PRIMA-1 induces p53-madiated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation.
Cancer Sci. 2017 Nov 23;:
Authors: Furukawa H, Makino T, Yamasaki M, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y
TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore the function of mutant TP53; however, its antitumor effect and mechanism in ESCC remain unclear. After evaluating the TP53 mutation status of a panel of eleven ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different p53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in TP53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1's function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with TP53 missense mutations, whereas no apoptosis was induced in ESCC with wild type TP53 and TP53 with frameshift and nonsense mutations. Importantly, the knockdown of Noxa cancelled the apoptosis induced by PRIMA treatment in ESCC cell lines with TP53 missense mutations. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with TP53 missense mutations. This article is protected by copyright. All rights reserved.
PMID: 29168598 [PubMed - as supplied by publisher]
Specific Immunotherapy in LAR: a randomized, double-blind placebo controlled trial with Phleum pratense subcutaneous allergen immunotherapy.
Allergy. 2017 Nov 23;:
Authors: Rondón C, Blanca-López N, Campo P, Mayorga C, Jurado-Escobar R, Torres MJ, Canto G, Blanca M
BACKGROUND: Allergen immunotherapy has been shown to be an effective treatment for local allergic rhinitis (LAR) to house dust mites. Studies with pollen allergen immunotherapy are limited to observational studies. The aim of this study was to evaluate the clinical efficacy and safety of Phleum pratense subcutaneous immunotherapy (Phl-SCIT) in LAR.
METHODS: In a randomized double-blind placebo-controlled study, 56 patients with moderate-severe LAR to grass pollen received Phl-SCIT with a depigmented-polymerized pollen vaccine or placebo for the first year, and Phl-SCIT the second one. The blind was maintained throughout the study. Primary outcome was combined symptoms-medication score (CSMS) during grass pollen season (GPS). Secondary clinical outcomes included organ-specific symptoms, medication free days, rhinitis severity, and asthma control. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), nasal allergen provocation test (NAPT), skin testing, serum levels of specific-IgG4 and specific-IgE, and safety were also evaluated.
RESULTS: SCIT had a short-term and sustained effect with significant improvements of all primary and secondary clinical outcomes and RQLQ score. SCIT significantly increased serum sIgG4 levels and allergen tolerance, from the 6(th) to 24(th) months of treatment. At the end of the study 83% of patients treated with ≥6 months of SCIT tolerated a concentration of Phl over 50 times higher than baseline, and 56% gave a negative NAPT. SCIT was well-tolerated; six mild local reactions occurred, and there were no serious adverse events related to the study medication.
CONCLUSIONS: Subcutaneous immunotherapy with depigmented-polymerized allergen extracts is a safe and clinically effective treatment for LAR to Phleum pratense.clinicaltrials. gov identifier: NCT02126111. This article is protected by copyright. All rights reserved.
PMID: 29168570 [PubMed - as supplied by publisher]
Point-of-use fortification of foods with micronutrient powders containing iron in children of preschool and school-age.
Cochrane Database Syst Rev. 2017 Nov 23;11:CD009666
Authors: De-Regil LM, Jefferds MED, Peña-Rosas JP
BACKGROUND: Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that at least half of the cases are due to iron deficiency. Point-of-use fortification of foods with micronutrient powders (MNP) has been proposed as a feasible intervention to prevent and treat anaemia. It refers to the addition of iron alone or in combination with other vitamins and minerals in powder form, to energy-containing foods (excluding beverages) at home or in any other place where meals are to be consumed. MNPs can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour or colour.
OBJECTIVES: To assess the effects of point-of-use fortification of foods with iron-containing MNP alone, or in combination with other vitamins and minerals on nutrition, health and development among children at preschool (24 to 59 months) and school (five to 12 years) age, compared with no intervention, a placebo or iron-containing supplements.
