Association Study of Serotonin 3 Receptor Subunit Gene Variants in Antipsychotic-Induced Weight Gain.

Neuropsychobiology. 2017 May 23;74(3):169-175

Authors: Zai CC, Tiwari AK, Chowdhury NI, Brandl EJ, Shaikh SA, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ

Abstract
BACKGROUND: Schizophrenia (SCZ) is a chronic severe neuropsychiatric disorder, where pharmacological treatment has been hindered by adverse effects, including antipsychotic-induced weight gain (AIWG) and related complications. Genetic studies have been exploring the appetite regulation and energy homeostasis pathways in AIWG with some promising leads. The serotonin system has been shown to participate in these pathways.
METHODS: In the current study, we examined single nucleotide polymorphisms across the serotonin receptor genes HTR3A and HTR3B. Prospective weight change was assessed for a total of 149 SCZ patients of European ancestry.
RESULTS: We did not find the tested HTR3A or HTR3B gene markers to be associated with AIWG in our sample.
CONCLUSION: Our preliminary findings suggest that these receptors may not play a major role in predicting AIWG.

PMID: 28531893 [PubMed - as supplied by publisher]

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis: MR Imaging of Airway Mucus Contrasts as a Tool for Diagnosis.

Radiology. 2017 May 22;:162350

Authors: Dournes G, Berger P, Refait J, Macey J, Bui S, Delhaes L, Montaudon M, Corneloup O, Chateil JF, Marthan R, Fayon M, Laurent F

Abstract
Purpose To assess the diagnostic accuracy of mucus contrast characterization by using magnetic resonance (MR) imaging to discriminate allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Materials and Methods The study was approved by the local Ethics Committee, and all patients or their parents gave written informed consent. One hundred ten consecutive patients with CF were screened between January 2014 and July 2015. All patients underwent a non-contrast material-enhanced MR protocol that included routine T1-weighted and T2-weighted sequences. The presence of mucus with both high T1 and low T2 signal intensities and the so-called inverted mucoid impaction signal (IMIS) sign was qualitatively and quantitatively assessed by two physicians who were blinded to all other data. The reference standard for a diagnosis of ABPA was the criteria of the Cystic Fibrosis Foundation Consensus Conference. ABPA status was followed up for 1 year. Reproducibility was assessed by using the κ test, correlation was assessed by using the Spearman coefficient, and diagnostic accuracy was assessed by calculating the sensitivity and specificity of IMIS. Results One hundred eight patients with CF were included (mean age, 20 years ± 11 [standard deviation]; range, 6-53 years): 18 patients with ABPA and 90 patients without ABPA. At the lobar level, inter- and intrareader reproducibility were very good (κ > 0.90). IMIS had 94% sensitivity (95% confidence interval [CI]: 73%, 99%) and 100% specificity (95% CI: 96%, 100%) for the diagnosis of ABPA. A complete resolution of IMIS was observed in patients with ABPA after 3 months of specific treatment that was significantly correlated with decrease in total immunoglobulin E level (ρ = 0.47; P = .04). Conclusion The IMIS sign was both specific and sensitive for the diagnosis of ABPA in CF. Allergic fungal inflammation appears to induce characteristic modifications of mucus contrasts that are assessable by using a noninvasive, contrast material-free, and radiation-free method. (©) RSNA, 2017 Online supplemental material is available for this article.

PMID: 28530849 [PubMed - as supplied by publisher]

EIT based pulsatile impedance monitoring during spontaneous breathing in cystic fibrosis.

