Funding Opportunity RFA-RM-17-010 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite applications (via limited competition) for SPARC Technologies to Understand the Control of Organ Function by the Peripheral Nervous System.

Funding Opportunity RFA-AR-18-005 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose preclinical studies to advance the development of biomarkers or treatments for rare musculoskeletal, rheumatic or skin diseases. Rare diseases have a prevalence of fewer than 200,000 affected individuals in the United States. Also eligible for potential funding through this initiative are studies of FDA-designated orphan products for musculoskeletal, rheumatic or skin diseases.

Notice NOT-OD-17-053 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-254 from the NIH Guide for Grants and Contracts. This FOA encourages applications for the Lasker Clinical Research Scholars Program for the purpose of supporting the research activities during the early stage careers of independent clinical researchers.

Funding Opportunity PAR-17-252 from the NIH Guide for Grants and Contracts. The primary objective of this FOA is to stimulate innovative Convergent Neuroscience (CN) approaches to establish causal and/or probabilistic linkages across contiguous levels of analysis (e.g., gene, molecule, cell, circuit, system, behavior) in an explanatory model of psychopathology. In particular, applicants should focus on how specific constituent biological processes at one level of analysis contribute to quantifiable properties at other levels, either directly or as emergent phenomena. Although not required, it is preferable that applications link at least three levels of analysis and include an emphasis on genetics. The projects under this FOA will develop novel methods, theories, and approaches through a CN team framework, bringing together highly synergistic inter/transdisciplinary teams from neuroscience and the orthogonal fields of the physical sciences (e.g., data/computational science, physics, engineering, mathematics). Successful teams will combine, expand upon, or develop conceptual frameworks and theoretical approaches, and build explanatory computational models that connect contiguous levels of analysis. Such frameworks, theories, and computational explanatory models should be validated through experimental approaches to elucidate biological underpinnings of complex behavioral (including cognitive and affective) outcomes in psychopathology. Additionally, a goal of this program is to advance research in CN by creating a shared community framework of resources which may be used by the broader research community to further research, as such, a successful team will be expected to have robust plan for sharing data and other resources.

Funding Opportunity PAR-17-253 from the NIH Guide for Grants and Contracts. The primary objective of this FOA is to stimulate innovative Convergent Neuroscience (CN) approaches to establish causal and/or probabilistic linkages across contiguous levels of analysis (e.g., gene, molecule, cell, circuit, system, behavior) in an explanatory model of psychopathology. In particular, applicants should focus on how specific constituent biological processes at one level of analysis contribute to quantifiable properties at other levels, either directly or as emergent phenomena. Although not required, it is preferable that applications link at least three levels of analysis and include an emphasis on genetics. The projects under this FOA will develop novel methods, theories, and approaches through a CN team framework, bringing together highly synergistic inter/transdisciplinary teams from neuroscience and the orthogonal fields of the physical sciences (e.g., data/computational science, physics, engineering, mathematics). Successful teams will combine, expand upon, or develop conceptual frameworks and theoretical approaches, and build explanatory computational models that connect contiguous levels of analysis. Such frameworks, theories, and computational explanatory models should be validated through experimental approaches to elucidate biological underpinnings of complex behavioral (including cognitive and affective) outcomes in psychopathology. Additionally, a goal of this program is to advance research in CN by creating a shared community framework of resources which may be used by the broader research community to further research, as such, a successful team will be expected to have a robust plan for sharing data and other resources.

Notice NOT-DK-17-011 from the NIH Guide for Grants and Contracts

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"systems biology"

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Related Articles

Baseline Regularization for Computational Drug Repositioning with Longitudinal Observational Data.

IJCAI (U S). 2016 Jul;2016:2521-2528

Authors: Kuang Z, Thomson J, Caldwell M, Peissig P, Stewart R, Page D

Abstract
Computational Drug Repositioning (CDR) is the knowledge discovery process of finding new indications for existing drugs leveraging heterogeneous drug-related data. Longitudinal observational data such as Electronic Health Records (EHRs) have become an emerging data source for CDR. To address the high-dimensional, irregular, subject and time-heterogeneous nature of EHRs, we propose Baseline Regularization (BR) and a variant that extend the one-way fixed effect model, which is a standard approach to analyze small-scale longitudinal data. For evaluation, we use the proposed methods to search for drugs that can lower Fasting Blood Glucose (FBG) level in the Marshfield Clinic EHR. Experimental results suggest that the proposed methods are capable of rediscovering drugs that can lower FBG level as well as identifying some potential blood sugar lowering drugs in the literature.

