[Usefulness of measurement of nitric oxide in exhaled air in diagnostics and treatment of allergic rhinitis and asthma in children and adolescents].

Dev Period Med. 2018;22(2):135-143

Authors: Kowalczyk A, Krogulska A

Abstract
Nitric oxide is produced by enzymes called nitric oxide synthases. It fulfills many important functions in the human body, but produced in excess amount has a proinflammatory activity. Fractional exhaled nitric oxide measurements are used in the diagnosis and monitoring of eosinophilic inflammation in the lower airways, but should not be used as an independent parameter to make a diagnosis of asthma or for the monitoring of asthma treatment. Evaluation of fractional exhaled nitric oxide concentrations is also used to determine the pathogenesis of symptoms in patients with rhinitis. In addition, they are helpful in detecting and monitoring eosinophilic inflammation in the lower respiratory tract that coexists with inflammation in the upper airways. Fractional exhaled nitric oxide concentrations may be abnormal (lowered or elevated) in other chronic diseases, such as cystic fibrosis, primary ciliary dyskinesia and inflammatory bowel diseases. Many factors, e.g. atopy, genetic polymorphisms of NOS, and the lipid profile affect the fractional exhaled nitric oxide measurement. Nasal nitric oxide measurement is useful in assessing the prevalence and severity of eosinophilic inflammation in the upper respiratory tract.

PMID: 30056400 [PubMed - in process]

EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis - Study design and patient demographics.

Contemp Clin Trials. 2018 Jul 26;:

Authors: Stuart Elborn J, Ahuja S, Springman E, Mershon J, Grosswald R, Rowe SM

Abstract
Inflammation causes irreparable damage in the cystic fibrosis (CF) lung. Despite high standards of care and the advent of new therapies, inflammation continues to cause significant loss of lung function and morbidity. Acebilustat is a once-daily, oral molecule with anti-inflammatory activity through the inhibition of LTA4 hydrolase and modulation of LTB4. It has potential to reduce lung function decline and pulmonary exacerbations in patients with CF and is currently being tested in a Phase II multicenter, randomized, double-blind, placebo-controlled, parallel-group study (EMPIRE-CF). Strict inclusion criteria based on modeling of the Cystic Fibrosis Foundation Patient Registry data were selected to enrich the trial with patients most likely to benefit from chronic anti-inflammatory therapy that reduces lung function decline. 200 patients between 18 and 30 years of age, with an FEV1 percent predicted (pp) ≥50%, and ≥1 exacerbation in the past year have been enrolled. Patients are randomized 1:1:1 to placebo, acebilustat 50 mg or 100 mg for 48 weeks, taken concomitantly with their current standard of care, and stratified based on concomitant CFTR modulator use, baseline FEV1pp (50% to 75% and >75%), and number of exacerbations in the past year (1 or >1). The primary endpoints are absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints include rate of pulmonary exacerbations and time to first pulmonary exacerbation. Biomarkers of inflammation will also be assessed. EMPIRE-CF is expected to identify the optimal patient population, dose, duration and endpoints for future acebilustat trials, and widen understanding of the drug's efficacy in patients with CF.

PMID: 30056216 [PubMed - as supplied by publisher]

mHealth and Aging.

J Am Med Dir Assoc. 2018 Jul 25;:

Authors: Valenzuela PL, Morales JS, Santos-Lozano A, Serra-Rexach JA, Izquierdo M, Lucia A

PMID: 30056007 [PubMed - as supplied by publisher]

Signal Percolation within a Bacterial Community.

