Literature Watch
New biologics in the treatment of rare glomerular diseases of childhood.
New biologics in the treatment of rare glomerular diseases of childhood.
Curr Opin Pharmacol. 2017 04;33:27-33
Authors: Cravedi P, Angeletti A, Remuzzi G
Abstract
Minimal change disease and focal segmental glomerulosclerosis are rare but important causes of end-stage kidney disease in children. Though their pathogenesis is still unclear, evidence of immune abnormalities provided the background for the use of immunosuppressive drugs, such as corticosteroids, calcineurin inhibitors, antiproliferative and alkylating agents. Unfortunately, these treatments fail to achieve a sustained remission in a significant portion of patients and are burdened by significant toxicities. Recent developments of new biologics, including anti-CD20 monoclonal antibodies rituximab and ofatumumab, offered the opportunity to selectively target immune cell subsets or activation pathways, leading to more effective and safer hypothesis-driven treatments.
PMID: 28456094 [PubMed - indexed for MEDLINE]
Three-Dimensional Approach for Modeling Nasal Mucociliary Clearance via Computational Fluid Dynamics (CFD)
Formulation drug product quality attributes in dermal physiologically-based pharmacokinetic models for topical dermatological drug products and transdermal delivery systems
Revision: Notice of Correction to Application Instructions in RFA-HL-19-008: Limited Competition: Clinical Research Sites for the MACS/WIHS Combined Cohort Study (MACS/WIHS-CCS) (U01 Clinical Trial Not Allowed)
NIA Limited Competition: Renewals of, and Revisions to, Existing Alzheimer's Disease Patient Registry Cooperative Agreement Awards (U01 - Clinical Trial Not Allowed)
Notice of Intent to Publish a Funding Opportunity Announcement for BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00)
A conserved Shh cis-regulatory module highlights a common developmental origin of unpaired and paired fins.
A conserved Shh cis-regulatory module highlights a common developmental origin of unpaired and paired fins.
Nat Genet. 2018 Mar 19;:
Authors: Letelier J, de la Calle-Mustienes E, Pieretti J, Naranjo S, Maeso I, Nakamura T, Pascual-Anaya J, Shubin NH, Schneider I, Martinez-Morales JR, Gómez-Skarmeta JL
Abstract
Despite their evolutionary, developmental and functional importance, the origin of vertebrate paired appendages remains uncertain. In mice, a single enhancer termed ZRS is solely responsible for Shh expression in limbs. Here, zebrafish and mouse transgenic assays trace the functional equivalence of ZRS across the gnathostome phylogeny. CRISPR/Cas9-mediated deletion of the medaka (Oryzias latipes) ZRS and enhancer assays identify the existence of ZRS shadow enhancers in both teleost and human genomes. Deletion of both ZRS and shadow ZRS abolishes shh expression and completely truncates pectoral fin formation. Strikingly, deletion of ZRS results in an almost complete ablation of the dorsal fin. This finding indicates that a ZRS-Shh regulatory module is shared by paired and median fins and that paired fins likely emerged by the co-option of developmental programs established in the median fins of stem gnathostomes. Shh function was later reinforced in pectoral fin development with the recruitment of shadow enhancers, conferring additional robustness.
PMID: 29556077 [PubMed - as supplied by publisher]
New drug candidates for treatment of atypical meningiomas: An integrated approach using gene expression signatures for drug repurposing.
New drug candidates for treatment of atypical meningiomas: An integrated approach using gene expression signatures for drug repurposing.
PLoS One. 2018;13(3):e0194701
Authors: Zador Z, King AT, Geifman N
Abstract
BACKGROUND: Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision and radiotherapy remains the mainstay therapy but medical treatments are limited. We explore new drug candidates using computational drug repurposing based on the gene expression signature of atypical meningioma tissue with subsequent analysis of drug-generated expression profiles. We further explore possible mechanisms of action for the identified drug candidates using ingenuity pathway analysis (IPA).
METHODS: We extracted gene expression profiles for atypical meningiomas (12 samples) and normal meningeal tissue (4 samples) from the Gene Expression Omnibus, which were then used to generate a gene signature comprising of 281 differentially expressed genes. Drug candidates were explored using both the Board Institute Connectivity Map (cmap) and Library of Integrated Network-Based Cellular Signatures (LINCS). Functional analysis of significant differential gene expression for drug candidates was performed with IPA.
RESULTS: Using our integrated approach, we identified multiple, already licensed, drug candidates such as emetine, verteporfin, phenoxybenzamine and trazodone. Analysis with IPA revealed that these drugs target signal cascades potentially relevant in pathogenesis of meningiomas, particular examples are the effect on ERK by trazodone, MAP kinases by emetine, and YAP-1 protein by verteporfin.
