Combined lung-liver-pancreas transplantation in a recipient with cystic fibrosis.

J Cyst Fibros. 2017 May 23;:

Authors: Barbas AS, Dib MJ, Al-Adra DP, Goldaracena N, Sapisochin G, Waddell TK, Keshavjee S, Selzner N, Chaparro C, Cattral MS

Abstract
Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF.

PMID: 28549610 [PubMed - as supplied by publisher]

Development and validation of CF-Medication Beliefs Questionnaire: A mixed-methods approach.

J Cyst Fibros. 2017 May 23;:

Authors: Eakin MN, Chung SE, Hoehn J, Borrelli B, Rand-Giovannetti D, Riekert KA

Abstract
BACKGROUND: Beliefs about medication have been associated with adherence in other diseases but there are no existing disease-specific medication beliefs questionnaires for CF. This mixed-methods validated the Cystic Fibrosis Medication Belief Questionnaire (CF-MBQ), based on social cognitive theory.
METHODS: Based on previous research, items were developed for five domains: motivation, self-efficacy, perceived importance, and decisional balance to take or miss medications. Cognitive interviews were conducted with 15 adult patients with CF to refine item development. 128 patients with CF completed an online survey and objective medication adherence was measured using pharmacy refill data.
RESULTS: The five subscales demonstrated strong psychometric properties, with adequate-to-good internal consistency scores. More importantly, each domain demonstrated construct validity with adherence.
CONCLUSIONS: These theoretically-derived measures may be important for clinical purposes to provide guidance on appropriate interventions to improve adherence and for research to provide enhanced understanding on patient determinants of medication adherence.

PMID: 28549609 [PubMed - as supplied by publisher]

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

J Cardiovasc Transl Res. 2017 May 26;:

Authors: Landis BJ, Schubert JA, Lai D, Jegga AG, Shikany AR, Foroud T, Ware SM, Hinton RB

Abstract
Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.

PMID: 28550590 [PubMed - as supplied by publisher]

TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1.

J Cell Biol. 2017 May 26;:

Authors: Genova T, Grolez GP, Camillo C, Bernardini M, Bokhobza A, Richard E, Scianna M, Lemonnier L, Valdembri D, Munaron L, Philips MR, Mattot V, Serini G, Prevarskaya N, Gkika D, Pla AF

Abstract
Endothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein-protein interaction, thus preventing its cytoplasm-plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration.

PMID: 28550110 [PubMed - as supplied by publisher]

Central Nervous System Involvement in Acute Lymphoblastic Leukemia Is Mediated by Vascular Endothelial Growth Factor.

Blood. 2017 May 26;:

Authors: Münch V, Trentin L, Herzig J, Demir S, Seyfried F, Kraus JM, Kestler HA, Köhler R, Barth TFE, Te Kronnie G, Debatin KM, Meyer LH

Abstract
In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite non-detectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse free survival indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia cell entry into the CNS need to be understood in order to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia cell entry into the CNS using a primograft ALL mouse model. We found, that primary ALL cells transplanted onto NOD/SCID mice faithfully recapitulate clinical and pathological features of meningeal infiltration seen in ALL patients. ALL cells, which have entered the CNS and are infiltrating the meninges, are characterized by high expression of vascular endothelial growth factor A (VEGF) While cellular viability, growth, proliferation and survival of ALL cells were found to be independent of VEGF, trans-endothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia upon in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL cell entry into the CNS, which by targeting of VEGF signaling may serve as a novel strategy to control CNS leukemia in patients replacing conventional CNS-toxic treatment.

PMID: 28550041 [PubMed - as supplied by publisher]

Early transcriptome responses of the bovine midcycle corpus luteum to prostaglandin F2α includes cytokine signaling.

Mol Cell Endocrinol. 2017 May 23;:

Authors: Talbott H, Hou X, Qiu F, Zhang P, Guda C, Yu F, Cushman RA, Wood JR, Wang C, Cupp AS, Davis JS

Abstract
In ruminants, prostaglandin F2alpha (PGF2α)-mediated luteolysis is essential prior to estrous cycle resumption, and is a target for improving fertility. To deduce early PGF2α-provoked changes in the corpus luteum a short time-course (0.5-4 h) was performed on cows at midcycle. A microarray-determined transcriptome was established and examined by bioinformatic pathway analysis. Classic PGF2α effects were evident by changes in early response genes (FOS, JUN, ATF3) and prediction of active pathways (PKC, MAPK). Several cytokine transcripts were elevated and NF-κB and STAT activation were predicted by pathway analysis. Self-organizing map analysis grouped differentially expressed transcripts into ten mRNA expression patterns indicative of temporal signaling cascades. Comparison with two analogous datasets revealed a conserved group of 124 transcripts similarly altered by PGF2α treatment, which both, directly and indirectly, indicated cytokine activation. Elevated levels of cytokine transcripts after PGF2α and predicted activation of cytokine pathways implicate inflammatory reactions early in PGF2α-mediated luteolysis.