Cell Syst. 2018 Jul 14;:

Authors: Larkin JW, Zhai X, Kikuchi K, Redford SE, Prindle A, Liu J, Greenfield S, Walczak AM, Garcia-Ojalvo J, Mugler A, Süel GM

Abstract
Signal transmission among cells enables long-range coordination in biological systems. However, the scarcity of quantitative measurements hinders the development of theories that relate signal propagation to cellular heterogeneity and spatial organization. We address this problem in a bacterial community that employs electrochemical cell-to-cell communication. We developed a model based on percolation theory, which describes how signals propagate through a heterogeneous medium. Our model predicts that signal transmission becomes possible when the community is organized near a critical phase transition between a disconnected and a fully connected conduit of signaling cells. By measuring population-level signal transmission with single-cell resolution in wild-type and genetically modified communities, we confirm that the spatial distribution of signaling cells is organized at the predicted phase transition. Our findings suggest that at this critical point, the population-level benefit of signal transmission outweighs the single-cell level cost. The bacterial community thus appears to be organized according to a theoretically predicted spatial heterogeneity that promotes efficient signal transmission.

PMID: 30056004 [PubMed - as supplied by publisher]

Improved Hemoglobin Response with Ferric Carboxymaltose in Patients with Gastrointestinal-Related Iron-Deficiency Anemia Versus Oral Iron.

Dig Dis Sci. 2018 Jul 28;:

Authors: Lichtenstein GR, Onken JE

Abstract
AIMS: To compare the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) versus oral iron and other IV iron therapies in patients with iron-deficiency anemia (IDA) resulting from gastrointestinal (GI) disorders.
METHODS: A pooled analysis of four prospective, randomized, active-controlled trials in patients with IDA was performed. Efficacy measures included change from baseline in hemoglobin (Hb), ferritin, and transferrin saturation (TSAT) and correlations of baseline Hb, ferritin, and TSAT to change in Hb. The incidence and type of adverse events were evaluated.
RESULTS: A total of 191 patients were evaluated. The mean change in Hb from baseline to the maximum value was 0.8 g/dL with oral iron (P = 0.001 vs. FCM), 2.2 g/dL with FCM, 2.0 g/dL with any IV iron (P = 0.391 vs. FCM), and 1.9 g/dL with iron sucrose (P = 0.329 vs. FCM). Patients treated with FCM and iron sucrose had larger increases in Hb. This effect may have been attributed to a lower baseline Hb level. Drug-related adverse events occurred in 11.9, 12, 26.2, and 25% and serious adverse events (SAEs) occurred in 6.9, 4, 9.8, and 12.5% of patients in the FCM, oral iron, other IV iron therapies, and iron sucrose groups, respectively. No SAEs were considered treatment related in the FCM group, compared with two treatment-related SAEs in two patients (6.3%) in the iron sucrose group.
CONCLUSIONS: FCM is an effective therapy in patients with IDA who have GI disorders and has a safety profile comparable to that of other IV iron agents.

PMID: 30056562 [PubMed - as supplied by publisher]

Safety, Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects.

Clin Ther. 2018 Jul 25;:

Authors: Wilson R, Jarvis E, Montembault M, Hamblin JN, Hessel EM, Cahn A

Abstract
PURPOSE: Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.
METHODS: This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n = 12) and B (n = 12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n = 6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.
FINDINGS: 21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0-24 values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 μg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ∼2- to 4-fold higher than on the single dose (peak, trough, and AUC0-24 levels), achieving steady-state by day 6. Mean AUC0-24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal.
IMPLICATIONS: Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ∼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.

PMID: 30055824 [PubMed - as supplied by publisher]

Bronchiectasis patient characteristics and healthcare utilization history in U.S. Medicare enrollees with prescription drug plans, 2006-2014.

Chest. 2018 Jul 25;:

