Antiphospholipid syndrome.

Best Pract Res Clin Rheumatol. 2016 Feb;30(1):133-48

Authors: Khamashta M, Taraborelli M, Sciascia S, Tincani A

Abstract
Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of thrombosis (arterial and/or venous), often multiple, and/or pregnancy morbidity. Thrombosis is one of the major disease mechanisms, mainly caused by activating endothelial cells, monocytes, and platelets. At present, the management of APS patients with a history of thrombosis is based on long-term antithrombotic therapy, due to the high rate of recurrent thrombosis (29% per year without treatment). Obstetrical APS includes heterogeneous pregnancy complications whose pathogenesis has been increasingly elucidated in the past years. This is due to the current management and treatment, as 80% of APS patients achieve a live birth. The standard approach of APS is not supported by extensive evidence and the best options for refractory and incomplete cases need to be clarified. New and promising molecules are under investigation.

PMID: 27421221 [PubMed - in process]

Buffering of protons released by mineral formation during amelogenesis in mice.

Eur J Oral Sci. 2016 Jul 16;

Authors: Bronckers AL, Lyaruu DM, Jalali R, DenBesten PK

Abstract
Regulation of pH by ameloblasts during amelogenesis is critical for enamel mineralization. We examined the effects of reduced bicarbonate secretion and the presence or absence of amelogenins on ameloblast modulation and enamel mineralization. To that end, the composition of fluorotic and non-fluorotic enamel of several different mouse mutants, including enamel of cystic fibrosis transmembrane conductance regulator-deficient (Cftr null), anion exchanger-2-deficient (Ae2a,b null), and amelogenin-deficient (Amelx null) mice, was determined by quantitative X-ray microanalysis. Correlation analysis was carried out to compare the effects of changes in the levels of sulfated-matrix (S) and chlorine (Cl; for bicarbonate secretion) on mineralization and modulation. The chloride (Cl(-) ) levels in forming enamel determined the ability of ameloblasts to modulate, remove matrix, and mineralize enamel. In general, the lower the Cl(-) content, the stronger the negative effects. In Amelx-null mice, modulation was essentially normal and the calcium content was reduced least. Retention of amelogenins in enamel of kallikrein-4-deficient (Klk4-null) mice resulted in decreased mineralization and reduced the length of the first acid modulation band without changing the total length of all acidic bands. These data suggest that buffering by bicarbonates is critical for modulation, matrix removal and enamel mineralization. Amelogenins also act as a buffer but are not critical for modulation.

PMID: 27422589 [PubMed - as supplied by publisher]

UDP-glucose promotes neutrophil recruitment in the lung.

Purinergic Signal. 2016 Jul 15;

Authors: Sesma JI, Weitzer CD, Livraghi-Butrico A, Dang H, Donaldson S, Alexis NE, Jacobson KA, Harden TK, Lazarowski ER

Abstract
In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y14 receptors (P2Y14R). However, the physiological/pathophysiological consequences of UDP-sugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the βENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was co-instilled with the P2Y14R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to βENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.

PMID: 27421735 [PubMed - as supplied by publisher]

Sleep and Pain in Pediatric Illness: A Conceptual Review.

CNS Neurosci Ther. 2016 Jul 15;

