scholarly journals Surveillance of Colorectal Cancer (CRC) in Cystic Fibrosis (CF) Patients

2021 ◽  
Vol 3 (2) ◽  
pp. 84-95
Author(s):  
Fabio Ingravalle ◽  
Giovanni Casella ◽  
Adriana Ingravalle ◽  
Claudio Monti ◽  
Federica De Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cystic Fibrosis ◽  
General Population ◽  
Genetic Disorder ◽  
The United States ◽  
Screening Colonoscopy ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Increased Risk ◽  
Speciality Training

Cystic Fibrosis (CF) is the commonest inherited genetic disorder in Caucasians due to a mutation in the gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), and it should be considered as an Inherited Colorectal Cancer (CRC) Syndrome. In the United States, physicians of CF Foundation established the “Developing Innovative Gastroenterology Speciality Training Program” to increase the research on CF in gastrointestinal and hepatobiliary diseases. The risk to develop a CRC is 5–10 times higher in CF patients than in the general population and even greater in CF patients receiving immunosuppressive therapy due to organ transplantation (30-fold increased risk relative to the general population). Colonoscopy should be considered the best screening for CRC in CF patients. The screening colonoscopy should be started at the age of 40 in CF patients and, if negative, a new colonoscopy should be performed every 5 years and every 3 years if adenomas are detected. For transplanted CF patients, the screening colonoscopy could be started at the age of 35, in transplanted patients at the age of 30 and, if before, at the age of 30. CF transplanted patients, between the age of 35 and 55, must repeat colonoscopy every 3 years. Our review draws attention towards the clinically relevant development of CRC in CF patients, and it may pave the way for further screenings and studies.

scholarly journals Endocrine and Metabolic Diseases Among Colorectal Cancer Survivors in a Population-Based Cohort

2019 ◽  
Vol 112 (1) ◽  
pp. 78-86
Author(s):  
Makenzie L Hawkins ◽  
Brenna E Blackburn ◽  
Kerry Rowe ◽  
John Snyder ◽  
Vikrant G Deshmukh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factor ◽  
General Population ◽  
Metabolic Diseases ◽  
The United States ◽  
Population Cohort ◽  
Increased Risk ◽  
General Population Cohort ◽  
Time Periods

Abstract Background There are an estimated 1.4 million colorectal cancer (CRC) survivors in the United States. Research on endocrine and metabolic diseases over the long term in CRC survivors is limited. Obesity is a risk factor for CRC; thus it is of interest to investigate diseases that may share this risk factor, such as diabetes, for long-term health outcomes among CRC survivors. Methods A total of 7114 CRC patients were identified from the Utah Population Database and matched to a general population cohort of 25 979 individuals on birth year, sex, and birth state. Disease diagnoses (assessed over three time periods of 1–5 years, 5–10 years, and >10 years) were identified using electronic medical records and statewide ambulatory and inpatient discharge data. Cox proportional hazard models were used to estimate the risk of endocrine and metabolic disease. Results Across all three time periods, risks for endocrine and metabolic diseases were statistically significantly greater for CRC survivors compared with the general population cohort. At 1–5 years postdiagnosis, CRC survivors’ risk for diabetes mellitus with complications was statistically significantly elevated (hazard ratio [HR] = 1.36, 99% confidence interval [CI] = 1.09 to 1.70). CRC survivors also experienced a 40% increased risk of obesity at 1–5 years postcancer diagnosis (HR= 1.40, 99% CI= 1.66 to 2.18) and a 50% increased risk at 5–10 years postdiagnosis (HR = 1.50, 99% CI= 1.16 to 1.95). Conclusions Endocrine and metabolic diseases were statistically significantly higher in CRC survivors throughout the follow-up periods of 1–5 years, 5–10 years, and more than 10 years postdiagnosis. As the number of CRC survivors increases, understanding the long-term trajectory is critical for improved survivorship care.