PMID: 28392671 [PubMed - in process]

Related Articles

First case of Currarino syndrome and trimethylaminuria: two rare diseases for a complex clinical presentation.

J Dig Dis. 2016 Sep;17(9):628-632

Authors: Scimone C, Donato L, Rinaldi C, Sidoti A, D'Angelo R

PMID: 27335202 [PubMed - indexed for MEDLINE]

Related Articles

Inflammatory Myofibroblastic Tumor of the Lung.

J Coll Physicians Surg Pak. 2016 Apr;26(4):331-3

Authors: Ekinci GH, Haciomeroglu O, Sen AC, Alpay L, Guney PA, Yilmaz A

Abstract
Inflammatory myofibroblastic tumor of the lung is a rare condition, with a reported incidence between 0.04 - 1.2% of all tumors of the lung. We present a case of inflammatory myofibroblastic tumor of the lung. A61-year man presented to the outpatient department complaining of cough and blood-streaked sputum for 5 days. The computed tomography scan of the chest demonstrated a 4.5 x 4 cm, calcified pulmonary mass in the anterior segment of the right upper lobe. Bronchoscophy and computed tomography-guided transthoracic fine needle aspiration was inconclusive. The tumor was removed via wedge resection. Histological and immunohistochemical findings were consistent with inflammatory myofibroblastic tumor of the lung.

PMID: 27097710 [PubMed - indexed for MEDLINE]

Related Articles

Segmental Schwannomatosis of the Spine: Report of a Rare Case and Brief Review of Literature.

Ortop Traumatol Rehabil. 2016 Jan-Feb;18(1):73-8

Authors: Baruah RK, Bora S, Haque R

Abstract
UNLABELLED: To report a case of segmental schwannomatosis involving the dorsal and lumbar spine and describe its excision as well as review of literature on schwannomatosis involving the spine.
SUMMARY OF BACKGROUND DATA: Schwannomas are nerve sheath tumours which usually occur as solitary lesions. Presence of multiple schwannomas suggests a genetic predisposition to tumorogenesis and possible association with neurofibromatosis. However, in very rare cases multiple schwannomas exist without typical features of neurofibromatosis and constitute a clinically and genetically distinct rare syndrome termed schwannomatosis. A 31-year-old female presented with low back pain with left lower limb radiculopathy and sensory deficit over the L4-L5 dermatome. Auditory and ophthalmologic examinations were normal. MRI showed two discrete intradural masses at D12-L2 and L3-L5. MRI of the brain was negative for any vestibular schwannoma. The tumours were excised discretely through a single midline incision to improve the symptoms. HPE of both the tumours revealed them to be schwannomas. Karyotyping from lymphocyte DNA revealed no abnormality.
CONCLUSION: This is the 3rd case of schwannomatosis involving the dorsal and lumbar spine, in which excision of the tumours led to resolution of symptoms.

PMID: 27053311 [PubMed - indexed for MEDLINE]

Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia.

World J Biol Psychiatry. 2017 Apr 10;:1-5

Authors: Zai CC, Tiwari AK, Chowdhury NI, Yilmaz Z, de Luca V, Müller DJ, Potkin SG, Lieberman JA, Meltzer HY, Voineskos AN, Remington G, Kennedy JL

Abstract
OBJECTIVES: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed.
METHODS: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD.
RESULTS: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003).
CONCLUSIONS: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted.

PMID: 28394697 [PubMed - as supplied by publisher]

Related Articles

Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients.

J Clin Lab Anal. 2017 Apr 10;:

Authors: Atasilp C, Chansriwong P, Sirachainan E, Reungwetwattana T, Puangpetch A, Prommas S, Sirilerttrakul S, Rerkarmnuaychoke B, Wongwaisayawan S, Sukasem C

Abstract
BACKGROUND: Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G.
METHODS: A 100 μL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G.
RESULTS: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G.
CONCLUSION: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.

PMID: 28393405 [PubMed - as supplied by publisher]

Related Articles

Interaction between COX-1 and COX-2 Variants Associated with Aspirin Resistance in Chinese Stroke Patients.