Authors: Henkle E, Chan B, Curtis JR, Aksamit TR, Daley CL, Winthrop KL

Abstract
BACKGROUND: Bronchiectasis is an increasingly common chronic inflammatory airway disease. There is an urgent need to understand the epidemiology of bronchiectasis in older adults. We describe the prevalence and characteristics of bronchiectasis patients within the U.S. Medicare population.
METHODS: Among the 40% of Medicare enrollees with prescription drug plans during 2006-2014 we identified bronchiectasis patients over age 65 by ICD-9-CM claims (494.0 or 494.1) from a pulmonologist and no claim for cystic fibrosis. We calculated the prevalence during 2012-2014. Incident or "newly diagnosed" patients were those enrolled in Medicare at least 12 months prior to the first bronchiectasis diagnosis. We described clinical and healthcare utilization characteristics for this cohort during the prior 12-month (baseline) period, and explored differences between those with and without a chronic obstructive pulmonary disease (COPD) diagnosis.
RESULTS: We identified 252,362 bronchiectasis patients meeting all eligibility criteria. The average annual prevalence during 2012-2014 was 701/100,000. Newly diagnosed patients were mean age 76 years, predominately female (65%) and White, non-Hispanic (84%). During the baseline period, 12% were hospitalized for respiratory infections. Fifty-one percent had a dual diagnosis of COPD. Newly diagnosed bronchiectasis patients with COPD had significantly different characteristics and utilization, e.g. were more likely hospitalized for respiratory infections during the baseline period (16% vs. 7%) and have a smoking history (46% vs. 17%), compared to those without a dual COPD diagnosis.
CONCLUSION: We confirmed a high prevalence of bronchiectasis in the U.S. and significant heterogeneity in bronchiectasis patients with and without COPD that should be further explored.

PMID: 30055168 [PubMed - as supplied by publisher]

The Efficacy of MRI in the diagnostic workup of cystic fibrosis-associated liver disease: A clinical observational cohort study.

Eur Radiol. 2018 Jul 27;:

Authors: Poetter-Lang S, Staufer K, Baltzer P, Tamandl D, Muin D, Bastati N, Halilbasic E, Hodge JC, Trauner M, Kazemi-Shirazi L, Ba-Ssalamah A

Abstract
PURPOSE: To identify independent imaging features and establish a diagnostic algorithm for diagnosis of cystic fibrosis (CF)-associated liver disease (CFLD) in CF patients compared to controls using gadoxetic acid-enhanced MRI.
METHODS: A total of 90 adult patients were enrolled: 50 with CF, 40 controls. The CF group was composed of two subgroups: a retrospective test subgroup (n = 33) and a prospective validation subgroup (n = 17). Controls (patients with normal liver enzymes and only benign focal liver lesions) were divided accordingly (27:13). MRI variables, including quantitative and qualitative parameters, were used to distinguish CFLD from controls using clinical symptoms, laboratory tests and Debray criteria. Disease severity was classified according to Child-Pugh and Albumin-Bilirubin (ALBI) scores. Fifteen qualitative single-lesion CF descriptors were defined. Two readers independently evaluated the images. Univariate statistical analysis was performed to obtain significant imaging features that differentiate CF patients from controls. Through multivariate analysis using chi-squared automatic interaction detector (CHAID) methodology the most important descriptors were identified. Diagnostic performance was assessed by receiver-operating characteristic (ROC) analysis.
RESULTS: Three independent imaging descriptors distinguished CFLD from controls: (1) presence of altered gallbladder morphology; (2) periportal tracking; and (3) periportal fat deposition. Prospective validation of the classification algorithm demonstrated a sensitivity of 94.1% and specificity of 84.6% for discriminating CFLD from controls. Disease severity was well associated with the imaging features.
CONCLUSIONS: A short unenhanced MRI protocol can identify the three cardinal imaging features of CFLD. The hepatobiliary phase of gadoxetic acid-enhanced MRI can define CFLD progression.
KEY POINTS: • Using a multivariate classification analysis, we identified three independent imaging features, altered gallbladder morphology (GBAM), periportal tracking (PPT) and periportal fat deposition (PPFD), that could diagnose CFLD with high sensitivity, 94.1 % (95% CI: 71.3-99.9) and moderate specificity, 84.6 % (95% CI: 54.6-98.1). • Based upon the results of this study, gadoxetic acid-enhanced MRI with DWI is able to diagnose early-stage CFLD, as well as its progression.

PMID: 30054796 [PubMed - as supplied by publisher]

Respiratory care in familial dysautonomia: Systematic review and expert consensus recommendations.