Authors: Allen JM, Graef DM, Ehrentraut JH, Tynes BL, Crabtree VM

Abstract
BACKGROUND: Sleep disruption is a common comorbidity of pediatric pain. Consequences of pain and disrupted sleep, evidence for the pain-sleep relation, and how aspects of illness, treatment, and pharmacological pain management may contribute to or exacerbate these issues are presented.
AIMS: This conceptual review explored the relation between pain and sleep in children diagnosed with chronic medical or developmental conditions. The goal of this review is to expand upon the literature by examining common themes in sleep disturbances associated with painful conditions across multiple pediatric illnesses. Populations reviewed include youth with intellectual and developmental disabilities (IDD), migraines, cystic fibrosis (CF), sickle cell disease (SCD), cancer, juvenile idiopathic arthritis (JIA), juvenile fibromyalgia (JFM), and functional gastrointestinal disorders (FGIDs).
RESULTS: Consistent evidence demonstrates that children with medical or developmental conditions are more vulnerable to experiencing pain and subjective sleep complaints than healthy peers. Objective sleep concerns are common but often under-studied. Evidence of the pain-sleep relationship exists, particularly in pediatric SCD, IDD, and JIA, with a dearth of studies directly examining this relation in pediatric cancer, JFM, CF, and FGIDs. Findings suggest that assessing and treating pain and sleep disruption is important when optimizing functional outcomes.
CONCLUSION: It is essential that research further examine objective sleep, elucidate the pain-sleep relationship, consider physiological and psychosocial mechanisms of this relationship, and investigate nonpharmacological interventions aimed at improving pain and sleep in vulnerable pediatric populations.

PMID: 27421251 [PubMed - as supplied by publisher]

Comparative proteomic and metabolomic analysis reveal the antiosteoporotic molecular mechanism of icariin from Epimedium brevicornu Maxim.

J Ethnopharmacol. 2016 Jul 12;

Authors: Xue L, Jiang Y, Han T, Zhang N, Qin L, Xin H, Zhang Q

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Icariin, a principal flavonoid glycoside of Epimedium brevicornu Maxim, has been widely proved to possess antiosteoporotic activity with promoting bone frormation and decreasing bone resorption. However, the involving mechanisms remain unclear.
AIM OF THE STUDY: To clear a global insight of signal pathways involved in anti-osteoporotic mechanism of icariin at proteins and metabolites level by integrating the proteomics and NMR metabonomics, in a systems biology approach.
MATERIAL AND METHODS: Mice were divided into sham, OVX model and icariin-treated OVX group, after 90 days treatment, difference gel electrophoresis combined with MALDI-TOF/TOF proteomics analysis on bone femur and serum metabolomics were carried out for monitor intracellular processes and elucidate anti-osteoporotic mechanism of icariin. Osteoblast and osteoclast were applied to evaluate the potential signal pathways.
RESULTS: 23 proteins in bone femur, and 8 metabolites in serum, were significantly altered and identified, involving in bone remodeling, energy metabolism, cytoskeleton, lipid metabolism, MAPK signaling, Ca(2+) signaling et, al. Furthermore, animal experiment show icariin could enhance the BMD and BMC, decrease CTX-I level in ovariectomized mice. The mitochondrial membrane potential and the intracellular ATP levels were increased significantly, and the cytoskeleton were improved in icariin-treatment osteoblast and osteoclast. Icariin also increased mRNA expression of Runx2 and osterix of OB, decreased CTR and CAII mRNA expression and protein expression of P38 and JNK. However, icariin did not reveal any inhibition of the collagenolytic activity of cathepsin K, mRNA expression of MMP-9 and protein expression of ERK in osteoclast.
CONCLUSION: we consider icariin as multi-targeting compounds for treating with osteoporosis, involve intiating osteoblastogenesis, inhibiting adipogenesis, and preventing osteoclast differentiation.

PMID: 27422162 [PubMed - as supplied by publisher]

Mesoscopic Model of Neuronal System Deficits in Multiple Sclerosis.

J Theor Biol. 2016 Jul 12;

Authors: Safarbali B, Hadaeghi F, Gharibzadeh S

Abstract
Multiple Sclerosis (MS) is a devastating autoimmune disease which deteriorates the connections in central nervous system (CNS) through the attacks to oligodendrocytes. Studying its origin and progression, in addition to clinical developments such as MRI brain images, cerebrospinal fluid (CSF) variation and quantitative measures of disability (EDSS), which sought to early diagnosis and efficient therapy, there is an increasing interest in developing computational models using the experimental data obtained from MS patients. From the perspective of mathematical modelling, although the origin of systemic symptoms might be attributed to cellular phenomena in microscopic level such as axonal demyelination, symptoms mainly are observed in macroscopic levels. How to fill the gap between these two levels of system modelling, however, remains as a challenge in systems biology studies. Trying to provide a conceptual framework to bridge between these two levels of modelling in systems biology, we have suggested a mesoscopic model composed of interacting neuronal population, which successfully replicates the changes in neuronal population synchrony due to MS progression.

