Canine and Feline Models of Human Genetic Diseases and Their Contributions to Advancing Clinical Therapies
.

Yale J Biol Med. 2017 Sep;90(3):417-431

Authors: Gurda BL, Bradbury AM, Vite CH

Abstract
For many lethal or debilitating genetic disorders in patients there are no satisfactory therapies. Several barriers exist that hinder the developments of effective therapies including the limited availability of clinically relevant animal models that faithfully recapitulate human genetic disease. In 1974, the Referral Center for Animal Models of Human Genetic Disease (RCAM) was established by Dr. Donald F. Patterson and continued by Dr. Mark E. Haskins at the University of Pennsylvania with the mission to discover, understand, treat, and maintain breeding colonies of naturally occurring hereditary disorders in dogs and cats that are orthologous to those found in human patients. Although non-human primates, sheep, and pig models are also available within the medical community, naturally occurring diseases are rarely identified in non-human primates, and the vast behavioral, clinicopathological, physiological, and anatomical knowledge available regarding dogs and cats far surpasses what is available in ovine and porcine species. The canine and feline models that are maintained at RCAM are presented here with a focus on preclinical therapy data. Clinical studies that have been generated from preclinical work in these models are also presented.

PMID: 28955181 [PubMed - indexed for MEDLINE]

Resilience to health challenges is related to different ways of thinking: mediators of physical and emotional quality of life in a heterogeneous rare-disease cohort.

Qual Life Res. 2017 Nov;26(11):3075-3088

Authors: Schwartz CE, Michael W, Rapkin BD

Abstract
BACKGROUND: We sought to understand what distinguishes people who confront health challenges but still manage to thrive. This study investigated whether resilience helps to explain the impact of health challenges on quality of life (QOL) outcomes, and how resilience relates to appraisal.
METHODS: A web-based survey of rare-disease panel participants included the Centers for Disease Control Healthy Days Core Module, the PROMIS-10, and comorbidities. The QOL Appraisal Profile-v2 assessed cognitive processes underlying QOL. Resilience was operationalized statistically using residual modeling, and hierarchical regressions tested the mediation hypothesis that resilience accounts for a significant amount of the relationship of appraisal to QOL.
RESULTS: The study sample (n = 3,324; mean age 50; 86% female; 90% White) represented a range of diagnostic codes, with cancer and diseases of the nervous system being the most prevalent health conditions. After adjusting for comorbidities (catalysts), resilience was associated with better physical and emotional functioning, and different appraisal processes were associated with better or worse physical or emotional functioning. After controlling for catalysts, 62% of the association of Physical Functioning and 23% of the association between Emotional Functioning and appraisal were mediated by resilience. Physical and emotional resilience comprised some of the same appraisal processes, but physically resilient people were characterized by more appraisal processes than their emotionally resilient counterparts.
CONCLUSIONS: Resilient people employ different appraisal processes than non-resilient people, and these processes differ for physical and emotional outcomes. Resilience was a stronger mediator of the relationship between physical rather than emotional functioning and appraisal.

PMID: 28660463 [PubMed - indexed for MEDLINE]

Sonographic and Magnetic Resonance Imaging Characteristics of Juvenile Papillomatosis: Three Cases With Different Manifestations.

Ultrasound Q. 2017 Jun;33(2):174-178

Authors: Yilmaz R, Bayramoglu Z, Bicen F, Kayhan A, Yesil S, Acunas G

Abstract
Juvenile papillomatosis (JP) is an infrequently seen benign proliferative lesion in women younger than 30 years. Herein, we present different clinical manifestations of histopathologically proven JP of the breast, in addition to magnetic resonance and sonographic imaging features of these cases. Patient 1 exhibited nipple discharge and papillary carcinoma accompanied after the operation. Patient 2 presented with a giant mass with cystic and numerous solid nodular components that filled the entire right breast. Patient 3 exhibited cystic areas in a well-circumscribed hypoechoic solid mass besides ahypoechoic mass with indistinct borders, which was evaluated as multifocal JP.

PMID: 28538449 [PubMed - indexed for MEDLINE]

Ovarian Artery Embolization as a Treatment for Persistent Ovarian Remnant Syndrome.