PMID: 28549990 [PubMed - as supplied by publisher]

Drug repurposing to target proteostasis and prevent neurodegeneration: accelerating translational efforts.

Brain. 2017 Jun 01;140(6):1544-1547

Authors: Mercado G, Hetz C

PMID: 28549133 [PubMed - in process]

Drug repositioning based on triangularly balanced structure for tissue-specific diseases in incomplete interactome.

Artif Intell Med. 2017 Mar;77:53-63

Authors: Yu L, Zhao J, Gao L

Abstract
Finding new uses for existing drugs has become a new strategy for decades to treat more patients. Few traditional approaches consider the tissue specificities of diseases. Moreover, disease genes, drug targets and protein interaction (PPI) networks remain largely incomplete and the relationships between drugs and diseases conform to the triangularly balanced structure. Therefore, based on tissue specificities of diseases, we apply the triangularly balanced theory and the module distance defined for incomplete interaction networks to build drug-disease associations. Our method is named as TTMD (Tissue specificity, Triangle balance theory and Module Distance). Firstly, we combine three different drug similarity networks. Then, in the tissue-specific PPI network of a disease, we calculate its similarities with drugs using module distance. Finally, breast cancer and hepatocellular carcinoma (HCC) are taken as case studies. In the top-5% of predicted associations, 96.9% and 90.3% results match with known associations in Comparative Toxicogenomics Database (CTD) for breast cancer and hepatocellular carcinoma respectively. Clinical verification, literature mining and KEGG pathways enrichment analysis are further conducted for the top-5% newly predicted associations. Overall, TTMD is an effective approach for predicting new drug indications for tissue-specific diseases and provides potential values for the treatments of complex diseases.

PMID: 28545612 [PubMed - in process]

Lessons from Retinoblastoma: Implications for Cancer, Development, Evolution, and Regenerative Medicine.

Trends Mol Med. 2016 Oct;22(10):863-876

Authors: Dyer MA

Abstract
Retinoblastoma is a rare childhood cancer of the developing retina, and studies on this orphan disease have led to fundamental discoveries in cancer biology. Retinoblastoma has also emerged as a model for translational research for pediatric solid tumors, which is particularly important as personalized medicine expands in oncology. Research on retinoblastomas has been combined with the exploration of retinal development and retinal degeneration to advance a new model of cell type-specific disease susceptibility termed 'cellular pliancy'. The concept can even be extended to species-specific regeneration. This review discusses the remarkable path of retinoblastoma research and how it has shaped the most current efforts in basic, translational, and clinical research in oncology and beyond.

PMID: 27567287 [PubMed - indexed for MEDLINE]

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients.

Mol Genet Genomic Med. 2017 May;5(3):269-279

Authors: Cousin MA, Matey ET, Blackburn PR, Boczek NJ, McAllister TM, Kruisselbrink TM, Babovic-Vuksanovic D, Lazaridis KN, Klee EW

Abstract
BACKGROUND: We characterized the pharmacogenomics (PGx) results received by diagnostic odyssey patients as secondary findings during clinical whole exome sequencing (WES) testing as a part of their care in Mayo Clinic's Individualized Medicine Clinic to determine the potential benefits and limitations to this cohort.
METHODS: WES results on 94 patients included a subset of PGx variants in CYP2C19,CYP2C9, and VKORC1 if identified in the patient. Demographic, phenotypic, and medication usage information was abstracted from patient medical data. A pharmacist interpreted the PGx results in the context of the patients' current medication use and made therapeutic recommendations.
RESULTS: The majority was young with a median age of 10 years old, had neurological involvement in the disease presentation (71%), and was currently taking medications (90%). Of the 94 PGx-evaluated patients, 91% had at least one variant allele reported and 20% had potential immediate implications on current medication use.
CONCLUSION: Due to the disease complexity and medication needs of diagnostic odyssey patients, there may be immediate benefit obtained from early life PGx testing for many and most will likely find benefit in the future. These results require conscientious interpretation and management to be actionable for all prescribing physicians throughout the lifetime of the patient.

PMID: 28546997 [PubMed - in process]

Gut microbiota and hepatitis-B-virus-induced chronic liver disease: implications for faecal microbiota transplantation therapy.