Respir Med. 2018 Aug;141:37-46

Authors: Kazachkov M, Palma JA, Norcliffe-Kaufmann L, Bar-Aluma BE, Spalink CL, Barnes EP, Amoroso NE, Balou SM, Bess S, Chopra A, Condos R, Efrati O, Fitzgerald K, Fridman D, Goldenberg RM, Goldhaber A, Kaufman DA, Kothare SV, Levine J, Levy J, Lubinsky AS, Maayan C, Moy LC, Rivera PJ, Rodriguez AJ, Sokol G, Sloane MF, Tan T, Kaufmann H

Abstract
BACKGROUND: Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia.
METHODS: We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system.
RESULTS: Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy.
CONCLUSIONS: Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

PMID: 30053970 [PubMed - in process]

Drug repurposing of quinine as antiviral against dengue virus infection.

Virus Res. 2018 Jul 25;:

Authors: Malakar S, Sreelatha L, Dechtawewat T, Noisakran S, Yenchitsomanus PT, Chu JJH, Limjindaporn T

Abstract
Dengue virus (DENV) disease outbreaks continue to develop across the globe with significant associated mortality and economic burden, yet no treatment has been approved to combat this virus. In an attempt to identify novel drug candidates as therapeutics for DENV infection, we evaluated four US Food and Drug Administration (FDA) approved drugs including aminolevullic acid, azelaic acid, mitoxantrone hydrochloride, and quinine sulfate, and tested their ability to inhibit DENV replication using focus-forming unit assay to quantify virus production. Of the four investigated compounds, quinine was found to have the most pronounced anti-DENV activity. Quinine inhibited DENV production of DENV by about 80% compared to untreated controls, while the other three drugs decreased virus production by only about 50%. Moreover, quinine inhibited DENV production of all four serotypes of DENV. Reduction in virus production was documented in three different cell lines of human origin. Quinine significantly inhibited DENV replication by reducing DENV RNA and viral protein synthesis in a dose-dependent manner. In addition, quinine ameliorated expression of genes related to innate immune response. These findings suggest the efficacy of quinine for stimulating antiviral genes to reduce DENV replication. The antiviral activity of quinine observed in this study may have applicability in the development of new drug therapies against DENV.

PMID: 30055216 [PubMed - as supplied by publisher]

A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells.

Mol Oncol. 2018 Jul 28;:

Authors: Kim I, Choi YS, Song JH, Choi EA, Park S, Lee EJ, Rhee JK, Kim SC, Chang S

Abstract
Pancreatic cancer is one of the most difficult cancers to cure, due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed IC50 of 0.39-1.13μM toward PDAC cells, but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6-TG. Lastly, we used a patient-derived xenograft model to confirm that 6-TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6-TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

PMID: 30055072 [PubMed - as supplied by publisher]

Integrative omics analyses broaden treatment targets in human cancer.

Genome Med. 2018 Jul 27;10(1):60

Authors: Sengupta S, Sun SQ, Huang KL, Oh C, Bailey MH, Varghese R, Wyczalkowski MA, Ning J, Tripathi P, McMichael JF, Johnson KJ, Kandoth C, Welch J, Ma C, Wendl MC, Payne SH, Fenyö D, Townsend RR, Dipersio JF, Chen F, Ding L

Abstract
BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers.
METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.
RESULTS: Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability.
CONCLUSIONS: Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.

PMID: 30053901 [PubMed - in process]

Emerging roles of Myc in stem cell biology and novel tumor therapies.

J Exp Clin Cancer Res. 2018 Jul 27;37(1):173

Authors: Yoshida GJ

Abstract
The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a "double-edged sword" promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger "awakening" of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.

PMID: 30053872 [PubMed - in process]

IL-6 gene polymorphism is associated with protein serum level and disease activity in Polish patients with rheumatoid arthritis.