Cardiovasc Intervent Radiol. 2017 Aug;40(8):1278-1280

Authors: Chan TL, Singh H, Benton AS, Harkins GJ

Abstract
Ovarian remnant syndrome (ORS) is a rare condition in which ovarian tissue persists at the site of prior oophorectomy and often causes debilitating pelvic pain. Gold standard of treatment is surgical resection. We report a case of persistent ORS in a 44-year-old female who was successfully treated with ovarian artery embolization after failure of standard medical and gynecologic therapies. The ovarian tissue remnant was reduced by 75% in volume, and the patient was near symptom-free four months after the procedure.

PMID: 28280977 [PubMed - indexed for MEDLINE]

LAILAPS-QSM: A RESTful API and JAVA library for semantic query suggestions.

PLoS Comput Biol. 2018 Mar 12;14(3):e1006058

Authors: Chen J, Scholz U, Zhou R, Lange M

Abstract
In order to access and filter content of life-science databases, full text search is a widely applied query interface. But its high flexibility and intuitiveness is paid for with potentially imprecise and incomplete query results. To reduce this drawback, query assistance systems suggest those combinations of keywords with the highest potential to match most of the relevant data records. Widespread approaches are syntactic query corrections that avoid misspelling and support expansion of words by suffixes and prefixes. Synonym expansion approaches apply thesauri, ontologies, and query logs. All need laborious curation and maintenance. Furthermore, access to query logs is in general restricted. Approaches that infer related queries by their query profile like research field, geographic location, co-authorship, affiliation etc. require user's registration and its public accessibility that contradict privacy concerns. To overcome these drawbacks, we implemented LAILAPS-QSM, a machine learning approach that reconstruct possible linguistic contexts of a given keyword query. The context is referred from the text records that are stored in the databases that are going to be queried or extracted for a general purpose query suggestion from PubMed abstracts and UniProt data. The supplied tool suite enables the pre-processing of these text records and the further computation of customized distributed word vectors. The latter are used to suggest alternative keyword queries. An evaluated of the query suggestion quality was done for plant science use cases. Locally present experts enable a cost-efficient quality assessment in the categories trait, biological entity, taxonomy, affiliation, and metabolic function which has been performed using ontology term similarities. LAILAPS-QSM mean information content similarity for 15 representative queries is 0.70, whereas 34% have a score above 0.80. In comparison, the information content similarity for human expert made query suggestions is 0.90. The software is either available as tool set to build and train dedicated query suggestion services or as already trained general purpose RESTful web service. The service uses open interfaces to be seamless embeddable into database frontends. The JAVA implementation uses highly optimized data structures and streamlined code to provide fast and scalable response for web service calls. The source code of LAILAPS-QSM is available under GNU General Public License version 2 in Bitbucket GIT repository: https://bitbucket.org/ipk_bit_team/bioescorte-suggestion.

PMID: 29529024 [PubMed - as supplied by publisher]

New findings in pharmacogenetics of schizophrenia.

Curr Opin Psychiatry. 2018 Mar 09;:

Authors: Zai CC, Tiwari AK, Zai GC, Maes MS, Kennedy JL

Abstract
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects.
RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications.
SUMMARY: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.

PMID: 29528898 [PubMed - as supplied by publisher]

CYP Induction and Xeno-Sensing Receptors PXR, CAR, AHR and PPARα at the Crossroads of Toxicokinetics and Toxicodynamics.

Basic Clin Pharmacol Toxicol. 2018 Mar 12;:

Authors: Hakkola J, Bernasconi C, Coecke S, Richert L, Andersson TB, Pelkonen O

Abstract
Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor α (PPARα) are ligand-activated transcription factors that regulate expression of many xenobiotic metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic pathways. However, it is now apparent that the xenobiotic receptors regulate also many endogenous functions and signalling pathways, and xenobiotic exposure thus may dysregulate an array of fundamental cell functions. This MiniReview surveys and discusses the multi-faceted roles of xenobiotic receptors, for which CYP induction may serve as the first alert and possibly a biomarker for exposure to xenobiotics. With the current emergence of the Adverse Outcome Pathway (AOP) concept, these receptors are being and will be assigned as molecular initiating events or key events in numerous discrete toxicity pathways. This article is protected by copyright. All rights reserved.

PMID: 29527807 [PubMed - as supplied by publisher]

Matrix effect management in liquid chromatography mass spectrometry: the internal standard normalized matrix effect.