scholarly journals VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

2013 ◽  
Vol 24 (19) ◽  
pp. 3016-3024 ◽  
Author(s):  
Hong Yu Ren ◽  
Diane E. Grove ◽  
Oxana De La Rosa ◽  
Scott A. Houck ◽  
Pattarawut Sopha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Genetic Disorder ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Folding Defect ◽  
Membrane Spanning ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

scholarly journals Motion-Genetic Testing is Useful in the Diagnosis of Nonhereditary Pancreatic Conditions: Arguments Against the Motion

2003 ◽  
Vol 17 (1) ◽  
pp. 53-55 ◽  
Author(s):  
Jonathan A Cohn
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Gene Interactions ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Lung Disease ◽  
Increased Risk ◽  
Idiopathic Chronic Pancreatitis ◽  
Cystic Fibrosis Transmembrane ◽  
Compound Heterozygotes

Mutations of two genes, the cystic fibrosis transmembrane conductance regulator gene (CFTR) and the pancreatic secretory trypsin inhibitor gene (PSTI), are associated with an increase in the risk of idiopathic chronic pancreatitis. Persons who have mutations of bothCFTRalleles (one severely and one mildly affected) are especially susceptible to this disease. Because these compound heterozygotes have sufficient residualCFTRfunction, they do not develop cystic fibrosis lung disease. OnePSTImutation, N34S, independently increases the risk of pancreatitis. Thus, the risk of pancreatitis is greatest among individuals who areCFTRcompound heterozygotes and who also have thePSTImutation. Nonetheless, most people withCFTRandPSTImutations do not develop pancreatitis. This fact indicates that environmental influences and gene-gene interactions also affect pancreatitis risk. AlthoughCFTRandPSTIgenetic testing can identify persons at an increased risk of pancreatitis, there are several reasons why the routine screening of individuals with nonhereditary pancreatitis is not recommended at this time: most disease-associated mutations are not detected by readily available techniques, genetic counselling guidelines do not exist, most patients with mutations do not develop pancreatitis and the results of testing do not affect the clinical management of pancreatitis.

scholarly journals Human Genetics Society of Australasia Position Statement: Population-Based Carrier Screening for Cystic Fibrosis

2014 ◽  
Vol 17 (6) ◽  
pp. 578-583 ◽  
Author(s):  
Martin B. Delatycki ◽  
Jo Burke ◽  
Louise Christie ◽  
Felicity Collins ◽  
Michael Gabbett ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Human Genetics ◽  
Genetic Disorder ◽  
Position Statement ◽  
Population Based ◽  
Heterozygous Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Common Life ◽  
Cystic Fibrosis Transmembrane

Since the discovery in 1989 that mutations in cystic fibrosis transmembrane conductance regulator (CFTR) underlie cystic fibrosis (CF), the most common life shortening genetic disorder in Caucasians, it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition.

scholarly journals CFTR misfolds during native-centric simulations due to entropic penalties of native state formation

2018 ◽  
Author(s):  
J. Shi ◽  
T. Cleveland ◽  
A. C. Powe ◽  
G. McGaughey ◽  
V. S. Pande
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Dynamics Simulation ◽  
Transmembrane Conductance Regulator ◽  
Free Energy Surface ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Kinetic Traps ◽  
Induced Defects

AbstractCystic fibrosis (CF) is a common genetic disorder that affects approximately 70,000 people worldwide. It is caused by mutation-induced defects in synthesis, folding, processing, or function of the Cystic Fibrosis Transmembrane conductance Regulator protein (CFTR), a chloride-selective ion channel required for the proper functioning of secretory epithelia in tissues such as the lung, pancreas, and skin. The most common cause of CF is the single-residue deletion of F508 (F508del), a mutation present in one or both alleles in 90% of patients that induces severe folding defects and results in greatly reduced expression of the protein. Despite its medical importance, high-resolution mechanistic information about CFTR folding is lacking. In this study, we used molecular dynamics simulation with a native-centric force field to examine the folding and assembly of both full-length CFTR and the isolated first nucleotide-binding domain (NBD1). We observed that the protein was capable of substantial misfolding on both the intradomain and interdomain scale due to entropically favorable kinetic traps that exist on CFTR’s folding free energy surface. These results suggest that even wild type CFTR, in the absence of any disease-related mutations, has suboptimal folding efficiency. We speculate that such entropically-driven misfolding also occurs in disease-prone mutants such as F508del and contributes to the protein’s poor in vivo activity.

