More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing.

Inflamm Bowel Dis. 2017 Oct;23(10):1873-1881

Authors: Broekman MMTJ, Coenen MJH, van Marrewijk CJ, Wanten GJA, Wong DR, Verbeek ALM, Klungel OH, Hooymans PM, Guchelaar HJ, Scheffer H, Derijks LJJ, de Jong DJ, TOPIC Recruitment Team

Abstract
BACKGROUND: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy.
METHODS: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression.
RESULTS: Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels.
CONCLUSIONS: Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.

PMID: 28644183 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/05/31

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80 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

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11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/05/31

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

80 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/05/31

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Dengue Antiviral Development: A Continuing Journey.

Adv Exp Med Biol. 2018;1062:319-332

Authors: Low JG, Gatsinga R, Vasudevan SG, Sampath A

Abstract
Dengue fever is a leading cause of illness and mortality in the tropics and subtropics. There are no therapeutics currently available and a recently approved vaccine is not very efficacious demanding an urgent need to develop an effective antiviral. The path to successful dengue drug development depends on availability of relevant preclinical testing models and better understanding of dengue pathogenesis. In recent years, efforts to develop dengue therapeutics have focused on both repurposing approved drugs as well as discovery of new chemical entities that act via virus or host targeted mechanisms. Here, we discuss the various innovative approaches, their outcome, and the lessons gleaned from the development efforts.

PMID: 29845542 [PubMed - in process]

Linking drug target and pathway activation for effective therapy using multi-task learning.

Sci Rep. 2018 May 29;8(1):8322

Authors: Yang M, Simm J, Lam CC, Zakeri P, van Westen GJP, Moreau Y, Saez-Rodriguez J

Abstract
Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways' activation. A typical insight would be: "Activation of pathway Y will confer sensitivity to any drug targeting protein X". We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for brain, skin and stomach tissues. Such an analysis of interactions across tissues might help target discovery, drug repurposing and patient stratification strategies.

PMID: 29844324 [PubMed - in process]

Niclosamide Exhibits Potent Anticancer Activity and Synergizes with Sorafenib in Human Renal Cell Cancer Cells.

Cell Physiol Biochem. 2018 May 24;47(3):957-971

Authors: Yu X, Liu F, Zeng L, He F, Zhang R, Yan S, Zeng Z, Shu Y, Zhao C, Wu X, Lei J, Zhang W, Yang C, Wu K, Wu Y, An L, Huang S, Ji X, Gong C, Yuan C, Zhang L, Feng Y, Huang B, Liu W, Zhang B, Dai Z, Wang X, Liu B, Haydon RC, Luu HH, Gan H, He TC, Chen L

Abstract
BACKGROUND/AIMS: As the most lethal urological cancers, renal cell carcinoma (RCC) comprises a heterogeneous group of cancer with diverse genetic and molecular alterations. There is an unmet clinical need to develop efficacious therapeutics for advanced, metastatic and/or relapsed RCC. Here, we investigate whether anthelmintic drug Niclosamide exhibits anticancer activity and synergizes with targeted therapy Sorafenib in suppressing RCC cell proliferation.
METHODS: Cell proliferation and migration were assessed by Crystal violet staining, WST-1 assay, cell wounding and cell cycle analysis. Gene expression was assessed by qPCR. In vivo anticancer activity was assessed in xenograft tumor model.
RESULTS: We find that Niclosamide effectively inhibits cell proliferation, cell migration and cell cycle progression, and induces apoptosis in human renal cancer cells. Mechanistically, Niclosamide inhibits the expression of C-MYC and E2F1 while inducing the expression of PTEN in RCC cells. Niclosamide is further shown to synergize with Sorafenib in suppressing RCC cell proliferation and survival. In the xenograft tumor model, Niclosamide is shown to effectively inhibit tumor growth and suppress RCC cell proliferation.
CONCLUSIONS: Niclosamide may be repurposed as a potent anticancer agent, which can potentiate the anticancer activity of the other agents targeting different signaling pathways in the treatment of human RCC.

PMID: 29843133 [PubMed - as supplied by publisher]

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates.

Sci Rep. 2016 12 01;6:38083

Authors: Thiede JM, Kordus SL, Turman BJ, Buonomo JA, Aldrich CC, Minato Y, Baughn AD

Abstract
The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents.

PMID: 27905500 [PubMed - indexed for MEDLINE]

Cutaneous leiomyosarcoma on the face.