Bioanalysis. 2017 07;9(14):1093-1105

Authors: De Nicolò A, Cantù M, D'Avolio A

Abstract
LC-MS is becoming a standard for many applications, thanks to high sensitivity and selectivity; nevertheless, some issues are still present, particularly due to matrix effect (ME). Considering this, the use of optimal internal standards (ISs, usually stable-isotope labeled) is important, but not always possible because of cost or availability. Therefore, a deep investigation of the inter-lot variability of the ME and of the correcting power of the chosen IS (isotope-labeled or not) is mandatory. While the adoption of isotopically labeled ISs considered as a 'gold standard' to mitigate ME impact on analytical results, there is not consensus about the standard technique to evaluate it during method validation. In this paper, currently available techniques to evaluate, reduce or counterbalance ME are presented and discussed. Finally, these techniques were summarized in a flowchart for a robust management of ME, particularly considering the concept of 'internal standard normalized ME'.

PMID: 28737421 [PubMed - indexed for MEDLINE]

Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.

J Cyst Fibros. 2017 May;16(3):371-379

Authors: Donaldson SH, Solomon GM, Zeitlin PL, Flume PA, Casey A, McCoy K, Zemanick ET, Mandagere A, Troha JM, Shoemaker SA, Chmiel JF, Taylor-Cousar JL

Abstract
BACKGROUND: Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.
METHODS: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.
RESULTS: Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28.
CONCLUSIONS: The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

PMID: 28209466 [PubMed - indexed for MEDLINE]

Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis.

Br J Clin Pharmacol. 2017 Jun;83(6):1287-1297

Authors: Janssen EJH, Bastiaans DET, Välitalo PAJ, van Rossum AMC, Jacqz-Aigrain E, Lyall H, Knibbe CAJ, Burger DM

Abstract
AIM: The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h ) is not reached.
METHODS: Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg-1 )]. Steady state AUC0-24h was calculated per individual (adult target 8.9 mg·h l-1 ).
RESULTS: A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 l h-1 (4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC0-24h was reached.
CONCLUSION: Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg-1  day-1 if the adult target for AUC0-24h is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed.

PMID: 28079918 [PubMed - indexed for MEDLINE]

Nanomedicine and personalised medicine: understanding the personalisation of health care in the molecular era.

Sociol Health Illn. 2017 May;39(4):547-565

Authors: Noury M, López J

Abstract
Globally supported by public policy and investment, nanomedicine is presented as an ongoing medical revolution that will radically change the practice of health care from diagnostic to therapeutic, and everything in between. One of nanomedicine's major promises is that of personalised medicine, enabling diagnostics and therapeutics tailored to individual needs and developing a truly 'patient-friendly' medical approach. Based on qualitative interviews with nanomedicine researchers in Canada, this article explores the emerging concept of personalised medicine as it becomes entangled with nanomedical research. More precisely, drawing on insights from science studies and the sociology of expectations, it analyses researchers' perceptions of personalised medicine in the cutting edge of current nanomedicine research. Two perceptions of personalisation are identified; a molecular conception of individuality and a technical conception of personalisation. The article concludes by examining the relationship between the two conceptions and contrasts them with the normative reflex of a more expansive conception of personalised medicine.

PMID: 27782304 [PubMed - indexed for MEDLINE]

An Interventionalist's Guide to Hemoptysis in Cystic Fibrosis.

Radiographics. 2018 Mar-Apr;38(2):624-641

Authors: Monroe EJ, Pierce DB, Ingraham CR, Johnson GE, Shivaram GM, Valji K

Abstract
Massive hemoptysis occurs in a minority of patients with cystic fibrosis, with an annual incidence of 1%. Although rare, massive hemoptysis can be a severe and potentially fatal complication of this disease. Beyond the acute life-threatening event, hemoptysis in patients with cystic fibrosis has been associated with faster decline in lung function, accelerated need for lung transplant, and increased mortality. The bronchial arteries are the culprit vessels in over 90% of cases of hemoptysis. This normally quiescent vascular system undergoes remarkable hypertrophy, collateralization, and angiogenesis before the onset of hemoptysis, introducing numerous pitfalls for the interventionalist. However, in experienced hands, bronchial artery embolization is a safe and potentially lifesaving therapy. Preprocedural noninvasive imaging, specifically computed tomographic angiography, has been repeatedly validated for helping to localize the likely site of bleeding, characterizing pertinent arterial anatomy, and promoting efficient and effective intervention; it has been recommended for all stable patients with hemoptysis. Success in the angiographic suite requires a thorough understanding of normal and variant bronchial arterial anatomy, appropriate patient selection, and a meticulous embolization technique. A meticulous approach to imaging and intervention, conscientious of both visualized and nonvisualized collateral pathways and nontarget vessels, can minimize potentially devastating complications. This review summarizes the current literature, modern procedural techniques, and emerging controversies, serving to guide an evolving approach to management of patients with cystic fibrosis and hemoptysis. ©RSNA, 2018.

