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Characterizing the differential roles of striatal 5-HT1A auto- and hetero-receptors in the reduction of l-DOPA-induced dyskinesia.

Exp Neurol. 2017 Jun;292:168-178

Authors: Meadows SM, Chambers NE, Conti MM, Bossert SC, Tasber C, Sheena E, Varney M, Newman-Tancredi A, Bishop C

Abstract
l-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to l-DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5-HT1A receptors (5-HT1AR) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HT1AR agonists often compromise clinical efficacy or display intrinsic side effects and their site(s) of actions remain debatable. Recently, highly selective G-protein biased 5-HT1AR agonists, F13714 and F15599, were shown to potently target 5-HT1A auto- or hetero-receptors, respectively. The current investigation sought to identify the signaling mechanisms and neuroanatomical substrates by which 5-HT1AR produce behavioral effects. In experiment 1, hemi-parkinsonian, l-DOPA-primed rats received systemic injections of vehicle, F13714 (0.01 or 0.02mg/kg), or F15599 (0.06 or 0.12mg/kg) 5min prior to l-DOPA (6mg/kg), after which LID, motor performance and 5-HT syndrome were rated. Both compounds significantly reduced LID, without affecting motor performance, however, acute administration of F13714 significantly induced 5-HT syndrome at anti-dyskinetic doses. In experiment 2, we elucidated the role of striatal 5-HT1AR in the effects of F13714 and F15599. Hemi-parkinsonian, l-DOPA-primed rats received bilateral intra-striatal microinjections of either F13714 (0, 2 or 10μg/side) or F15599 (0, 10 or 30μg/side) 5min prior to systemic l-DOPA (6mg/kg). Intra-striatal effects mimicked systemic effects, suggesting that striatal 5-HT1AR sub-populations play an important role in the anti-LID and pro-5-HT syndrome profiles of F13714 and F15599. Finally, in experiment 3, we examined the effects of F13714 and F15599 on D1 receptor (D1R) agonist-induced dyskinesia by administering either compound 5min prior to SKF 38393 (2mg/kg). While F13714 resulted in a mild delay in D1R-mediated dyskinesia, F15599 had no effect. Collectively these data suggest that the F-series compounds articulate their anti-LID effects through activation of a diverse set of striatal 5-HT1A hetero-receptor populations.

PMID: 28342749 [PubMed - indexed for MEDLINE]

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Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma.

J Clin Oncol. 2017 Apr 10;35(11):1194-1202

Authors: Kohn CG, Zeichner SB, Chen Q, Montero AJ, Goldstein DA, Flowers CR

Abstract
Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.

PMID: 28221865 [PubMed - indexed for MEDLINE]

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Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats.

Int J Environ Res Public Health. 2016 Nov 30;13(12):

Authors: Zhang X, Zhang X, Yuan B, Ren L, Zhang T, Lu G

Abstract
Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0-80 and 0-120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006's NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.

PMID: 27916918 [PubMed - indexed for MEDLINE]

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Re: Antipsychotic medication side effect assessment tools: A systematic review.

Aust N Z J Psychiatry. 2017 02;51(2):199-200

Authors: Ashoorian D, Rock D, Davidson R, Clifford R

PMID: 27422561 [PubMed - indexed for MEDLINE]

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N-acetylcysteine regimens for paracetamol overdose: Time for a change?

Emerg Med Australas. 2016 Dec;28(6):749-751

Authors: Wong A, Graudins A

Abstract
Paracetamol overdose is one of the commonest pharmaceutical poisonings in the world. For nearly four decades, intravenous acetylcysteine regimens have been used to treat most patients successfully and prevent or mitigate hepatotoxicity. However, the rate of occurrence of adverse reactions to acetylcysteine is quite high, and there is a potential for these to be reduced. Recent studies show that distributing the loading-dose of acetylcysteine over the first few hours of treatment may decrease the incidence of adverse reactions. In addition, varying the duration of acetylcysteine administration may potentially benefit certain cohorts of poisoned patients, depending on their risk of developing hepatotoxicity.

PMID: 27193944 [PubMed - indexed for MEDLINE]

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Funding Opportunity PA-17-442 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages administrative supplements for the NINDS Research Education Program for Residents and Fellows in Neurology, Neurosurgery, Neuropathology, Neuroradiology and Emergency Medicine (R25, PAR-13-384 and subsequent reissuances)

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Funding Opportunity PAR-17-439 from the NIH Guide for Grants and Contracts. The National Institute of Allergy and Infectious Diseases (NIAID) announces a program that provides NIAID-supported K01, K08, and K23 recipients with the opportunity to apply for Small Research Grant (R03) support at some point during the final two years of their K award. Through the use of this mechanism, NIAID seeks to enhance the capability of its K01, K08, and K23 award recipients to conduct research as they complete their transition to fully independent investigator status (e.g., R01 support). The R03 grant mechanism supports different types of projects, including pilot and feasibility studies; secondary analysis of existing data; small, self-contained research projects; development of research methodology; and development of new research technology. The R03 is, therefore, intended to support research projects that can be carried out in a short period of time with limited resources and that may provide preliminary data to support a subsequent R01, or equivalent, application.