An Bras Dermatol. 2018 Mar;93(2):262-264

Authors: Murback NDN, Takita LC, Castro BC, Hans Filho G

Abstract
Leiomyosarcoma is a rare skin tumor, most common in white men in the fifth to eighth decades of life. Primary tumors are classified in dermal or subcutaneous, that differ by clinical and prognostic features. They may appear on any site of the body, but are rare on the face. A 54-year-old female was admitted with a 5cm exophytic nodular lesion of 8 months duration on the right cheek, site of previous chronic radiodermatitis. Histopathology revealed spindle-shaped cell neoplasia, positive for smooth muscle actin on immunohistochemistry. Cutaneous leiomyosarcomas on the face are rare and may occur in previously irradiated areas. Immunohistochemistry is mandatory for an accurate diagnosis. Its similarity with other tumors may complicate the diagnosis, with delay expansion of the tumor.

PMID: 29723357 [PubMed - indexed for MEDLINE]

Multicystic peritoneal mesothelioma: A short review.

Curr Probl Cancer. 2017 Sep - Oct;41(5):340-348

Authors: Zhang CH, Yu JW, Luo M

Abstract
Multicystic peritoneal mesothelioma (MCPM) is a rare neoplasm, predominantly affecting female patients during their reproductive years. The lesion is usually distributed diffusely in the abdomen and pelvis, but the peritoneum of the pelvic organs is the most common site. MCPM is composed of fluid-filled translucent cysts, connected by varying amounts of fibrous tissue, and lined by a layer of mesothelial cells. Because of the rarity of this disease, the pathogenesis and natural history of MCPM remain poorly understood and continuously debated. Some authors consider it to be a reactive process for its association with prior surgery or abdominal inflammation. But its high rate of local-regional recurrence, as well as its malignant potential, suggests a neoplastic etiology. Preoperative diagnosis is often very difficult. Imaging methods, such as ultrasound, computed tomography, and magnetic resonance imaging, are of little value for an accurate diagnosis of MCPM. The definitive diagnosis relies on histologic examination of target lesions combined with immunohistochemical stains. There is no consensus on the clinical management of MCPM, although surgical removal remains the first-line treatment of choice. But no standards have been reached concerning which surgical options-traditional debulking surgery or more aggressive one-should be chosen. Alternative therapeutic approaches include hand-off treatment, hormonal supplementation, laser vaporization, and sclerotherapy, and they all come with uncertain results. Moreover, the lesions show no response to adjuvant chemotherapy and radiotherapy. This article aimed to focus on those controversial problems in pathogenesis, natural history, diagnosis, and treatment strategies to help medical workers to better understand this rare disease.

PMID: 28528021 [PubMed - indexed for MEDLINE]

[Healthcare services for people in Lower Saxony (Germany) suffering from a rare disease: Findings from a survey among medical professionals].

Z Evid Fortbild Qual Gesundhwes. 2016;113:36-44

Authors: Pauer F, Pflaum U, Lührs V, Frank M, Graf von der Schulenburg JM

Abstract
BACKGROUND: In the European Union, about 30 million people are affected by one of the 7,000 to 8,000 diseases being defined as rare. In Germany alone, an estimated 4 million people suffer from a rare disease. In many cases, therapeutic options and knowledge of specific rare diseases are strongly limited.
OBJECTIVE: The aim of this study was to identify the deficits and challenges confronting healthcare services for people suffering from a rare disease from the medical professional's perspective.
METHOD: As many as 530 medical professionals were invited to complete an online questionnaire, which was also available on the website of the General Medical Council of Lower Saxony. The questionnaire focused on questions in the following fields: structure of the medical care system; diagnosis and therapy; information sources and information exchange; and improvement of healthcare situation. Data were analyzed using IBM SPSS 22.
RESULT: We received 65 completed questionnaires. The evaluation indicates deficits in the medical services provided for people with a rare disease and shortcomings in the communication between clinical disciplines. In addition, diagnostic and therapeutic options are limited, and quality-tested information is rare.
CONCLUSION: Many of the identified deficits have already been addressed in the German national plan of action for people affected by rare diseases. Furthermore, newly discovered deficits have been evaluated. The German government implemented healthcare structures to improve healthcare services for people with rare diseases. However, budget deficits for specialized structures have occurred inhibiting the expansion of healthcare services. Moreover, many patients need systemic treatment requiring the further development of interdisciplinary care.

PMID: 27480187 [PubMed - indexed for MEDLINE]

Enhanced functionalities for annotating and indexing clinical text with the NCBO Annotator.