PMID: 27422137 [PubMed - as supplied by publisher]

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

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/16

PubMed comprises more than 24 million 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.

Suppressive effects of methylthiouracil on polyphosphate-mediated vascular inflammatory responses.

J Cell Mol Med. 2016 Jul 15;

Authors: Min G, Ku SK, Jeong S, Baek MC, Bae JS

Abstract
Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro-inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP-activated HUVECs and mice. MTU suppressed the PolyP-mediated vascular barrier permeability, up-regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor-κB, tumour necrosis factor-α and interleukin-6. Furthermore, MTU demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.

PMID: 27421058 [PubMed - as supplied by publisher]

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

FEBS Open Bio. 2016 May;6(5):442-60

Authors: Kozako T, Soeda S, Yoshimitsu M, Arima N, Kuroki A, Hirata S, Tanaka H, Imakyure O, Tone N, Honda S, Soeda S

Abstract
Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

PMID: 27419050 [PubMed]

Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors.

Meta Gene. 2016 Sep;9:159-64

Authors: Deshpande N, V S, V V RK, H V V M, M S, Banerjee R, Tandan M, D NR

Abstract
INTRODUCTION AND OBJECTIVE: Polymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects.
METHODS: DNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH.
RESULTS: Of the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers.
CONCLUSION: Our study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.

PMID: 27419077 [PubMed]

Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature.

Open Forum Infect Dis. 2016 Apr;3(2):ofw116

Authors: Galiatsatos P, Melia MT, Silhan LL

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development.

PMID: 27419184 [PubMed]

Is it feasible to radiologically monitor the evolution of non-CF bronchiectasis?

Respirology. 2016 Aug;21(6):1137

Authors: Crivelli P, Sverzellati N, Sotgiu G, Aliberti S

PMID: 27416880 [PubMed - in process]

When communities collide.

Elife. 2016;5

Authors: Merritt J, Kuehn S

Abstract
A new model demonstrates how microbial communities can survive encounters with other communities as a cohesive group, even in the complete absence of cooperation.

PMID: 27420812 [PubMed - as supplied by publisher]

Optimizing cyanobacterial product synthesis: Meeting the challenges.

Bioengineered. 2016 Jul 15;:0

Authors: Zavřel T, Červený J, Knoop H, Steuer R

Abstract
The synthesis of renewable bioproducts using photosynthetic microorganisms holds great promise. Sustainable industrial applications, however, are still scarce and the true limits of phototrophic production remain unknown. One of the limitations of further progress is our insufficient understanding of the quantitative changes in photoautotrophic metabolism that occur during growth in dynamic environments. We argue that a proper evaluation of the intra- and extracellular factors that limit phototrophic production requires the use of highly-controlled cultivation in photobioreactors, coupled to real-time analysis of production parameters and their evaluation by predictive computational models. In this addendum, we discuss the importance and challenges of systems biology approaches for the optimization of renewable biofuels production. As a case study, we present the utilization of a state-of-the-art experimental setup together with a stoichiometric computational model of cyanobacterial metabolism for quantitative evaluation of ethylene production by a recombinant cyanobacterium Synechocystis sp. PCC 6803.

PMID: 27420605 [PubMed - as supplied by publisher]

Developmentally regulated long non-coding RNAs in Xenopus tropicalis.