HLA. 2018 Jul 27;:

Authors: Wielińska J, Dratwa M, Świerkot J, Korman L, Iwaszko M, Wysoczańska B, Bogunia-Kubik K

Abstract
IL-6 is a pro-inflammatory cytokine involved in development of rheumatoid arthritis (RA). The present study aimed to determine the possible association of the IL6 (rs1800795, G>C) polymorphism with RA susceptibility, disease progression and protein serum levels. Distribution of IL6 alleles and genotypes was similar in RA patients and controls. As expected, patients before induction of anti-TNF agents had significantly higher IL-6 levels as compared to controls (p=0.002). The CC homozygous patients were characterized with the highest average concentrations of this pro-inflammatory cytokine before treatment (p=0.028) and they also more frequently presented with more active disease (p=0.048). These results imply that the IL6 rs1800795 CC homozygosity may play a rather unfavourable role in RA. This article is protected by copyright. All rights reserved.

PMID: 30054992 [PubMed - as supplied by publisher]

Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma.

Clin Cancer Res. 2018 Jul 27;:

Authors: Cabel L, Jeannot E, Bièche I, Vacher S, Callens C, Bazire L, Morel A, Bernard-Tessier A, Chemlali W, Schnitzler A, Lièvre A, Otz J, Minsat M, Vincent-Salomon A, Pierga JY, Buecher B, Mariani P, Proudhon C, Bidard FC, Cacheux W

Abstract
PURPOSE: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. The present study was designed to monitor HPV circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC.
EXPERIMENTAL DESIGN: We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR.
RESULTS: HPV ctDNA was detected before CRT in 29 of 33 patients with stage II-III ASCC (sensitivity: 88%, 95%CI=[72-95]); ctDNA positivity rate was associated with tumor stage (64% and 100% in stage II and III, respectively; p=0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N+ than in N- tumors (median 85 copies/ml, range (8-9333) vs 32 copies/ml, range (3-1350); p=0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, 3 of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival (p<0.0001).
CONCLUSIONS: This is the first proof of concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In the present study, we show that residual ctDNA levels after CRT are associated with very poor outcome.

PMID: 30054279 [PubMed - as supplied by publisher]

The march of pluripotent stem cells in cardiovascular regenerative medicine.

Stem Cell Res Ther. 2018 Jul 27;9(1):201

Authors: Abou-Saleh H, Zouein FA, El-Yazbi A, Sanoudou D, Raynaud C, Rao C, Pintus G, Dehaini H, Eid AH

Abstract
Cardiovascular disease (CVD) continues to be the leading cause of global morbidity and mortality. Heart failure remains a major contributor to this mortality. Despite major therapeutic advances over the past decades, a better understanding of molecular and cellular mechanisms of CVD as well as improved therapeutic strategies for the management or treatment of heart failure are increasingly needed. Loss of myocardium is a major driver of heart failure. An attractive approach that appears to provide promising results in reducing cardiac degeneration is stem cell therapy (SCT). In this review, we describe different types of stem cells, including embryonic and adult stem cells, and we provide a detailed discussion of the properties of induced pluripotent stem cells (iPSCs). We also present and critically discuss the key methods used for converting somatic cells to pluripotent cells and iPSCs to cardiomyocytes (CMs), along with their advantages and limitations. Integrating and non-integrating reprogramming methods as well as characterization of iPSCs and iPSC-derived CMs are discussed. Furthermore, we critically present various methods of differentiating iPSCs to CMs. The value of iPSC-CMs in regenerative medicine as well as myocardial disease modeling and cardiac regeneration are emphasized.

PMID: 30053890 [PubMed - in process]

Mutations in Known Disease Genes Account for the Majority of Autosomal Recessive Retinal Dystrophies.

Clin Genet. 2018 Jul 28;:

Authors: Patel N, Alkuraya H, Alzahrani SS, Nowilaty SR, Seidahmed MZ, Alhomedan A, Ben-Omran T, Ghazi NG, Al-Aqeel A, Al-Owain M, Alzaidan HI, Faqeih E, Kurdi W, Rahbeeni Z, Ibrahim N, Abdulwahab F, Hashem M, Shaheen R, Abouelhoda M, Monies D, Khan AO, Aldahmesh MA, Alkuraya FS

Abstract
Retinal dystrophies (RD) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multi-gene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole-exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also demonstrate the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including 1 deep intronic and 1 genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will likely account for only a minor role in the mutation burden. This article is protected by copyright. All rights reserved.