Physiol Meas. 2017 Jun;38(6):1214-1225

Authors: Krueger-Ziolek S, Schullcke B, Gong B, Müller-Lisse U, Moeller K

Abstract
OBJECTIVE: Evaluating the lung function in patients with obstructive lung disease by electrical impedance tomography (EIT) usually requires breathing maneuvers containing deep inspirations and forced expirations. Since these maneuvers strongly depend on the patient's co-operation and health status, normal tidal breathing was investigated in an attempt to develop continuous maneuver-free measurements.
APPROACH: Ventilation related and pulsatile impedance changes were systematically analyzed during normal tidal breathing in 12 cystic fibrosis (CF) patients and 12 lung-healthy controls (HL). Tidal breaths were subdivided into three inspiratory (In1, In2, In3) and three expiratory (Ex1, Ex2, Ex3) sections of the same amplitude of global impedance change. Maximal changes of the ventilation and the pulsatile impedance signal occurring during these sections were determined (▵I V and ▵I P). Differences in ▵I V and ▵I P among sections were ascertained in relation to the first inspiratory section. In addition, ▵I V/▵I P was calculated for each section.
MAIN RESULTS: Medians of changes in ▵I V were  <0.05% in all sections for both subject groups. Both groups showed a similar pattern of ▵I P changes during tidal breathing. Changes in ▵I P first decreased during inspiration (In2), then increased towards the end of inspiration (In3) and reached a maximum at the beginning of expiration (Ex1). During the last two sections of expiration (Ex2, Ex3) ▵I P changes decreased. The CF patients showed higher variations in ▵I P changes compared to the controls (CF:  -426.5%, HL:  -158.1%, coefficient of variation). Furthermore, ▵I V/▵I P significantly differed between expiratory sections for the CF patients (Ex1-Ex2, p  <  0.01; Ex1-Ex3, p  <  0.001; Ex2-Ex3, p  <  0.05), but not for the controls. No significant differences in ▵I V/▵I P between inspiratory sections were determined for both groups.
SIGNIFICANCE: Differences in ▵I P changes and in ▵I V/▵I P between both subject groups were speculated to be caused by higher breathing efforts of the CF patients due to airway obstruction leading to higher intrathoracic pressures, and thus to greater changes in lung perfusion.

PMID: 28530203 [PubMed - in process]

[LONG TERM TREATMENT WITH MACROLIDES IN CHRONIC LUNG DISEASES].

Harefuah. 2016 Sep;155(9):567-571

Authors: Shteinberg M, Schneer S, Lavon O, Adir Y

Abstract
INTRODUCTION: Macrolide agents have both antibacterial properties as well as various effects on the inflammatory system. In recent years there is growing evidence regarding the favourable effects of macrolides in a range of chronic respiratory conditions. Historically, erythromycin and clarithromycin were found to stabilize pulmonary deterioration in diffuse panbronchiolitis. In cystic fibrosis patients colonized with pseudomonas aeruginosa, long term treatment with azithromycin reduces exacerbations and presents improved lung function. A similar effect on prevention of exacerbations has been demonstrated in noncystic fibrosis bronchiectasis. In patients undergoing lung transplantation, long term azithromycin prevents bronchiolitis obliterans syndrome. In patients with chronic obstructive pulmonary disease (COPD), azithromycin prevents acute exacerbations. Chronic treatment with macrolides is associated with adverse effects including gastrointestinal symptoms, interactions with other drugs and cardiovascular complications. Of the macrolides, azithromycin is associated with the lowest interactions and adverse effects and is also the most investigated.

PMID: 28530085 [PubMed - in process]

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases.

Theranostics. 2017;7(6):1543-1588

Authors: Ha H, Debnath B, Neamati N

Abstract
The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

PMID: 28529637 [PubMed - in process]

Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis.

J Cyst Fibros. 2017 May 18;:

Authors: Labaste A, Ohlmann C, Mainguy C, Jubin V, Perceval M, Coutier L, Reix P

Abstract
The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.

PMID: 28529073 [PubMed - as supplied by publisher]

Discovery and biosynthesis of gladiolin: a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis.

J Am Chem Soc. 2017 May 22;:

Authors: Song L, Jenner M, Masschelein J, Jones C, Bull MJ, Harris SR, Hartkoorn RC, Vocat A, Romero-Canelón I, Coupland P, Webster G, Dunn M, Weiser R, Paisey C, Cole ST, Parkhill J, Mahenthiralingam E, Challis GL