Bioinformatics. 2018 Jun 01;34(11):1962-1965

Authors: Tchechmedjiev A, Abdaoui A, Emonet V, Melzi S, Jonnagaddala J, Jonquet C

Abstract
Summary: Second use of clinical data commonly involves annotating biomedical text with terminologies and ontologies. The National Center for Biomedical Ontology Annotator is a frequently used annotation service, originally designed for biomedical data, but not very suitable for clinical text annotation. In order to add new functionalities to the NCBO Annotator without hosting or modifying the original Web service, we have designed a proxy architecture that enables seamless extensions by pre-processing of the input text and parameters, and post processing of the annotations. We have then implemented enhanced functionalities for annotating and indexing free text such as: scoring, detection of context (negation, experiencer, temporality), new output formats and coarse-grained concept recognition (with UMLS Semantic Groups). In this paper, we present the NCBO Annotator+, a Web service which incorporates these new functionalities as well as a small set of evaluation results for concept recognition and clinical context detection on two standard evaluation tasks (Clef eHealth 2017, SemEval 2014).
Availability and implementation: The Annotator+ has been successfully integrated into the SIFR BioPortal platform-an implementation of NCBO BioPortal for French biomedical terminologies and ontologies-to annotate English text. A Web user interface is available for testing and ontology selection (http://bioportal.lirmm.fr/ncbo_annotatorplus); however the Annotator+ is meant to be used through the Web service application programming interface (http://services.bioportal.lirmm.fr/ncbo_annotatorplus). The code is openly available, and we also provide a Docker packaging to enable easy local deployment to process sensitive (e.g. clinical) data in-house (https://github.com/sifrproject).
Contact: andon.tchechmedjiev@lirmm.fr.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29846492 [PubMed - in process]

Low-Hanging Fruit and Antioxidant Therapy in Cystic Fibrosis.

Am J Respir Crit Care Med. 2018 May 30;:

Authors: Cantin AM

PMID: 29847144 [PubMed - as supplied by publisher]

In vitro synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii grown in planktonic phase and in biofilms.

J Antimicrob Chemother. 2018 May 29;:

Authors: Pollini S, Boncompagni S, Di Maggio T, Di Pilato V, Spanu T, Fiori B, Blasi F, Aliberti S, Sergio F, Rossolini GM, Pallecchi L

Abstract
Objectives: To investigate the potential synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii strains grown in planktonic phase or as biofilms.
Methods: Sixteen strains were investigated, including nine colistin-susceptible (MIC range 0.5-1 mg/L) and seven colistin-resistant (MIC range 16-256 mg/L) strains. Synergism of colistin in combination with N-acetylcysteine was investigated by chequerboard assays. The activity of colistin/N-acetylcysteine combinations was further evaluated by time-kill assays with planktonic cultures (three colistin-resistant strains and one colistin-susceptible strain) and by in vitro biofilm models (three colistin-resistant and three colistin-susceptible strains).
Results: Chequerboard assays revealed a relevant synergism of colistin/N-acetylcysteine combinations with all colistin-resistant strains, whereas no synergism was observed with colistin-susceptible strains. Time-kill assays showed a concentration-dependent potentiation of colistin activity by N-acetylcysteine against colistin-resistant strains, with eradication of the culture by combinations of N-acetylcysteine at 8000 mg/L plus colistin at 2 or 8 mg/L. A static effect during the first 8 h of incubation was demonstrated with the colistin-susceptible strain exposed to 0.25 × MIC colistin plus 8000 mg/L N-acetylcysteine. A remarkable antibiofilm synergistic activity of 8 mg/L colistin plus 8000 mg/L N-acetylcysteine was demonstrated with all colistin-resistant and colistin-susceptible strains. The effects were greater with colistin-resistant strains (marked reduction of viable biofilm cells was observed at sub-MIC colistin concentrations).
Conclusions: N-acetylcysteine, at concentrations achievable by topical administration, was shown to revert the colistin-resistant phenotype in A. baumannii, and to exert a relevant activity against biofilms of colistin-susceptible and colistin-resistant A. baumannii strains.

PMID: 29846610 [PubMed - as supplied by publisher]

Prevalence and clinical outcomes of nontuberculous mycobacteria in a Brazilian cystic fibrosis reference center.

Pathog Dis. 2018 May 28;:

Authors: Aiello T, Levy C, Zaccariotto T, Pereira MC, da Silva MN, Ribeiro J, Ribeiro A, Toro ADC, Mauch R

Abstract
Nontuberculous mycobacteria (NTM) have been well established as an opportunistic pathogenic bacterial group for cystic fibrosis (CF) patients, with a prevalence ranging from 3 to 23% worldwide. A myriad of factors can bias the prevalence rate in different CF centers, especially misdiagnosis as systematic screening for NTM are still lacking in a number of centers. Here, we evaluated the presence and clinical outcomes of NTM isolation in microbiological respiratory cultures from CF patients attending a Brazilian reference center after setting up a systematic diagnostic protocol. Of 117 patients with respiratory samples cultured for NTM research, we found seven patients (6%) with at least one positive result for NTM [four males (57.1%), Median Age = 21 years (9 - 58)]. These cases are reported one-by-one. Median FEV1 was 40%, all patients showed signs of lung deterioration, with a median number of pulmonary exacerbations of three per patient/year. However, the impact of NTM isolation remains unclear in our center as all patients were coinfected with other CF respiratory pathogens. Our NTM prevalence assimilate to the lowest levels reported in literature, which is possibly influenced by the routinely applied Bacille Calmette-Guérin (BCG) vaccine.

