: Kaguelidou F, Alberti C, Biran V, Bourdon O, Farnoux C, Zohar S, Jacqz-Aigrain E

Abstract
OBJECTIVE: Proton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker.
DESIGN: Double blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%).
SETTING: Neonatal Intensive Care unit of the Robert Debré University Hospital in Paris, France.
PATIENTS: Neonates with a postmenstrual age ≥ 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index ≥ 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth.
INTERVENTION: Five preselected doses of oral omeprazole from 1 to 3 mg/kg/day.
MAIN OUTCOME MEASURES: Primary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index <5% during the 24-h pH monitoring registered 72±24 hours after omeprazole initiation.
RESULTS: Fifty-four neonates with a reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3-99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24).
CONCLUSIONS: Omeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole doses remains to be determined.

PMID: 28002471 [PubMed - indexed for MEDLINE]

Prediction models for platinum-based chemotherapy response and toxicity in advanced NSCLC patients.

Cancer Lett. 2016 Jul 10;377(1):65-73

Authors: Yin JY, Li X, Li XP, Xiao L, Zheng W, Chen J, Mao CX, Fang C, Cui JJ, Guo CX, Zhang W, Gao Y, Zhang CF, Chen ZH, Zhou H, Zhou HH, Liu ZQ

Abstract
In this study, we aimed to establish a platinum-based chemotherapy response and toxicity prediction model in advanced non-small cell lung cancer (NSCLC) patients. 416 single nucleotide polymorphisms (SNPs) in 185 genes were genotyped, and their association with drug response and toxicity were estimated using logistic regression. Nine data mining techniques were employed to establish the prediction model; the sensitivity, specificity, overall accuracy and receiver operating characteristic (ROC) curve were used to assess the models' performance. Finally, selected models were validated in an independent cohort. The models established by naïve Bayesian algorithm had the best performance. The response prediction model achieved a sensitivity of 0.90 and a specificity of 0.47 with the ROC area under curve (AUC) of 0.80. The overall toxicity prediction model achieved a sensitivity of 0.86 and a specificity of 0.46 with the ROC AUC of 0.73. The hematological toxicity prediction model achieved a sensitivity of 0.89 and a specificity of 0.39 with the ROC AUC of 0.76. The gastrointestinal toxicity prediction model achieved a sensitivity of 0.93 and a specificity of 0.35 with the ROC AUC of 0.80. In conclusion, we provided platinum-based chemotherapy response and toxicity prediction models for advanced NSCLC patients.

PMID: 27126360 [PubMed - indexed for MEDLINE]

Expanded Cystic Fibrosis Therapy.

JAMA. 2017 Jul 04;318(1):20

Authors: Voelker R

PMID: 28672301 [PubMed - in process]

Interventions for chronic kidney disease in people with sickle cell disease.

Cochrane Database Syst Rev. 2017 Jul 03;7:CD012380

Authors: Roy NB, Fortin PM, Bull KR, Doree C, Trivella M, Hopewell S, Estcourt LJ

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD.Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD.Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, and increases in prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease.
OBJECTIVES: To assess the effectiveness of any intervention in preventing or reducing kidney complications or chronic kidney disease in people with SCD (including red blood cell transfusions, hydroxyurea and angiotensin-converting enzyme inhibitor (ACEI)), either alone or in combination with each other.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 05 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 13 April 2017.
SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent or reduce kidney complications or chronic kidney disease in people with SCD. There were no restrictions by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias.
MAIN RESULTS: We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo.We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm. Hydroxyurea versus placebo We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m²)) (one study; 142 participants; very low-quality evidence).In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence).Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence).No deaths occurred in the trial. Quality of life was not reported. ACEI versus placeboWe are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD -49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence).All-cause mortality, serious adverse events and quality of life were not reported.
AUTHORS' CONCLUSIONS: In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children's ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations.We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications.This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications.Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD.We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD.

PMID: 28672087 [PubMed - as supplied by publisher]

Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention.

Pediatr Pulmonol. 2017 Jul 03;:

Authors: Konstan MW, Wagener JS, VanDevanter DR, Pasta DJ, Millar SJ, Morgan WJ, Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis

Abstract
OBJECTIVES: The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1 ) decline.
METHODOLOGY: Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients).
RESULTS: Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEV1 /year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV1 /year.
CONCLUSIONS: Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable.

PMID: 28672067 [PubMed - as supplied by publisher]

Clinical Model of Exercise-Related Dyspnea in Adult Patients With Cystic Fibrosis.

J Cardiopulm Rehabil Prev. 2017 Jun 30;:

Authors: Stevens D, Neyedli HF

Abstract
PURPOSE: Dyspnea is a highly distressing symptom of pulmonary disease that can make performing physical activities challenging. However, little is known regarding the strongest predictors of exercise-related dyspnea in adult cystic fibrosis (CF). Therefore, the purpose of the present study was to determine the best clinical model of exercise-related dyspnea in this patient group.
METHODS: A retrospective analysis of pulmonary function and cardiopulmonary exercise testing data from patients with CF being followed up at the Adult CF Program at St Michael's Hospital, Toronto, Canada, from 2002 to 2008 were used for the analysis.
RESULTS: Patients (n = 88) were male 66%; aged 30.4 ± 9.4 years; body mass index (BMI) 23.1 ± 3.3 kg/m; forced expiratory volume in 1 second (FEV1) 70% ± 19% predicted; and peak oxygen uptake 74% ± 20% predicted. A multivariate linear regression model assessing the effects of age, sex, BMI, airway obstruction (FEV1), perceived muscular leg fatigue, and dynamic hyperinflation explained 54% of the variance in dyspnea severity at peak exercise (P < .01). Relative importance analysis showed that the presence of dynamic hyperinflation and perceived muscular leg fatigue were the largest contributors.
CONCLUSIONS: Pulmonary rehabilitation programs may consider strategies to reduce dynamic hyperinflation and promote muscular function to best improve exercise-related dyspnea in this patient group.The best predictors of exercise-related dyspnea in adult cystic fibrosis are unclear. In this study, a multivariate linear regression model showed that dynamic hyperinflation and perception of muscular leg fatigue were the greatest contributors to exercise-related dyspnea. Pulmonary rehabilitation programs that target these responses may best improve exercise-related dyspnea in this patient group.

PMID: 28671937 [PubMed - as supplied by publisher]