Funding Opportunity RFA-AG-18-016 from the NIH Guide for Grants and Contracts. The overall goal of this funding announcement is to elicit applications for novel strategies to enhance referral, participation, and adherence in cardiac rehabilitation (CR) of older and vulnerable patients who are eligible for CR under current Medicare eligibility criteria. Specifically, NIA seeks clinical trials that address one or more specific age-related factors including patient-related issues, CR program goals and components, and CR program setting-related aspects. These three age-related issues represent distinct, but potentially interrelated, areas that are impacted by advancing age and are not currently addressed in traditional CR programs. Determination of the specific aspects of CR programs that may be better suited to medically complex and vulnerable older adults, such as eligibility, patient-centered goals and outcomes, and novel components and delivery systems may ultimately improve referral, enrollment, completion and overall benefit of this Medicare-supported resource. Successful modified programs should strive to improve function, independence and quality of life while reducing disability, future CV events, readmissions, morbidity and mortality.

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The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer.

Gut Liver. 2016 Sep 15;10(5):665-71

Authors: Amin S, Boffetta P, Lucas AL

Abstract
Survival from pancreatic cancer remains poor. Conventional treatment has resulted in only marginal improvements in survival compared with survival in the previous several decades. Thus, considerable interest has emerged regarding the potential use of common pharmaceutical agents as chemopreventative and chemotherapeutic options. Aspirin, metformin, statins, β-blockers, and bisphosphonates have biologically plausible mechanisms to inhibit pancreatic neoplasia, whereas dipeptidyl-peptidase 4 inhibitors may promote it. Regardless, real-world epidemiological data remain inconclusive. This review examines the hypotheses, evidence, and current state of the literature for each of these medications and their potential roles in the prevention and treatment of pancreatic cancer.

PMID: 27563018 [PubMed - indexed for MEDLINE]

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International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Am J Hum Genet. 2017 May 04;100(5):695-705

Authors: Boycott KM, Rath A, Chong JX, Hartley T, Alkuraya FS, Baynam G, Brookes AJ, Brudno M, Carracedo A, den Dunnen JT, Dyke SOM, Estivill X, Goldblatt J, Gonthier C, Groft SC, Gut I, Hamosh A, Hieter P, Höhn S, Hurles ME, Kaufmann P, Knoppers BM, Krischer JP, Macek M, Matthijs G, Olry A, Parker S, Paschall J, Philippakis AA, Rehm HL, Robinson PN, Sham PC, Stefanov R, Taruscio D, Unni D, Vanstone MR, Zhang F, Brunner H, Bamshad MJ, Lochmüller H

Abstract
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

PMID: 28475856 [PubMed - indexed for MEDLINE]

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Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis.

J Exp Med. 2016 Jul 25;213(8):1497-512

Authors: Rowe RG, Wang LD, Coma S, Han A, Mathieu R, Pearson DS, Ross S, Sousa P, Nguyen PT, Rodriguez A, Wagers AJ, Daley GQ

Abstract
For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.

PMID: 27401346 [PubMed - indexed for MEDLINE]

Minimally inconsistent reasoning in Semantic Web.

PLoS One. 2017;12(7):e0181056

Authors: Zhang X

Abstract
Reasoning with inconsistencies is an important issue for Semantic Web as imperfect information is unavoidable in real applications. For this, different paraconsistent approaches, due to their capacity to draw as nontrivial conclusions by tolerating inconsistencies, have been proposed to reason with inconsistent description logic knowledge bases. However, existing paraconsistent approaches are often criticized for being too skeptical. To this end, this paper presents a non-monotonic paraconsistent version of description logic reasoning, called minimally inconsistent reasoning, where inconsistencies tolerated in the reasoning are minimized so that more reasonable conclusions can be inferred. Some desirable properties are studied, which shows that the new semantics inherits advantages of both non-monotonic reasoning and paraconsistent reasoning. A complete and sound tableau-based algorithm, called multi-valued tableaux, is developed to capture the minimally inconsistent reasoning. In fact, the tableaux algorithm is designed, as a framework for multi-valued DL, to allow for different underlying paraconsistent semantics, with the mere difference in the clash conditions. Finally, the complexity of minimally inconsistent description logic reasoning is shown on the same level as the (classical) description logic reasoning.

PMID: 28750030 [PubMed - in process]