Abstract
An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin is structurally-related to etnangien, a highly unstable antibiotic from Sorangium cellulosum that is also active against Mycobacteria. Like etnangien, gladiolin was found to inhibit RNA polymerase, a validated drug target in M. tuberculosis. However, gladiolin lacks the highly labile hexaene moiety of etnangien and was thus found to possess significantly increased chemical stability. Moreover, gladiolin displayed low mammalian cytotoxicity and good activity against several M. tuberculosis clinical isolates, including four that are resistant to isoniazid and one that is resistant to both isoniazid and rifampicin. Overall, these data suggest that gladiolin may represent a useful starting point for the development of novel drugs to tackle multidrug-resistant tuberculosis. The B. gladioli BCC0238 genome was sequenced using Single Molecule Real Time (SMRT) technology. This resulted in four contiguous sequences: two large circular chromosomes and two smaller putative plasmids. Analysis of the chromosome sequences identified 49 putative specialized metabolite biosynthetic gene clusters. One such gene cluster, located on the smaller of the two chromosomes, encodes a trans-acyltransferase (trans-AT) polyketide synthase (PKS) multienzyme that was hypothesized to assemble gladiolin. Insertional inactivation of a gene in this cluster encoding one of the PKS subunits abrogated gladiolin production, confirming that the gene cluster is responsible for biosynthesis of the antibiotic. Comparison of the PKSs responsible for the assembly of gladiolin and etnangien showed that they possess a remarkably similar architecture, obfuscating the biosynthetic mechanisms responsible for most of the structural differences between the two metabolites.

PMID: 28528545 [PubMed - as supplied by publisher]

A genetic risk factor for thrombophilia in a Han Chinese family.

Mol Med Rep. 2017 Apr;15(4):1668-1672

Authors: Sun G, Jia Y, Meng J, Ou M, Zhu P, Cong S, Luo Y, Sui W, Dai Y

Abstract
Thrombophilia is a multifactorial disorder involving environmental and genetic factors. Well‑known factors that result in predisposition to congenital disorders associated with thrombophilia include antithrombin deficiency, protein C and S deficiency, Factor V Leiden mutation, abnormal prothrombin and antiphospholipid syndrome. The present study revealed an association between a mutation of the F2 gene, which codes for coagulation factor II, thrombin, and the risk of thrombophilia in a Han Chinese family, of which four members (I‑2, II‑2, II‑3 and III‑1) had a history of deep venous thromboembolism. The disease was measured in this family using laboratory measurements and computed tomography angiography. To identify the abnormality underlying the increased thrombophilia risk, whole‑exome sequencing technology was used to analyze two affected individuals (II‑2 and III‑1). An exonic missense F2 mutation, T165M (NM_000506:c.C494T:p.T165M;rs5896), was identified from a total of 2,222 and 2,203 genetic variations observed in the two affected individuals, respectively, which were subsequently filtered and confirmed using Sanger sequencing. I‑2, II‑3 and III‑1 shared this mutation with the proband (II‑2), and II‑6 had a heterozygous form of the mutation. This deleterious mutation was not identified in normal controls. The present study may improve understanding of the function of the F2 gene.

PMID: 28259966 [PubMed - indexed for MEDLINE]

Developmental dysplasia of the hip: usefulness of next generation genomic tools for characterizing the underlying genes - a mini review.

Clin Genet. 2016 Jul;90(1):16-20

Authors: Basit S, Hannan MA, Khoshhal KI

Abstract
Developmental dysplasia of the hip (DDH) is one of the most common skeletal anomalies. DDH encompasses a spectrum of the disorder ranging from minor acetabular dysplasia to irreducible dislocation, which may lead to premature arthritis in later life. Involvement of genetic factors underlying DDH became evident when several studies reported chromosomal loci linked to DDH in families with multiple affected individuals. Moreover, using association studies, variants in genes involved in chondrogenesis and joint formation have been shown to be associated with DDH. At least, one study identified a pathogenic variant in the chemokine receptor gene in DDH. No genetic analysis has been reported or carried out in DDH patients from the Middle East. Here, we review the literature related to genetics of DDH and emphasized the usefulness of new generation technologies in identifying genetic variants underlying DDH in consanguineous families.

PMID: 26842108 [PubMed - indexed for MEDLINE]

[PULMONARY FIBROSIS INDUCED BY ANTI־TNF-Αlpha TREATMENT].

