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Andrew Thomas, Yashaswini Ramananda, Kyushik Mun, Anjaparavanda P Naren, Kavisha Arora
The World Health Organization (WHO) has reported a world-wide surge in cases of cholera caused by the intestinal pathogen Vibrio cholerae, and, combined, such surges have claimed several million lives, mostly in early childhood. Elevated cAMP production in intestinal epithelial cells challenged with cholera toxin (CTX) results in diarrhea due to chloride transport by a cAMP-activated channel, the cystic fibrosis transmembrane conductance regulator (CFTR). However, the identity of the main cAMP-producing proteins that regulate CFTR in the intestine and may be relevant for secretory diarrhea is unclear...
June 14, 2018: Journal of Biological Chemistry
Stephanie Chin, Maurita Hung, Amy Won, Yu-Sheng Wu, Saumel Ahmadi, Donghe Yang, Salma Elmallah, Krimo Toutah, C Michael Hamilton, Robert N Young, Russell D Viirre, Christopher M Yip, Christine E Bear
The major Cystic Fibrosis (CF) causing mutation, the deletion of phenylalanine at position 508 (F508del) at the cystic fibrosis transmembrane conductance regulator (CFTR), occurs in approximately 90% of the CF population. Recently, a combination therapy, comprising a corrector (VX-809) that rescues the processing defects of F508del-CFTR and a potentiator (VX-770) that rescues mutant channel activity, was approved for CF patients homozygous for this mutation. However, clinical studies revealed that the efficacy of this drug on lung function was modest and variable amongst patients...
June 14, 2018: Molecular Pharmacology
Puay-Wah Phuan, Jung-Ho Son, Joseph-Anthony Tan, Clarabella Li, Ilaria Musante, Lorna Zlock, Dennis W Nielson, Walter E Finkbeiner, Mark J Kurth, Luis J Galietta, Peter M Haggie, Alan S Verkman
BACKGROUND: Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators. METHODS: Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators...
June 11, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Jarle Bruun, Anita Sveen, Rita Barros, Peter W Eide, Ina Eilertsen, Matthias Kolberg, Teijo Pellinen, Leonor David, Aud Svindland, Olli Kallioniemi, Marianne G Guren, Arild Nesbakken, Raquel Almeida, Ragnhild A Lothe
We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n=403) or immunohistochemistry (n=642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines...
June 14, 2018: Molecular Oncology
Shimaa Eissa, Nawal Alshehri, Mai Abduljabbar, Anas M Abdel Rahman, Majed Dasouki, Imran Y Nizami, Mohammad A Al-Muhaizea, Mohammed Zourob
Simultaneous and point-of-care detection of multiple protein biomarkers has significant impact on patient care. Spinal Muscular Atrophy (SMA), Cystic Fibrosis (CF) and Duchenne Muscular Dystrophy (DMD) are well known progressive hereditary disorders associated with increased morbidity as well as mortality. Therefore, rapid detection of biomarkers specific for these three disorders in newborns offers new opportunities for early diagnosis, delaying symptoms and effective treatment. Here, we report the development of a disposable carbon nanofiber (CNF)-based electrochemical immunosensor for simultaneous detection of survival motor neuron 1 (SMN1), cystic fibrosis transmembrane conductance regulator (CFTR) and DMD proteins...
May 28, 2018: Biosensors & Bioelectronics
Samantha DeStefano, Maarten Gees, Tzyh-Chang Hwang
BACKGROUND: N1303K, one of the common, severe disease-causing mutations in the CFTR gene, causes both defective biogenesis and gating abnormalities of the CFTR protein. The goals of the present study are to quantitatively assess the gating defects associated with the N1303K mutation and its pharmacological response to CFTR modulators including potentiators VX-770 and GLPG1837 and correctors VX-809, and VX-661. METHODS: Gating behavior and pharmacological responses to CFTR potentiators were assessed using patch-clamp technique in the excised, inside-out mode...