CONCLUSION: Gene expression profiling and use of drug expression profiles have yielded several plausible drug candidates for treating atypical meningioma, some of which have already been suggested by preceding studies. Although our analyses suggested multiple anti-tumour mechanisms for these drugs, further in vivo studies are required for validation.
IMPORTANCE OF THE STUDY: To our knowledge this is the first study which combines relatively new, yet established computational techniques to identify additional treatments for a difficult to manage cerebral neoplasm. Beyond proposing already approved drug candidates in the management of atypical meningioma the study highlights the promise held by computational techniques in improving our management strategies.
PMID: 29558515 [PubMed - in process]
Extensive impact of non-antibiotic drugs on human gut bacteria.
Extensive impact of non-antibiotic drugs on human gut bacteria.
Nature. 2018 Mar 19;:
Authors: Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A
Abstract
A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug-microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.
PMID: 29555994 [PubMed - as supplied by publisher]
Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.
Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.
Drug Des Devel Ther. 2018;12:455-462
Authors: Chang W, Teng J
Abstract
Background: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD.
Patients and methods: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received β-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5-20 mg/d. Patients in the control group only received memantine 5-20 mg/d. The Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Activities of Daily Living (ADL) were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks.
Results: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001), lower average ADL score (p=0.00002), and lower average CDR score (p=0.030). Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60-74-years-old male patients with moderate AD.
Conclusion: These results demonstrated that the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored.
PMID: 29551889 [PubMed - in process]
The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.
The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.
J Ocul Pharmacol Ther. 2017 Dec;33(10):718-734
Authors: Eaton JS, Miller PE, Bentley E, Thomasy SM, Murphy CJ
Abstract
PURPOSE: To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development.
METHODS: Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science.
RESULTS: The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species.
CONCLUSIONS: The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.
PMID: 29239680 [PubMed - indexed for MEDLINE]
A single center, open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults.
A single center, open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults.
Vaccine. 2017 Aug 03;35(34):4315-4320
Authors: Recuenco S, Warnock E, Osinubi MOV, Rupprecht CE
Abstract
In the USA, rabies vaccines (RVs) are licensed for intramuscular (IM) use only, although RVs are licensed for use by the intradermal (ID) route in many other countries. Recent limitations in supplies of RV in the USA reopened discussions on the more efficient use of available biologics, including utilization of more stringent risk assessments, and potential ID RV administration. A clinical trial was designed to compare the immunogenic and adverse effects of a purified chicken embryo cell (PCEC) RV administered ID or IM. Enrollment was designed in four arms, ID Pre-Exposure Prophylaxis (Pre-EP), IM Pre-EP, ID Booster, and IM Booster vaccination. Enrollment included 130 adult volunteers. The arms with IM administration received vaccine according to the current ACIP recommendations: Pre-EP, three 1mL (2.5 I.U.) RV doses, each on day 0, 7, and 21; or a routine Booster, one 1ml dose. The ID groups received the same schedule, but doses administered were in a volume of 0.1mL (0.25 I.U.). The rate of increase in rabies virus neutralizing antibody titers 14-21days after vaccination were similar in the ID and correspondent IM groups. The GMT values for ID vaccination were slightly lower than those for IM vaccination, for both naïve and booster groups, and these differences were statistically significant by t-test. Fourteen days after completing vaccination, all individuals developed RV neutralizing antibody titers over the minimum arbitrary value obtained with the rapid fluorescent focus inhibition test (RFFIT). Antibodies were over the set threshold until the end of the trial, 160days after completed vaccination. No serious adverse reactions were reported. Most frequent adverse reactions were erythema, induration and tenderness, localized at the site of injection. Multi use of 1mL rabies vaccine vials for ID doses of 0.1 was demonstrated to be both safe and inmunogenic.
PMID: 28688782 [PubMed - indexed for MEDLINE]
The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies.
The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies.
Immunotherapy. 2017 Jun;9(7):579-587
Authors: Ciccarese C, Iacovelli R, Bria E, Modena A, Massari F, Brunelli M, Fantinel E, Bimbatti D, Zamboni GA, Artibani W, Tortora G
Abstract
AIM: Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment-related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti-PD1/PD-L1 mAbs.
RESULTS: 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any-grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT.
PMID: 28595514 [PubMed - indexed for MEDLINE]
Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer.
Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer.
J Immunother. 2017 Jul/Aug;40(6):249-251
Authors: Leonardi GC, Oxnard GR, Haas A, Lang JP, Williams JS, Awad MM
Abstract
Programmed cell death protein 1 pathway inhibitors are now routinely administered to patients with non-small cell lung cancer, and prompt recognition of immune-related adverse events is critical to managing serious drug toxicities. Here, we describe a 66-year-old man with no known history of diabetes who presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for lung adenocarcinoma. Autoimmune diabetes is a rare but potentially life-threatening complication of programmed cell death protein 1 inhibitors.
PMID: 28557813 [PubMed - indexed for MEDLINE]
Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.
Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.
J Immunother. 2017 Jul/Aug;40(6):221-223
Authors: Diamantopoulos PT, Tsatsou K, Benopoulou O, Anastasopoulou A, Gogas H
Abstract
Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.
PMID: 28498142 [PubMed - indexed for MEDLINE]
[Stroke prophylaxis in atrial fibrillation : When, how and for whom?]
[Stroke prophylaxis in atrial fibrillation : When, how and for whom?]
Herz. 2017 Jun;42(4):373-379
Authors: Maurer T, Sohns C
Abstract
In patients suffering from atrial fibrillation (AF), modern antithrombotic therapy and anticoagulation strategies should be individualized based on shared decision making including patient preferences and the absolute and relative risks of stroke and bleeding. Estimation of the individual risk for stroke is still based on the CHA2DS2-VASc score. Based on the most recent guidelines for the management of AF, oral anticoagulation therapy should be considered for men with a CHA2DS2-VASc score ≥1 and women with a score ≥2, balancing the expected stroke reduction, risk of bleeding and patient preference. Both vitamin K antagonists and novel oral anticoagulants (NOAC) are effective for the prevention of stroke in AF. In AF patients treated with NOAC, kidney function should be regularly monitored to refine risk estimation and to enable dose adaptation. As an alternative to oral anticoagulation therapy, left atrial appendage occlusion may be considered for stroke prevention in patients with AF and contraindications for long-term anticoagulant treatment. This article provides a review of the indications and contraindications of modern stroke prophylaxis and discusses the approach to frequent clinical scenarios, such as treatment of patients with an acute coronary syndrome, coronary stent intervention or catheter ablation of AF.
PMID: 28439617 [PubMed - indexed for MEDLINE]
Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.
Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.
Curr HIV Res. 2017;15(3):216-224
Authors: Gallant J, Moyle G, Berenguer J, Shalit P, Cao H, Liu YP, Myers J, Rosenblatt L, Yang L, Szwarcberg J
Abstract
OBJECTIVES: Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.4%, respectively, at Week 48; and 72.1% and 74.1% at Week 144), and with comparable safety and tolerability. Here, we describe virologic response and treatment discontinuation by a wider range of subgroups than previously presented.
METHODS: Subgroup analyses by baseline CD4 count (≤200, 201-350, >350 cells/mm3), baseline HIV-1 RNA level (≤100,000, >100,000 copies/mL), race, sex, and age (<40, ≥40 years) evaluated ATV+COBI versus ATV+RTV univariate odds ratios (ORs) for virologic success (viral load <50 copies/mL, intention-to-treat US Food and Drug Administration Snapshot algorithm) and discontinuation due to adverse events (AEs) at Weeks 48 and 144. Of 692 patients randomized, 344 received ATV+COBI and 348 ATV+RTV.
RESULTS: ATV+COBI versus ATV+RTV ORs for virologic success did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.90; 95% confidence interval [CI]: 0.64, 1.26) or within subgroups, except in females, for whom ATV+COBI was favored at Week 144 (OR 2.36; 95% CI: 1.02, 5.47). However, there were more discontinuations due to withdrawal of consent and pregnancies in females receiving ATV+RTV versus ATV+COBI. ORs for discontinuation due to AEs did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.98; 95% CI: 0.61, 1.58) or within subgroups.
CONCLUSION: These findings indicate that both ATV+COBI and ATV+RTV, each with FTC/TDF, are effective and well-tolerated treatment options across a wide demographic range of HIV-infected patients.
PMID: 27774892 [PubMed - indexed for MEDLINE]
pharmacogenomics; +12 new citations
12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/03/20
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.
"systems biology"; +54 new citations
54 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/03/20
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.
Generation of two induced pluripotent stem cell (iPSC) lines from p.F508del Cystic Fibrosis patients.
Generation of two induced pluripotent stem cell (iPSC) lines from p.F508del Cystic Fibrosis patients.
Stem Cell Res. 2018 Mar 11;29:1-5
Authors: Fleischer A, Lorenzo IM, Palomino E, Aasen T, Gómez F, Servera M, Asensio VJ, Gálvez V, Izpisúa-Belmonte JC, Bachiller D
Abstract
Cystic Fibrosis (CF) is a monogenic, lethal disease caused by mutations in the cystic fibrosis transmembrane conductance (CFTR) gene. Here we report the production of CF-iPS cell lines from two different p.F508del homozygous female patients (Table 1). Two different primary cell types, skin fibroblasts and keratinocytes, were transfected with retroviral cocktails containing four: c-MYC, KLF4, OCT4 and SOX2 (MKOS) or three: KLF4, OCT4 and SOX2 (KOS) reprogramming factors. Two fibroblast-derived MKOS lines are described in the main text. The lines carry the p.F508del mutation, have a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.
PMID: 29554588 [PubMed - as supplied by publisher]
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