PMID: 29528824 [PubMed - in process]

Difficult conversations: Discussing prognosis with children with cystic fibrosis.

Pediatr Pulmonol. 2018 Mar 12;:

Authors: Farber JG, Prieur MG, Roach C, Shay R, Walter M, Borowitz D, Dellon EP

Abstract
Background Despite the chronic, progressive, and life-threatening nature of cystic fibrosis (CF), there are no guidelines for when and how to communicate prognosis to children with CF.
METHODS: Semi-structured interviews with young adults with CF, parents of young adults with CF, and multidisciplinary CF health care providers assessed recall of and practices for communicating about prognosis. Recommendations for improvements were also solicited.
RESULTS: Young adults with CF recalled learning that life expectancy is limited by CF between the ages of 8 and 16 years, and that CF is a progressive disease between the ages of 7 and 19 years. They reported that the information often came from CF physicians or from online resources. Patients and parents reported earlier knowledge of prognosis than providers assumed. While learning about prognosis caused sadness and stress for some patients and families, others denied negative feelings. Interestingly, most patients reported that disclosure of prognosis had minimal impact on their adherence and treatment goals. Patients and parents reported wanting physicians to be involved in conversations about prognosis. However, providers noted several barriers to discussing prognosis, including their own reluctance, time limitations, and uncertainty about appropriate timing and content of communication.
CONCLUSIONS: Communication about prognosis is important but also difficult for providers, patients, and families. Appropriately timed conversations, using tools to facilitate communication, could ensure patients receive timely, accurate information.

PMID: 29528566 [PubMed - as supplied by publisher]

The timing and extent of acute physiotherapy involvement following lung transplantation: An observational study.

Physiother Res Int. 2018 Mar 12;:

Authors: Tarrant BJ, Holland A, Le Maitre C, Robinson R, Corbett M, Bondarenko J, Button B, Thompson B, Snell G

Abstract
BACKGROUND AND PURPOSE: Physiotherapy "standard care" for the acute post lung transplant recipient has not yet been documented. We aimed to analyse how soon patients commence exercise and how much time is dedicated to this during physiotherapy sessions acutely post lung transplantation.
METHODS: Prospective observational study of bilateral sequential and single lung transplant recipients for any indication, ≥18 years. Participants were observed during 6 physiotherapy sessions: 3 initial and 3 prior to acute inpatient discharge. Duration and content of each session was recorded, consisting of physical exercise and non-exercise tasks.
RESULTS: Thirty participants, 20 male, median age 58.5 (interquartile range 54.5-65.0) were observed over 173 sessions. Chronic obstructive pulmonary disease was the most common transplant indication (n = 12, 40%). Bilateral lung transplant was performed in 90% (n = 27) of participants. First time to mobilise was 2 (2-3) days. Participants received 14 (12.8-23.8) sessions over 18 (17-31) days. The mean duration of physiotherapy in the initial phase was 107.8 (standard deviation 21.8) min, with 22.9 (7.5) min spent exercising. In the final phase, exercise time increased to 28.1 (11.4) min out of 84.1 (24.6) min. Assessment was the most common non-exercise component, at 26.6 (7.9) and 22.1 (12.5) min across the three initial and final sessions.
IMPLICATIONS FOR PHYSIOTHERAPY PRACTICE: Lung transplant recipients spent 21-34% of observed sessions performing physical exercise beginning 48 hr following surgery. Remaining physiotherapist time was spent on assessment, respiratory interventions, education, and patient-specific duties. The use of physiotherapy assistants, structured, progressive exercise programs, and continued workplace innovation may enable a higher percentage of physiotherapist supervised physical exercise in the future.