June 7, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Margaret Rosenfeld, Claire E Wainwright, Mark Higgins, Linda T Wang, Charlotte McKee, Daniel Campbell, Simon Tian, Jennifer Schneider, Steve Cunningham, Jane C Davies
BACKGROUND: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months. METHODS: The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study...
June 6, 2018: Lancet Respiratory Medicine
Elizabeth L Kramer, William D Hardie, Satish K Madala, Cynthia R Davidson, John Paul Clancy
BACKGROUND: Cystic fibrosis (CF) produces variable lung disease phenotypes that are in part independent of CFTR genotype. Transforming growth factor beta (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathologic TGFβ effects. METHODS: A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only...
June 7, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Peter H Gilligan, Damian G Downey, J Stuart Elborn, Patrick A Flume, Sebastian Funk, Deirdre Gilpin, Timothy J Kidd, John McCaughan, B Cherie Millar, Philip G Murphy, Jacqueline C Rendall, Michael M Tunney, John E Moore
Infection is a common complication of cystic fibrosis (CF) airways disease. Current treatment approaches include early intervention with the intent to eradicate pathogens in the hope of delaying development of chronic infection and chronic use of aerosolized antibiotics to suppress infection. The use of molecules that help restore CFTR function, modulate pulmonary inflammation, or improve pulmonary clearance, may also influence the microbial communities in the airways. As the pipeline of these new entities continues to expand, it is important to define when key pathogens are eradicated from the lungs of CF patients and equally important, when new pathogens might emerge as a result of these novel therapies...
June 6, 2018: Journal of Clinical Microbiology
Murali Yanda, Qiangni Liu, Liudmila Cebotaru
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR) conventionally used to manage cystic fibrosis, in reducing renal cyst growth...
June 6, 2018: Journal of Biological Chemistry
Yan Lu, Yu-Wei Da, Yong-Biao Zhang, Xin-Gang Li, Min Wang, Li Di, Mi Pang, Lin Lei
Hereditary inclusion body myopathy (HIBM) is a rare autosomal recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant and occurs in adulthood. Our previous study reported a new subtype of HIBM linked to the susceptibility locus at 7q22.1-31.1. The present study is aimed to identify the candidate gene responsible for the phenotype in HIBM pedigree. After multipoint linkage analysis, we performed targeted capture sequencing on 16 members and whole-exome sequencing (WES) on 5 members...
2018: Frontiers in Neuroscience
Aaron Trimble, Cameron McKinzie, Mary Terrell, Elizabeth Stringer, Charles R Esther
With the growing class of CFTR modulator therapy available to more patients and with increasing pregnancies in individuals with CF, there is a growing need to understand the effects of these agents during pregnancy. There are few reports of their continued use in the literature, although it is likely that this is not an uncommon occurrence. We report the uncomplicated and successful pregnancy of a woman treated with lumacaftor/ivacaftor, as well as the clinical course of the infant during the first 9 months of life...
June 1, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Song Bai, Qiang Du, Xiaoliang Liu, Yuxin Tong, Bin Wu
OBJECTIVE: Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene can be involved in the development of congenital bilateral absence of the vas deferens (CBAVD). This study was aimed at investigating mutations in the promoter region of the CFTR gene and its associated effects on CFTR transcription in Chinese patients with CBAVD. METHODS: To identify CFTR promoter region mutations in Chinese CBAVD patients, fragments 1.4 kb upstream of the ATG start codon of the CFTR gene were sequenced in 66 Chinese patients with CBAVD and compared to the corresponding sequences from 60 healthy subjects and sequence data present in the NCBI database...
June 1, 2018: Gene
Vera F C Ferreira, Bruno L Oliveira, João D Santos, João D G Correia, Carlos M Farinha, Filipa Fernandes Mendes
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug-based therapies. Herein, we report the first proof-of-principle study of a non-invasive imaging probe able to detect CFTR at the plasma membrane. We radiolabelled the CFTR inhibitor, CFTRinh-172a, with technetium-99m via a pyrazolyl-diamine chelating unit, yielding a novel 99mTc(CO)3-complex...