Dev Biol. 2016 Jul 11;

Authors: Forouzmand E, Owens ND, Blitz IL, Paraiso KD, Khokha MK, Gilchrist MJ, Xie X, Cho KW

Abstract
Advances in RNA sequencing technologies have led to the surprising discovery that a vast number of transcripts emanate from regions of the genome that are not part of coding genes. Although some of the smaller ncRNAs such as microRNAs have well-characterized functions, the majority of long ncRNA (lncRNA) functions remain poorly understood. Understanding the significance of lncRNAs is an important challenge facing biology today. A powerful approach to uncovering the function of lncRNAs is to explore temporal and spatial expression profiling. This may be particularly useful for classes of lncRNAs that have developmentally important roles as the expression of such lncRNAs will be expected to be both spatially and temporally regulated during development. Here, we take advantage of our ultra-high frequency (temporal) sampling of Xenopus embryos to analyze gene expression trajectories of lncRNA transcripts over the first 3 days of development. We computationally identify 5689 potential single- and multi-exon lncRNAs. These lncRNAs demonstrate clear dynamic expression patterns. A subset of them displays highly correlative temporal expression profiles with respect to those of the neighboring genes. We also identified spatially localized lncRNAs in the gastrula stage embryo. These results suggest that lncRNAs have regulatory roles during early embryonic development.

PMID: 27418388 [PubMed - as supplied by publisher]

A roadmap for biocatalysis - functional and spatial orchestration of enzyme cascades.

Microb Biotechnol. 2016 Jul 15;

Authors: Schmidt-Dannert C, Lopez-Gallego F

Abstract
Advances in biological engineering and systems biology have provided new approaches and tools for the industrialization of biology. In the next decade, advanced biocatalytic systems will increasingly be used for the production of chemicals that cannot be made by current processes and/or where the use of enzyme catalysts is more resource efficient with a much reduced environmental impact. We expect that in the future, manufacture of chemicals and materials will utilize both biocatalytic and chemical synthesis synergistically. The realization of such advanced biomanufacturing processes currently faces a number of major challenges. Ready-to-deploy portfolios of biocatalysts for design to production must be created from biological diverse sources and through protein engineering. Robust and efficient multi-step enzymatic reaction cascades must be developed that can operate simultaneously in one-pot. For this to happen, bio-orthogonal strategies for spatial and temporal control of biocatalyst activities must be developed. Promising approaches and technologies are emerging that will eventually lead to the design of in vitro biocatalytic systems that mimic the metabolic pathways and networks of cellular systems which will be discussed in this roadmap.

PMID: 27418373 [PubMed - as supplied by publisher]

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

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/15

PubMed comprises more than 24 million 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.

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

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/15

PubMed comprises more than 24 million 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.

Genetic polymorphisms study of pharmacogenomic VIP variants in Han ethnic of China's Shaanxi province.

Environ Toxicol Pharmacol. 2016 Jun 27;46:27-35

Authors: Jin T, Zhao R, Shi X, He N, He X, Ouyang Y, Wang H, Wang B, Kang L, Yuan D

Abstract
BACKGROUND: Multiple factors include genetic and non-genetic interactions induce to different drug response among different individuals. Lots of researches proved that different frequencies of genetic variants exists different ethnic groups. The aim of this study was to screen Han volunteers in Shaanxi for VIP gene polymorphisms.
MATERIALS AND METHODS: We genotyped 80 Very Important Pharmacogenes (VIP) (selected from the PharmGKB database) in 192 unrelated, healthy Han ethnic adults from Shaanxi, the northwest of China, and then analyzed genotyping data wtih Structure and F-statistics (Fst) analysis.
RESULTS: We compared our data with 15 other populations (Deng, Kyrgyz, Tajik, Uygur and 11 HapMap populations), and found the frequency distribution of Han population in Shaanxi is most similar with CHB. Also, Structure and Fst showed that Shaanxi Han has a closest genetic background with CHB.
CONCLUSIONS: Our study have supplemented the Han Chinese data related to pharmacogenomics and illustrated differences in genotypic frequencies of selected VIP variants' among the Han population and 15 other populations.

PMID: 27414743 [PubMed - as supplied by publisher]

Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study.

BMC Cancer. 2016;16:467

Authors: Kasi PM, Kotani D, Cecchini M, Shitara K, Ohtsu A, Ramanathan RK, Hochster HS, Grothey A, Yoshino T

Abstract
BACKGROUND: TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan.
METHODS: CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm(3)). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test.
RESULTS: Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs.
CONCLUSIONS: Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.

PMID: 27412464 [PubMed - in process]