Harefuah. 2016 Oct;155(10):600-603

Authors: Baum S, Schachter O, Barzilai A

Abstract
INTRODUCTION: TNFα-targeted therapies have emerged as a new class of drugs in the treatment of various inflammatory diseases, including psoriasis. With the increasing use and longer follow-up periods of TNFα targeted therapies, a spectrum of immunological adverse events have been described, ranging from asymptomatic immunological alterations to life-threatening systemic diseases such as pulmonary fibrosis. We present a case of a 66 year old man diagnosed with psoriasis who developed pulmonary fibrosis three years after initiation of Etanercept (Enbrel) for his skin disease.
CONCLUSIONS: We presented a rare case of a patient who developed pulmonary fibrosis, possibly triggered by anti-TNFα treatment. We suggest that adverse effects related to anti-TNFα should be evaluated carefully, considering pulmonary fibrosis as a possible side effect, especially among patients with risk factors for its development.
DISCUSSION: There are growing numbers of reports of the paradoxical induction of pulmonary interstitial disease due to TNFα blockers, yet most of them are uncontrolled studies in patients with rheumatoid arthritis or other autoimmune diseases that can involve the lungs. Therefore, definitive conclusions are not possible at this stage. Recent studies described the poor prognosis of pulmonary fibrosis secondary to anti-TNFα therapy, with the mortality rate of up to 60% among patients with previous pulmonary disease. Coexisting or previous therapy with Methotrexate had stronger association with the development of drug-induced pulmonary fibrosis.

PMID: 28530055 [PubMed - in process]

Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review.

BMC Med. 2016 Nov 29;14(1):191

Authors: Onakpoya IJ, Heneghan CJ, Aronson JK

Abstract
BACKGROUND: We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time.
METHODS: We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria.
RESULTS: We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction.
CONCLUSIONS: Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.

PMID: 27894343 [PubMed - indexed for MEDLINE]

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

J Infect Dis. 2016 Dec 01;214(11):1717-1727

Authors: Madan A, Segall N, Ferguson M, Frenette L, Kroll R, Friel D, Soni J, Li P, Innis BL, Schuind A

Abstract
BACKGROUND:  Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development.
METHODS:  We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389).
RESULTS:  All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination.
CONCLUSIONS:  Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults.
CLINICAL TRIALS REGISTRATION:  NCT01999842.

PMID: 27609809 [PubMed - indexed for MEDLINE]

Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity.

Malar J. 2016 Jul 22;15(1):377

Authors: Hickey BW, Lumsden JM, Reyes S, Sedegah M, Hollingdale MR, Freilich DA, Luke TC, Charoenvit Y, Goh LM, Berzins MP, Bebris L, Sacci JB, De La Vega P, Wang R, Ganeshan H, Abot EN, Carucci DJ, Doolan DL, Brice GT, Kumar A, Aguiar J, Nutman TB, Leitman SF, Hoffman SL, Epstein JE, Richie TL

Abstract
BACKGROUND: In this phase 1 clinical trial, healthy adult, malaria-naïve subjects were immunized with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) by mosquito bite and then underwent controlled human malaria infection (CHMI). The PfRAS model for immunization against malaria had previously induced >90 % sterile protection against homologous CHMI. This study was to further explore the safety, tolerability and protective efficacy of the PfRAS model and to provide biological specimens to characterize protective immune responses and identify protective antigens in support of malaria vaccine development.
METHODS: Fifty-seven subjects were screened, 41 enrolled and 30 received at least one immunization. The true-immunized subjects received PfRAS via mosquito bite and the mock-immunized subjects received mosquito bites from irradiated uninfected mosquitoes. Sera and peripheral blood mononuclear cells (PBMCs) were collected before and after PfRAS immunizations.
RESULTS: Immunization with PfRAS was generally safe and well tolerated, and repeated immunization via mosquito bite did not appear to increase the risk or severity of AEs. Local adverse events (AEs) of true-immunized and mock-immunized groups consisted of erythaema, papules, swelling, and induration and were consistent with reactions from mosquito bites seen in nature. Two subjects, one true- and one mock-immunized, developed large local reactions that completely resolved, were likely a result of mosquito salivary antigens, and were withdrawn from further participation as a safety precaution. Systemic AEs were generally rare and mild, consisting of headache, myalgia, nausea, and low-grade fevers. Two true-immunized subjects experienced fever, malaise, myalgia, nausea, and rigours approximately 16 h after immunization. These symptoms likely resulted from pre-formed antibodies interacting with mosquito salivary antigens. Ten subjects immunized with PfRAS underwent CHMI and five subjects (50 %) were sterilely protected and there was a significant delay to parasitaemia in the other five subjects. All ten subjects developed humoral immune responses to whole sporozoites and to the circumsporozoite protein prior to CHMI, although the differences between protected and non-protected subjects were not statistically significant for this small sample size.
CONCLUSIONS: The protective efficacy of this clinical trial (50 %) was notably less than previously reported (>90 %). This may be related to differences in host genetics or the inherent variability in mosquito biting behavior and numbers of sporozoites injected. Differences in trial procedures, such as the use of leukapheresis prior to CHMI and of a longer interval between the final immunization and CHMI in these subjects compared to earlier trials, may also have reduced protective efficacy. This trial has been retrospectively registered at ISRCTN ID 17372582, May 31, 2016.