PMID: 29528538 [PubMed - as supplied by publisher]

Survival After Lung Transplantation of Cystic Fibrosis Patients Infected with Burkholderia dolosa (Genomovar VI).

Clin Transplant. 2018 Mar 12;:

Authors: Wang R, Welsh SK, Budev M, Goldberg H, Noone PG, Zaas D, Boyer D

Abstract
Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n=11) at various medical centers across the U.S between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1-year, 3-years, and 5-years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased 1-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa infected patients was 43% in patients that survived the first year post transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post transplant. This article is protected by copyright. All rights reserved.

PMID: 29528522 [PubMed - as supplied by publisher]

Exhaled NO as a predictor of exercise-induced asthma in cold air.

Nitric Oxide. 2018 Mar 08;:

Authors: Dreßler M, Salzmann-Manrique E, Zielen S, Schulze J

Abstract
PURPOSE: Physical activity is an important part of life, and exercise-induced asthma (EIA) can reduce the quality of life. A standardized exercise challenge is needed to diagnose EIA, but this is a time consuming, effortful and expensive method. Exhaled nitric oxide (eNO) as a marker of eosinophil inflammation is determined rapidly and easily. The aim of this study was to investigate eNO as surrogate marker for predicting a positive reaction in an exercise challenge in a cold chamber (ECC).
METHODS: A total of 143 subjects aged 6-45 years with suspected EIA were recruited for the study. The subjects underwent an eNO measurement, an ECC and a skin prick test (SPT). To define the sensitivity and specificity of eNO as predictor, a receiver-operating characteristic (ROC) curve was plotted. The individual probability of the occurrence of a positive reaction after ECC based on an eNO value was calculated using a logistic regression model.
RESULTS: An eNO cut-off value of 18.5 ppb (area under the curve (AUC) 0.71, p < 0.001) showed the best combination of sensitivity and specificity for a positive reaction (forced expiratory volume in 1 s (FEV1) decrease ≥ 10% after ECC) for the whole group. An eNO cut-off value of 46.0 ppb had a specificity of 100.0% to predict a significant FEV1 decrease and may save exercise testing in 22.4% of patients. A negative predictive level with a high sensitivity and negative predictive value (NPV) could not be defined. In the subgroup that was house dust might (HDM) allergy positive (HDM pos; n = 68, 45.5% of all subjects), an eNO cut-off value of 35.5 ppb (AUC 0.79, p < 0.01) showed the best combination of sensitivity and specificity for a positive reaction after the ECC with a specificity 100.0% and may save exercise testing in 45.6% of HDM pos patients. Using logistic regression, a 95% probability for a positive FEV1 decrease after ECC was estimated at 53 ppb for the whole group and at 47 ppb for the HDM pos subgroup.
CONCLUSIONS: Exhaled NO measurement is a screening tool for EIA, especially in HDM pos subjects. In a real-life setting, a cut-off value of 46.0 ppb detects EIA at 100% in all suspected patients, and a cut-off level of 35.5 ppb is valuable marker of EIA in patients with an HDM allergy. These levels can save time and costs in a large proportion of patients and will be helpful for clinicians.

PMID: 29526567 [PubMed - as supplied by publisher]

Attenuation of quorum sensing controlled virulence factors and biofilm formation in Pseudomonas aeruginosa by pentacyclic triterpenes, betulin and betulinic acid.

Microb Pathog. 2018 Mar 08;:

Authors: Rajkumari J, Borkotoky S, Murali A, Suchiang K, Mohanty SK, Busi S

Abstract
The production of virulence determinants and biofilm formation in numerous pathogens is regulated by the cell-density-dependent phenomenon, Quorum sensing (QS). The QS system in multidrug resistant opportunistic pathogen, P. aeruginosa constitutes of three main regulatory circuits namely Las, Rhl, and Pqs which are closely linked to its pathogenicity and establishment of chronic infections. In spite intensive antibiotic therapy, P. aeruginosa continue to be an important cause of nosocomial infections and also the major cause of mortality in Cystic Fibrosis patients with 80% of the adults suffering from chronic P. aeruginosa infection. Hence, targeting QS circuit offers an effective intervention to the ever increasing problem of drug resistant pathogens. In the present study, the pentacyclic triterpenes i.e. Betulin (BT) and Betulinic acid (BA) exhibited significant attenuation in production of QS-regulated virulence factors and biofilm formation in P. aeruginosa, at the sub-lethal concentration. The test compound remarkably interfered in initial stages of biofilm development by decreasing the exopolysaccharide production and cell surface hydrophobicity. Based on the in vivo studies, the test compounds notably enhanced the survival of Caenorhabditis elegans infected with P. aeruginosa. Furthermore, molecular docking analysis revealed that BT and BA can act as a strong competitive inhibitor for QS receptors, LasR and RhlR. The findings suggest that BT and BA can serve as potential anti-infectives in the controlling chronic infection of P. aeruginosa.