J Hosp Infect. 2017 Apr 15;:

Authors: Kang Y, Cai Y

Abstract
Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The liver is connected to the small intestine by the bile duct, which carries bile formed in the liver to the intestine. Nearly all of the blood that leaves the stomach and intestines must pass through the liver. Human intestines contain a wide diversity of microbes, collectively termed the 'gut microbiota'. Gut microbiota play a significant role in host metabolic processes and host immune modulation, and influence host development and physiology (organ development). Altered gut microbiota is a common complication in liver disease. Changes in intestinal microbiota seem to play an important role in induction and promotion of HBV-induced chronic liver disease progression, and specific species among the intestinal commensal bacteria may play either a pathogenic or a protective role in the development of HBV-induced chronic liver disease. Thus, the gut microbiome may represent fertile targets for prevention or management of HBV-induced chronic liver disease. Faecal microbiota transplantation (FMT) may be a useful therapy for HBV-related disease in the future. However, the data available in this field remain limited, and relevant scientific work has only just commenced. New technologies have enabled systematic studies of gut microbiota, and provided more realistic information about its composition and pathological variance. This review summarizes the cutting edge of research into the relationship between gut microbiota and HBV-induced chronic liver disease, and the future prospects of FMT therapy.

PMID: 28545829 [PubMed - as supplied by publisher]

State of Art of Cancer Pharmacogenomics in Latin American Populations.

Int J Mol Sci. 2017 May 23;18(6):

Authors: López-Cortés A, Guerrero S, Redal MA, Alvarado AT, Quiñones LA

Abstract
Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations.

PMID: 28545225 [PubMed - in process]

Widespread Down-Regulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients With Sepsis.

Crit Care Med. 2017 Mar;45(3):407-414

Authors: Matkovich SJ, Al Khiami B, Efimov IR, Evans S, Vader J, Jain A, Brownstein BH, Hotchkiss RS, Mann DL

Abstract
OBJECTIVES: The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts.
DESIGN: Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts.
SETTING: ICUs at Barnes-Jewish Hospital, St. Louis, MO.
PATIENTS: Twenty sepsis patients, 11 ischemic heart disease, nine dilated cardiomyopathy, and 11 nonfailing donors.
INTERVENTIONS: None other than those performed as part of patient care.
MEASUREMENTS AND MAIN RESULTS: Messenger RNA expression levels for 198 mitochondrially localized energy production components, including Krebs cycle and electron transport genes, decreased by 43% ± 5% (mean ± SD). Messenger RNAs for nine genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43% ± 4% in septic hearts. Surprisingly, the alterations in messenger RNA levels in septic cardiomyopathy were both distinct from and more profound than changes in messenger RNA levels in the hearts of patients with end-stage heart failure.
CONCLUSIONS: The expression profile of messenger RNAs in the heart of septic patients reveals striking decreases in expression levels of messenger RNAs that encode proteins involved in cardiac energy production and cardiac contractility and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in messenger RNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis.

PMID: 28067713 [PubMed - indexed for MEDLINE]

Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia.

Cancer Chemother Pharmacol. 2016 Nov;78(5):1051-1058

Authors: Varatharajan S, Panetta JC, Abraham A, Karathedath S, Mohanan E, Lakshmi KM, Arthur N, Srivastava VM, Nemani S, George B, Srivastava A, Mathews V, Balasubramanian P

Abstract
PURPOSE: Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML.
METHODS: In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters.
RESULTS: The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR.
CONCLUSION: Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.

PMID: 27738808 [PubMed - indexed for MEDLINE]

Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth.

J Matern Fetal Neonatal Med. 2016 Oct;29(20):3347-50

Authors: Langmia IM, Apalasamy YD, Omar SZ, Mohamed Z

Abstract
OBJECTIVE: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery.
METHOD: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform.
RESULTS: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3-11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women.
CONCLUSION: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery.

PMID: 26607028 [PubMed - indexed for MEDLINE]

Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity.

Nucleic Acids Res. 2017 May 26;:

Authors: Stolzenburg LR, Yang R, Kerschner JL, Fossum S, Xu M, Hoffmann A, Lamar KM, Ghosh S, Wachtel S, Leir SH, Harris A

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung phenotype. Genome-wide association studies (GWAS) previously identified additional genomic sites associated with CF lung disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which being intergenic is probably regulatory. To identify cis-acting elements, we used DNase-seq and H3K4me1 and H3K27Ac ChIP-seq to map open and active chromatin respectively, in lung epithelial cells. Two elements showed strong enhancer activity for the promoters of EHF and the 5΄ adjacent gene E47 like ETS transcription factor 5 (ELF5) in reporter gene assays. No enhancers of the APIP promoter were found. Circular chromosome conformation capture (4C-seq) identified direct physical interactions of elements within 11p13. This confirmed the enhancer-promoter associations, identified additional interacting elements and defined topologically associating domain (TAD) boundaries, enriched for CCCTC-binding factor (CTCF). No strong interactions were observed with the APIP promoter, which lies outside the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity.