PMID: 27448805 [PubMed - indexed for MEDLINE]

Effectiveness of adverse effects search filters: drugs versus medical devices.

J Med Libr Assoc. 2016 Jul;104(3):221-5

Authors: Farrah K, Mierzwinski-Urban M, Cimon K

Abstract
OBJECTIVE: The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase.
METHODS: The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve.
RESULTS: For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%-87%) than for drugs (88%-93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%-81%) than in MEDLINE (67%-87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure.
CONCLUSIONS: In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs.

PMID: 27366123 [PubMed - indexed for MEDLINE]

Rapid Responses to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: A Randomized Controlled Trial.

J Infect Dis. 2016 Sep 15;214(6):845-53

Authors: Atmar RL, Baehner F, Cramer JP, Song E, Borkowski A, Mendelman PM, NOR-201 Study Group

Abstract
BACKGROUND: Noroviruses pose a significant public health risk, particularly in very young individuals, older adults, and individuals with underlying conditions. We assessed 2 bivalent norovirus virus-like particle (VLP) vaccine candidate formulations in healthy adults aged 18-49 years.
METHODS: Enrolled subjects (n = 454) randomly assigned among 3 groups received intramuscular placebo (saline) or vaccines containing either 15 µg or 50 µg of GI.1 VLP and 50 µg GII.4 VLP (15/50 and 50/50 formulations) adjuvanted with monophosphoryl lipid A and Al(OH)3 We present safety and immunogenicity assessments up to 28 days after vaccination.
RESULTS: No vaccine-related serious adverse events or adverse events of special interest were reported. Reactions were mainly mild to moderate, the most frequent being transient pain, in 8%, 64%, and 73% of placebo, 15/50, and 50/50 groups, respectively; transient myalgia, headache, and fatigue were the commonest systemic adverse events. Subjects assessed per protocol (n = 442) displayed rapid immune responses to vaccination, peaking by days 7-10 and persisting through day 28. GI.1 responses were highest with the 50/50 formulation, but GII.4 responses were higher with the 15/50 formulation.
CONCLUSIONS: Both candidate VLP vaccines were well tolerated and elicited robust immune responses by 7-10 days that persisted through day 28. The 15/50 formulation displayed the best balance of tolerability and immunogenicity.
CLINICAL TRIALS REGISTRATION: NCT02142504.

PMID: 27354368 [PubMed - indexed for MEDLINE]

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP.

J Infect Dis. 2016 Sep 01;214(5):772-81

Authors: Rampling T, Ewer KJ, Bowyer G, Bliss CM, Edwards NJ, Wright D, Payne RO, Venkatraman N, de Barra E, Snudden CM, Poulton ID, de Graaf H, Sukhtankar P, Roberts R, Ivinson K, Weltzin R, Rajkumar BY, Wille-Reece U, Lee CK, Ockenhouse CF, Sinden RE, Gerry S, Lawrie AM, Vekemans J, Morelle D, Lievens M, Ballou RW, Cooke GS, Faust SN, Gilbert S, Hill AV

Abstract
BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.
METHOD: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.
RESULTS: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.
CONCLUSIONS: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.
CLINICAL TRIALS REGISTRATION: NCT01883609.