June 4, 2018: ChemMedChem
Tom K Lin, Maisam Abu-El-Haija, Jaimie D Nathan, Joseph P Palermo, Bradley Barth, Melena Bellin, Douglas S Fishman, Steven D Freedman, Cheryl E Gariepy, Matthew J Giefer, Tanja Gonska, Melvin B Heyman, Ryan Himes, Sohail Z Husain, Quin Liu, Asim Maqbool, Maria Mascarenhas, Brian McFerron, Veronique D Morinville, Chee Y Ooi, Emily Perito, John F Pohl, Sue Rhee, Sarah Jane Schwarzenberg, Uzma Shah, David Troendle, Steven L Werlin, Michael Wilschanski, M Bridget Zimmerman, Mark E Lowe, Aliye Uc
INTRODUCTION: The significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact. PATIENTS AND METHODS: We compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables...
June 2, 2018: Journal of Clinical Gastroenterology
Anne Hahn, Johanna J Salomon, Dominik Leitz, Dennis Feigenbutz, Lisa Korsch, Ina Lisewski, Katrin Schrimpf, Pamela Millar-Büchner, Marcus A Mall, Stephan Frings, Frank Möhrlen
Physiological processes of vital importance are often safeguarded by compensatory systems that substitute for primary processes in case these are damaged by gene mutation. Ca2+ -dependent Cl- secretion in airway epithelial cells may provide such a compensatory mechanism for impaired Cl- secretion via cystic fibrosis transmembrane conductance regulator (CFTR) channels in cystic fibrosis (CF). Anoctamin 1 (ANO1) Ca2+ -gated Cl- channels are known to contribute to calcium-dependent Cl- secretion in tracheal and bronchial epithelia...
June 2, 2018: Pflügers Archiv: European Journal of Physiology
Anna Evans Phillips, Jessica LaRusch, Phil Greer, Judah Abberbock, Samer Alkaade, Stephen T Amann, Michelle A Anderson, John Baillie, Peter A Banks, Randall E Brand, Darwin Conwell, Gregory A Coté, Christopher E Forsmark, Timothy B Gardner, Andres Gelrud, Nalini Guda, Michele Lewis, Mary E Money, Thiruvengadam Muniraj, Bimaljit S Sandhu, Stuart Sherman, Vikesh K Singh, Adam Slivka, Gong Tang, C Mel Wilcox, David C Whitcomb, Dhiraj Yadav
BACKGROUND: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US. METHODS: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA...
May 19, 2018: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Nasibeh Karimi, Reza Alibakhshi, Shekoufeh Almasi
Background: Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in Caucasian population. The incidence of disorder varies among different religious, ethnic and geographical isolates. The aim of this study was to identify the spectrum and the frequency of known and unknown disease-causing mutations in Iranian CF patients. Methods: Genomic DNA was extracted from peripheral whole blood with a QIAamp DNA Mini-Kit. Mutation analysis was done in the CFTR gene including complete coding region and intron/exon boundaries using a direct sequencing method...
January 2018: Journal of Reproduction & Infertility
Juan Shi, Hui Li, Chao Yuan, Meihui Luo, Jun Wei, Xiaoming Liu
Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoke and oxidative stress are main etiological risks in COPD. Interestingly, recent studies suggest a considerable overlap between chronic bronchitis (CB) phenotypic COPD and cystic fibrosis (CF), a common fatal hereditary lung disease caused by genetic mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Phenotypically, CF and COPD are associated with an impaired mucociliary clearance and mucus hypersecretion, although they are two distinct entities of unrelated origin...
2018: Oxidative Medicine and Cellular Longevity
Virginia De Rose, Kevin Molloy, Sophie Gohy, Charles Pilette, Catherine M Greene
Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions...
2018: Mediators of Inflammation
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