PMID: 29846573 [PubMed - as supplied by publisher]

Editorial Focus: CFTR-dependent bicarbonate secretion by Calu-3 cells.

Physiol Rep. 2018 May;6(10):e13691

Authors: Rubenstein RC

PMID: 29845767 [PubMed - in process]

Standard Polymeric Formula Tube Feeding in Neurologically Impaired Children: A Five-Year Retrospective Study.

Nutrients. 2018 May 28;10(6):

Authors: Dipasquale V, Catena MA, Cardile S, Romano C

Abstract
Malnutrition is frequent in neurologically impaired (NI) children. Enteral feeding via gastrostomy tube is increasingly being used to provide adequate nutrition. Our aim was to assess the outcomes of exclusive gastrostomy tube feeding with standard polymeric formula in children with NI, severe oro-motor dysfunction, and malnutrition, and to investigate the role of the underlying NI-associated disease. A five-year retrospective study from January 2013 to November 2017 was conducted. The primary aim was to assess the nutritional outcomes of exclusive gastrostomy tube feeding with standard polymeric formula in malnourished NI children. The secondary aim was to investigate gastrostomy complications and the impact of the underlying NI-associated disease on the nutritional outcomes. We enrolled 110 consecutive children with NI. Of these patients, 34.5% (N = 38) were categorized as malnourished and started exclusive enteral feeding with a standard (1.0 kcal/mL) polymeric formula (Nutrini, Nutricia) after percutaneous endoscopic gastrostomy (PEG) placement. Seventy-three percent of patients (N = 28) had cerebral palsy (CP); other diagnoses included metabolic (13%, N = 5) and genetic (13%, N = 5) diseases. Tricep skinfold thickness had significantly improved in all patients at 12-months follow-up, while body weight and body mass index showed significant increases mainly in children with CP. No serious complications occurred. We found that standard polymeric formula via gastrostomy tube represents a safe and efficient nutritional intervention in children with NI and malnutrition.

PMID: 29843419 [PubMed - in process]

Cystic Fibrosis: Translating Molecular Mechanisms into Effective Therapies.

Ann Am Thorac Soc. 2018 May 29;:

Authors: Jennings MT, Flume PA

Abstract
Cystic Fibrosis (CF) is a genetic disease the affects approximately 75,000 individuals around the world. Long regarded as a lethal and life-limiting disease, with the most severe manifestations expressed in the progressive decline of lung function, treatment advances focusing on airway clearance and management of chronic lung infection have resulted in improved outcomes for individuals with CF. These advances have been realized in conjunction with an improved understanding of the genetic basis of this disease, dating back to the discovery of the CF gene in 1989. The identification of the CF gene and the advancement of our understanding of the resultant cystic fibrosis transmembrane conductance regulator (CFTR) protein have led to the development of a new class of CF therapies designed to directly impact the function of this protein. These therapeutic developments have progressed, targeting the various mutations that can cause CF. These new medications, known as CFTR modulators, have changed the landscape of CF care and CF research. Their demonstrated effect in patients with specific CF mutations has ignited the hope that such therapies will soon be available to more individuals with this disease moving the CF community significantly closer to the ultimate goal of curing this disease.

PMID: 29812963 [PubMed - as supplied by publisher]

Differences in ion channel phenotype and function between humans and animal models.

Front Biosci (Landmark Ed). 2018 Jan 01;23:43-64

Authors: Tanner MR, Beeton C

Abstract
Ion channels play crucial roles in regulating a broad range of physiological processes. They form a very large family of transmembrane proteins. Their diversity results from not only a large number of different genes encoding for ion channel subunits but also the ability of subunits to assemble into homo- or heteromultimers, the existence of splice variants, and the expression of different regulatory subunits. These characteristics and the existence of very selective modulators make ion channels very attractive targets for therapy in a wide variety of pathologies. Some ion channels are already being targeted in the clinic while many more are being evaluated as novel drug targets in both clinical and preclinical studies. Advancing ion channel modulators from the bench to the clinic requires their assessment for safety and efficacy in animal models. While extrapolating results from one species to another is tempting, doing such without careful evaluation of the ion channels in different species presents a risk as the translation is not always straightforward. Here, we discuss differences between species in terms of ion channels expressed in selected tissues, differing roles of ion channels in some cell types, variable response to pharmacological agents, and human channelopathies that cannot fully be replicated in animal models.

PMID: 28930537 [PubMed - indexed for MEDLINE]