PMID: 30054919 [PubMed - as supplied by publisher]

Whole-exome sequencing identifies rare genetic variations in German families with pulmonary sarcoidosis.

Hum Genet. 2018 Jul 27;:

Authors: Kishore A, Petersen BS, Nutsua M, Müller-Quernheim J, Franke A, Fischer A, Schreiber S, Petrek M

Abstract
Genome-wide and candidate gene studies for pulmonary sarcoidosis have highlighted several candidate variants among different populations. However, the genetic basis of functional rare variants in sarcoidosis still needs to be explored. To identify functional rare variants in sarcoidosis, we sequenced exomes of 22 sarcoidosis cases from six families. Variants were prioritized using linkage and high-penetrance approaches, and filtered to identify novel and rare variants. Functional networking and pathway analysis of identified variants was performed using gene ontology based gene-phenotype, gene-gene, and protein-protein interactions. The linkage (n = 1007-7640) and high-penetrance (n = 11,432) prioritized variants were filtered to select variants with (a) reported allele frequency < 5% in databases (1.2-3.4%) or (b) novel (0.7-2.3%). Further selection based on functional properties and validation revealed a panel of 40 functional rare variants (33 from linkage region, 6 highly penetrant and 1 shared by both approaches). Functional network analysis implicated these gene variants in immune responses, such as regulation of pro-inflammatory cytokines including production of IFN-γ and anti-inflammatory cytokine IL-10, leukocyte proliferation, bacterial defence, and vesicle-mediated transport. The KEGG pathway analysis indicated inflammatory bowel disease as most relevant. This study highlights the subsets of functional rare gene variants involved in pulmonary sarcoidosis, such as, regulations of calcium ions, G-protein-coupled receptor, and immune system including retinoic acid binding. The implicated mechanisms in etiopathogenesis of familial sarcoidosis thus include Wnt signalling, inflammation mediated by chemokine and cytokine signalling and cadherin signalling pathways.

PMID: 30054724 [PubMed - as supplied by publisher]

[Genetic diagnostics of retinal dystrophies : Breakthrough with new methods of DNA sequencing].

Ophthalmologe. 2018 Jul 27;:

Authors: Bolz HJ

Abstract
Until the mid-2000s, knowledge about the genetic causes of retinal dystrophies was not adequately translated into molecular diagnostics and genetic counselling offered to the patients. Although many genes whose mutations underlie retinal degeneration, e.g., retinitis pigmentosa, Leber congenital amaurosis and cone-rod dystrophies were known, they could not be analyzed on a routine diagnostic basis because DNA sequencing was too expensive and time-consuming. New methods summarized under the term next-generation sequencing (NGS) procedures for high-throughput sequencing have changed this completely. In its initial application in research NGS greatly accelerated the pace of novel disease gene identification: the mutations of most patients with retinal dystrophies can today be found in genes which are known to be associated with the condition. Since approximately 2010, NGS has expanded into routine diagnostics. In most patients, this now enables a genetic diagnosis and therefore specific genetic counselling and medical treatment. Constantly improving bioinformatics and comprehensive databases facilitate the evaluation of the complex NGS data. Nevertheless, profound scientific knowledge regarding the genetics of retinal dystrophies is indispensable to avoid erroneous data interpretation. This is also true for the close interaction between ophthalmologists and medical geneticists.

PMID: 30054723 [PubMed - as supplied by publisher]

Inframe de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.

Cold Spring Harb Mol Case Stud. 2018 Jul 27;:

Authors: Koboldt DC, Kastury R, Waldrop MA, Kelly BJ, Mihalic Mosher T, McLaughlin H, Corsmeier D, Slaughter JL, Flanigan KM, McBride KL, Mehta L, Wilson RK, White P

Abstract
We describe two unrelated patients, a 12-year-old female and a 6-year-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an inframe 3 base pair deletion and is predicted to cause loss of an evolutionarily conserved Asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations which may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.

PMID: 30054298 [PubMed - as supplied by publisher]