PMID: 29526565 [PubMed - as supplied by publisher]

[Impact of Cystic Fibrosis Transmembrane Conductance Regulator on Malignant
 Properties of KRAS Mutant Lung Adenocarcinoma A549 Cells].

Zhongguo Fei Ai Za Zhi. 2018 Feb 20;21(2):89-98

Authors: Li H, Wang Y, Yang J, Liu X, Shi J

Abstract
BACKGROUND: The incidence of lung cancer is gradually increased, and the cystic fibrosis transmembrane conductance regulator (CFTR) has recently demonstrated to have an implication in the deoncogenesis and malignant transformation of many types of cancers. The aim of this study is to investigate impacts of CFTR on the malignant features of lung adenocarcinoma A549 cells.
METHODS: The capacity of cell proliferation, migration, invasion and clonogenicity of non-small cell lung cancer A549 cells were detected by CCK8 cell proliferation assay, cell scratch assay, Transwell cell invasion assay and clone formation assay, respectively. Meanwhile, the effect of CFTR gene on the expression of cancer stem cell related transcriptional factors was also detected by immunoblotting (Western blot) assay.
RESULTS: An overexpression of CFTR gene in A549 cells significantly inhibited the malignant capacity of A549 cells, including potencies of cell proliferation, migration, invasion and colony formation; while knockdown of CFTR gene expression by RNA interference in A549 cells resulted in an opposite effect seen in above cells overexpressing CFTR gene. Mechanistically, immunoblotting assay further revealed that the ectopic expression of CFTR gene led an inhibitory expression of stem cell-related transcriptional factors SOX2 and OCT3/4, and cancer stem cell surface marker CD133 in A549 cells, while a knockdown of CFTR expression yielded a moderately increased expression of these gene. However, an alteration of CFTR gene expression had neither effect on the expression of putative lung cancer stem cell marker aldehyde dehydrogenase1 (ALDH1), nor the frequency of ALDH1A-positive cells in A549 cells, as ascertained by the immunoblotting assay and cytometry analysis, respectively.
CONCLUSIONS: The CFTR exhibited an inhibitory role in the malignancy of lung adenocarcinoma A549 cells, suggesting that it may be a novel potential target for lung cancer treatment. However, its functions in other lung adenocarcinoma cell lines and its underlying molecular mechanisms require further investigation.

PMID: 29526175 [PubMed - in process]

Effect of freezing sputum on Pseudomonas aeruginosa population heterogeneity.

J Cyst Fibros. 2017 May;16(3):353-357

Authors: Poonja A, Heirali A, Workentine M, Storey DG, Somayaji R, Rabin HR, Surette MG, Parkins MD

Abstract
Pseudomonas aeruginosa develops profound population heterogeneity in CF airways. How changes in these populations relate to clinical status is unknown. In order to facilitate this understanding, frequent sampling of this community is required. To determine if the collection and storage of sputum at home may pose a viable option, we collected sputum from ten patients. Sputum samples were partitioned in two, with half immediately processed on MacConkey agar and half assessed after freezing for one week in a home-freezer. From each sample, 88 isolates were assessed for antibiotic susceptibility and virulence factor production. Freezing resulted in a 103CFU/ml drop in P. aeruginosa. However, across 1760 isolates, no consistent difference in either antibiotic susceptibility nor virulence factors was observed suggesting freezing induced indiscriminate killing. Home collection and freezing of sputum will enable frequent and convenient assessment of P. aeruginosa population dynamics in CF.

PMID: 28126444 [PubMed - indexed for MEDLINE]

Classification of CFTR mutation classes.

Lancet Respir Med. 2016 08;4(8):e37-e38

Authors: Marson FAL, Bertuzzo CS, Ribeiro JD

PMID: 27377414 [PubMed - indexed for MEDLINE]