PMID: 27307573 [PubMed - indexed for MEDLINE]

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Biomarkers in epilepsy-A modelling perspective.

Eur J Pharm Sci. 2017 May 17;:

Authors: van Dijkman SC, Voskuyl RA, de Lange EC

Abstract
Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking. Here we aim to 1) briefly categorise the available epilepsy biomarkers and identify gaps, and 2) provide a modelling perspective on approaches to fill such gaps. There is mainly a lack of biomarker types 2 (target occupancy) and 3 (target activation). Current literature typically focuses on qualitative biomarkers for diagnosis and prediction of treatment response or failure, leaving a need for biomarkers that help to quantitatively understand the overall system to explain and predict differences in disease and treatment outcome. Due to the complexity of epilepsy, filling the biomarker gaps will require collaboration and expertise from the fields of systems biology and systems pharmacology.

PMID: 28528284 [PubMed - as supplied by publisher]

Sputum transcriptomics reveal up-regulation of IL-1 receptor family members in severe asthma.

J Allergy Clin Immunol. 2017 May 17;:

Authors: Rossios C, Pavlidis S, Hoda U, Kuo CH, Wiegman C, Russell K, Sun K, Loza MJ, Baribaud F, Durham AL, Ojo O, Lutter R, Rowe A, Bansal A, Auffray C, Sousa A, Corfield J, Djukanovic R, Guo Y, Sterk PJ, Chung KF, Adcock IM, U-BIOPRED consortia project team

Abstract
BACKGROUND: Sputum analysis in asthma is used to define airway inflammatory processes and may guide therapy.
OBJECTIVE: To determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared to mild-moderate non-smoking asthmatics (MMA).
METHODS: Induced sputum was obtained from non-smoking SA (SAn), smokers/ex-smokers with SA (SAsm), MMA and healthy non-smoking controls. Differential cell counts, microarray analysis of cell pellets and SOMAscan analysis of sputum analytes was performed. CRID3 was used to inhibit the inflammasome in a mouse model of severe asthma.
RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in SA compared to MMA. 42 genes probes were up-regulated (>2-fold) in SAn compared to MMA including IL-1R family and NRLP3 inflammasome members (FDR<0.05). The inflammasome proteins NLRP1, NLRP3 and NLRC4 were associated with neutrophilic asthma and with sputum IL-1β protein whilst eosinophilic asthma was associated with an IL-13-induced Th2 signature and IL1RL1 mRNA expression. These differences were sputum-specific since no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsies in SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics (ADEPT) cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma.
CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA whilst NLRP3 inflammasome expression is highest in neutrophilic SA. Th2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation may represent interacting pathways in SA.

PMID: 28528200 [PubMed - as supplied by publisher]

Maintenance of ATP Homeostasis Triggers Metabolic Shifts in Gas-Fermenting Acetogens.

Cell Syst. 2017 May 16;:

Authors: Valgepea K, de Souza Pinto Lemgruber R, Meaghan K, Palfreyman RW, Abdalla T, Heijstra BD, Behrendorff JB, Tappel R, Köpke M, Simpson SD, Nielsen LK, Marcellin E

Abstract
Acetogens are promising cell factories for producing fuels and chemicals from waste feedstocks via gas fermentation, but quantitative characterization of carbon, energy, and redox metabolism is required to guide their rational metabolic engineering. Here, we explore acetogen gas fermentation using physiological, metabolomics, and transcriptomics data for Clostridium autoethanogenum steady-state chemostat cultures grown on syngas at various gas-liquid mass transfer rates. We observe that C. autoethanogenum shifts from acetate to ethanol production to maintain ATP homeostasis at higher biomass concentrations but reaches a limit at a molar acetate/ethanol ratio of ∼1. This regulatory mechanism eventually leads to depletion of the intracellular acetyl-CoA pool and collapse of metabolism. We accurately predict growth phenotypes using a genome-scale metabolic model. Modeling revealed that the methylene-THF reductase reaction was ferredoxin reducing. This work provides a reference dataset to advance the understanding and engineering of arguably the first carbon fixation pathway on Earth.

PMID: 28527885 [PubMed - as supplied by publisher]