J Stroke Cerebrovasc Dis. 2016 Sep;25(9):2136-44

Authors: Yi X, Cheng W, Lin J, Zhou Q, Wang C

Abstract
BACKGROUND: There have been conflicting results for the association between cyclooxygenase (COX) genetic variants and aspirin resistance (AR). The aim of this study was to investigate the association of the COX genetic variants and interaction among these variants with AR in patients with acute ischemic stroke (IS).
METHODS: We consecutively enrolled 850 acute IS patients. Platelet aggregation activity was measured before and after a 7- to 10-day aspirin treatment. The four variants from COX genes were examined using mass spectrometry. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods.
RESULTS: Among the 850 acute IS patients, 175 (20.6%) patients had AR, 45 (5.3%) patients had aspirin semiresistance (ASR), and 630 (74.1%) patients had aspirin sensitivity (AS). The genotype distributions of the 4 variants did not differ significantly between the ASR + AR group and the AS group using the single-locus analytical approach. However, the GMDR analysis showed a significant gene-gene interaction between COX-1 (rs3842787) and COX-2 (rs20417), and scored 10/10 for cross-validation consistency and 9 for the sign test (P = .0127). Individual patients with the combination of rs3842787CT and rs20417CC or rs3842787CT and rs20417GC had a significantly higher risk of ASR + AR than those with rs3842787CC and rs20417GG. The high-risk interactions between rs3842787 and rs20417 were independent predictors of ASR + AR, and were associated with lower reduction of platelet aggregation activity.
CONCLUSIONS: The interactions of rs3842787 and rs20417 were associated with AR. The combinational analysis used in this study may provide further insight into the complex genetic risk of AR.

PMID: 27318652 [PubMed - indexed for MEDLINE]

Related Articles

Precision Medicine, Cardiovascular Disease and Hunting Elephants.

Prog Cardiovasc Dis. 2016 May-Jun;58(6):651-60

Authors: Joyner MJ

Abstract
Precision medicine postulates improved prediction, prevention, diagnosis and treatment of disease based on patient specific factors especially DNA sequence (i.e., gene) variants. Ideas related to precision medicine stem from the much anticipated "genetic revolution in medicine" arising seamlessly from the human genome project (HGP). In this essay I deconstruct the concept of precision medicine and raise questions about the validity of the paradigm in general and its application to cardiovascular disease. Thus far precision medicine has underperformed based on the vision promulgated by enthusiasts. While niche successes for precision medicine are likely, the promises of broad based transformation should be viewed with skepticism. Open discussion and debate related to precision medicine are urgently needed to avoid misapplication of resources, hype, iatrogenic interventions, and distraction from established approaches with ongoing utility. Failure to engage in such debate will lead to negative unintended consequences from a revolution that might never come.

PMID: 26902518 [PubMed - indexed for MEDLINE]

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database.

Ophthalmic Genet. 2017 Apr 10;:1-6

Authors: Everage NJ, Bai Y, Loop B, Volkova N, Liu N, Enger C

Abstract
BACKGROUND: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP).
METHODS: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs).
RESULTS: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2-1.8).
CONCLUSIONS: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.

PMID: 28394650 [PubMed - as supplied by publisher]

Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

Nat Med. 2017 Apr 10;:

Authors: Romani L, Oikonomou V, Moretti S, Iannitti RG, D'Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, Fallarino F, Pallotta MT, Servillo G, Ferrari E, Puccetti P, Kroemer G, Pessia M, Maiuri L, Goldstein AL, Garaci E

Abstract
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

PMID: 28394330 [PubMed - as supplied by publisher]

How are the ancient cystic fibrosis patients? Cystic fibrosis diagnosed over 60 years-old.

Respir Med Case Rep. 2017;21:49-51

Authors: Prados C, Lerín M, Cabanillas JJ, Gómez-Carrera L, Álvarez-Sala R, cystic fibrosis group of Neumomadrid

Abstract
BACKGROUND AND AIMS: To specify the prevalence of patients diagnosed with CF at age of ≥60 year-old and to analyze their characteristics.
PATIENTS AND METHODS: Observational study of CF patients which were diagnosed at age ≥60 year-old. The analyzed variables were: age, sex, nationality, lung function parameters, conditions present at diagnosis, microbiological characteristics and genetic findings.
RESULTS: eight patients were included. 7 patients were female (87.5%) with a mean age of 70.6 years (median 71.5 years, range 60-78 years). The most important findings were: sweat test >60 mEq/l; heterozygotes F508del; bronchiectasis in CT; methicillin-sensitive Staphylococcus aureus (50%) in sputum. The most patients presented a normal or mild obstructive lung function.
CONCLUSIONS: CF must also be considered a disease diagnosed in adulthood, incorporating the sweat test within the usual techniques of differential diagnosis in patients with different diseases associated with CF, because genetic counselling is esencial.

PMID: 28393935 [PubMed - in process]

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy.

Crit Rev Biochem Mol Biol. 2017 Apr 10;:1-15

Authors: Barnett SD, Buxton IL

Abstract
S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, is closely tied to GSNOR regulation and defines this enzyme as an important therapeutic target.

PMID: 28393572 [PubMed - as supplied by publisher]