PMID: 28549169 [PubMed - as supplied by publisher]

Outbreaks of nontuberculous mycobacteria.

Curr Opin Infect Dis. 2017 May 25;:

Authors: Sood G, Parrish N

Abstract
PURPOSE OF REVIEW: The purpose of this review is to summarize the emerging literature on nontuberculous mycobacteria outbreaks in healthcare settings. As our ability to identify mycobacterial species develops, we are better able to recognize epidemiologic connections and better understand the prevalence and importance of these outbreaks and pseudo-outbreaks in healthcare settings.
RECENT FINDINGS: The number of outbreaks related to nontuberculous outbreaks is increasing because of heightened awareness and better diagnostic tests for species level identification of mycobacteria. Outbreaks in healthcare settings have been related to cardiac surgery, plastic surgery, including medical tourism, colonized humidifiers and heater-cooler devices, imperfect disinfection, and hospital water sources. Mycobacteria have a predilection to form biofilms, are resistant to disinfection and are prevalent in hospital water systems. Patients with structural lung disease like cystic fibrosis patients are at particularly high risk for mycobacterial infection. It has been thought that acquisition in this patient population is from common environmental exposure; however, there is increasing evidence that transmission in this patient population can occur through either direct or indirect patient-to-patient spread.
SUMMARY: Mycobacteria outbreaks in healthcare settings have been underrecognized. As we identify additional clusters of infection with better diagnostic tools and heightened awareness, we will likely need better infection control practices to prevent infections in healthcare settings.

PMID: 28548990 [PubMed - as supplied by publisher]

Co-evolution with Staphylococcus aureus leads to lipopolysaccharide alterations in Pseudomonas aeruginosa.

ISME J. 2017 May 26;:

Authors: Tognon M, Köhler T, Gdaniec BG, Hao Y, Lam JS, Beaume M, Luscher A, Buckling A, van Delden C

Abstract
Detrimental and beneficial interactions between co-colonizing bacteria may influence the course of infections. In cystic fibrosis (CF) airways, Staphylococcus aureus prevails in childhood, whereas Pseudomonas aeruginosa progressively predominates thereafter. While a range of interactions has been identified, it is unclear if these represent specific adaptations or correlated responses to other aspects of the environment. Here, we investigate how P. aeruginosa adapts to S. aureus by evolving P. aeruginosa in the presence and absence of S. aureus. P. aeruginosa populations that evolved for 150 generations were sequenced and compared to the ancestor strain. Mutations in the Wsp signaling system were identified in both treatments and likely occurred because of low oxygen availability. Despite showing increased killing activity, wsp mutants were less fit in the presence of S. aureus. In contrast, mutations in lipopolysaccharide (LPS) biosynthesis occurred exclusively in co-cultures with S. aureus and conferred a fitness gain in its presence. Moreover, they increased resistance towards beta-lactam antibiotics. Strikingly, both mutations in wsp and LPS genes are observed in clinical isolates from CF-patients. Our results suggest that P. aeruginosa LPS mutations are a direct consequence of S. aureus imposed selection in vitro.The ISME Journal advance online publication, 26 May 2017; doi:10.1038/ismej.2017.83.

PMID: 28548661 [PubMed - as supplied by publisher]

Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Paediatr Drugs. 2017 May 25;:

Authors: Burcham P, Sarzynski L, Khalfoun S, Novak KJ, Miller JC, Tumin D, Hayes D

Abstract
Cystic fibrosis (CF) is a common indication for lung transplantation (LTx) in children and adults with severe and irreversible lung disease. In the setting of LTx in the CF population, immunosuppressive medications are used to prevent allograft rejection despite the majority of these patients being chronically infected with numerous, and often antibiotic-resistant, pathogens. There is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children. This article provides a review of immunosuppression regimens in the pediatric and adult CF post-LTx population, investigating drug dosing and monitoring, and medication combinations. Currently used immunosuppressive medications and related systemic adverse effects are reviewed. With limitations of data in the pediatric population, future research should address immunosuppression in these children to help guide pediatric drug management as a means to optimize clinical outcomes after LTx.

PMID: 28547678 [PubMed - as supplied by publisher]

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

Mol Genet Genomic Med. 2017 May;5(3):223-236

Authors: Behar DM, Inbar O, Shteinberg M, Gur M, Mussaffi H, Shoseyov D, Ashkenazi M, Alkrinawi S, Bormans C, Hakim F, Mei-Zahav M, Cohen-Cymberknoh M, Dagan A, Prais D, Sarouk I, Stafler P, Bar Aluma BE, Akler G, Picard E, Aviram M, Efrati O, Livnat G, Rivlin J, Bentur L, Blau H, Kerem E, Singer A

Abstract
BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients.
METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts.
RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel.
CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

PMID: 28546993 [PubMed - in process]