scholarly journals Infertility in Females with Cystic Fibrosis Is Multifactorial: Evidence from Mouse Models

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2790-2797 ◽  
Author(s):  
Craig A. Hodges ◽  
Mark R. Palmert ◽  
Mitchell L. Drumm
Keyword(s):  
Cystic Fibrosis ◽  
General Population ◽  
Mouse Models ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Normal Female ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Estrous Cycles ◽  
Cystic Fibrosis Transmembrane

Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice originates from decreased fertilization due to inadequate sperm transport within the female reproductive tract. However, our data indicate that additional reproductive phenotypes in the CF female mice also contribute to the reduced fertility including small ovarian and uterine size, aberrant estrous cycles, and decreased oocyte ovulation rates. These data, along with previous work demonstrating that the gene mutated in CF, the cystic fibrosis transmembrane conductance regulator (CFTR), is normally expressed in tissues vital to reproduction, raises the possibility that CFTR may have a direct effect on fertility. If so, CFTR may also play an important role in normal female fertility within the general population.

scholarly journals A Rapid Membrane Potential Assay to Monitor CFTR Function and Inhibition

2013 ◽  
Vol 18 (9) ◽  
pp. 1132-1137 ◽  
Author(s):  
Rangan Maitra ◽  
Perumal Sivashanmugam ◽  
Keith Warner
Keyword(s):  
Cystic Fibrosis ◽  
Membrane Potential ◽  
Genetic Disorder ◽  
Fluid Secretion ◽  
Secretory Diarrhea ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Important Regulator ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an important regulator of ion transport and fluid secretion in humans. Mutations to CFTR cause cystic fibrosis, which is a common recessive genetic disorder in Caucasians. Involvement of CFTR has been noted in other important diseases, such as secretory diarrhea and polycystic kidney disease. The assays to monitor CFTR function that have been described to date either are complicated or require specialized instrumentation and training for execution. In this report, we describe a rapid FlexStation-based membrane potential assay to monitor CFTR function. In this assay, agonist-mediated activation of CFTR results in membrane depolarization that can be monitored using a fluorescent membrane potential probe. Availability of a simple mix-and-read assay to monitor the function of this important protein might accelerate the discovery of CFTR ligands to study a variety of conditions.

scholarly journals Modulation of Ion Transport to Restore Airway Hydration in Cystic Fibrosis

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 453
Author(s):  
James A. Reihill ◽  
Lisa E. J. Douglas ◽  
S. Lorraine Martin
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Genetic Disorder ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Loss Of Function ◽  
Transmembrane Conductance ◽  
Infection And Inflammation ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl− channel. Loss of Cl− secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways.

Patient and Family Issues Regarding Genetic Testing for Cystic Fibrosis

2011 ◽  
Vol 29 (1) ◽  
pp. 303-329 ◽  
Author(s):  
Kathleen J. H. Sparbel ◽  
Audrey Tluczek
Keyword(s):  
Cystic Fibrosis ◽  
Autosomal Recessive ◽  
The United States ◽  
National Institutes Of Health ◽  
Electrolyte Imbalance ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Respiratory Involvement ◽  
Family Issues ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a potentially life-shortening autosomal recessive genetic condition resulting in chronic progressive respiratory involvement, malnutrition, electrolyte imbalance, and male infertility. It is the most common autosomal inherited condition in the White population, and its presence is recorded with varying prevalence across ethnicities. Since the 1989 discovery of the genetic variant F508del, the most common cystic fibrosis transmembrane conductance regulator (CFTR) mutation, more than 1,900 CF mutations have been identifi ed. The 1997 National Institutes of Health (NIH) Consensus Statement on Cystic Fibrosis, along with 2001 and 2005 recommendations from the American College of Obstetricians and Gynecologists (ACOG), provide the basis for population CF carrier screening in the prenatal setting. Recommendations for newborn screening (NBS) for cystic fibrosis were released in 2004, with NBS programs in the United States initiated thereafter.

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