SEARCH METHODS: In December 2016, we searched the following databases: CENTRAL, MEDLINE, Embase, BIOSIS, Science Citation Index, Social Science Citation Index, CINAHL, LILACS, IBECS, Popline and SciELO. We also searched two trials registers in April 2017, and contacted relevant organisations to identify ongoing and unpublished trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs trials with either individual or cluster randomisation. Participants were children aged between 24 months and 12 years at the time of intervention. For trials with children outside this age range, we included studies where we were able to disaggregate the data for children aged 24 months to 12 years, or when more than half of the participants were within the requisite age range. We included trials with apparently healthy children; however, we included studies carried out in settings where anaemia and iron deficiency are prevalent, and thus participants may have had these conditions at baseline.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of trials against the inclusion criteria, extracted data from included trials, assessed the risk of bias of the included trials and graded the quality of the evidence.
MAIN RESULTS: We included 13 studies involving 5810 participants from Latin America, Africa and Asia. We excluded 38 studies and identified six ongoing/unpublished trials. All trials compared the provision of MNP for point-of-use fortification with no intervention or placebo. No trials compared the effects of MNP versus iron-containing supplements (as drops, tablets or syrup).The sample sizes in the included trials ranged from 90 to 2193 participants. Six trials included participants younger than 59 months of age only, four included only children aged 60 months or older, and three trials included children both younger and older than 59 months of age.MNPs contained from two to 18 vitamins and minerals. The iron doses varied from 2.5 mg to 30 mg of elemental iron. Four trials reported giving 10 mg of elemental iron as sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), chelated ferrous sulphate or microencapsulated ferrous fumarate. Three trials gave 12.5 mg of elemental iron as microencapsulated ferrous fumarate. Three trials gave 2.5 mg or 2.86 mg of elemental iron as NaFeEDTA. One trial gave 30 mg and one trial provided 14 mg of elemental iron as microencapsulated ferrous fumarate, while one trial gave 28 mg of iron as ferrous glycine phosphate.In comparison with receiving no intervention or a placebo, children receiving iron-containing MNP for point-of-use fortification of foods had lower risk of anaemia prevalence ratio (PR) 0.66, 95% confidence interval (CI) 0.49 to 0.88, 10 trials, 2448 children; moderate-quality evidence) and iron deficiency (PR 0.35, 95% CI 0.27 to 0.47, 5 trials, 1364 children; moderate-quality evidence) and had higher haemoglobin (mean difference (MD) 3.37 g/L, 95% CI 0.94 to 5.80, 11 trials, 2746 children; low-quality evidence).Only one trial with 115 children reported on all-cause mortality (zero cases; low-quality evidence). There was no effect on diarrhoea (risk ratio (RR) 0.97, 95% CI 0.53 to 1.78, 2 trials, 366 children; low-quality evidence).
AUTHORS' CONCLUSIONS: Point-of-use fortification of foods with MNPs containing iron reduces anaemia and iron deficiency in preschool- and school-age children. However, information on mortality, morbidity, developmental outcomes and adverse effects is still scarce.
PMID: 29168569 [PubMed - as supplied by publisher]
The Effect of Probiotics on Halitosis: a Systematic Review and Meta-analysis.
Probiotics Antimicrob Proteins. 2017 Nov 22;:
Authors: Yoo JI, Shin IS, Jeon JG, Yang YM, Kim JG, Lee DW
Although several studies have evaluated the inhibitory effect of probiotics on halitosis, findings are inconsistent. This systematic review and meta-analysis of randomized clinical trials (RCT) was conducted to summarize the evidence on the effect of probiotics on halitosis. RCT on any type of probiotic treatment with at least 2-week duration were identified through electronic databases (PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials) and hand searched between 1946 and January 17, 2017. Primary outcomes were organoleptic (OLT) scores and volatile sulfur compounds (VSC). Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. Meta-analysis was conducted to synthesize the evidence. Of the 153 articles identified, three met the inclusion criteria. Meta-analysis revealed that OLT scores (SMD = - 1.93, 95% CI - 2.85 to - 1.02, P < 0.0001) were significantly lower in subjects who received probiotics than in placebo groups, but no significant difference was observed at the VSC concentration (SMD = - 0.02, 95% CI - 2.12 to 2.07, P = 0.98). Current evidence is supportive of recommending probiotics for the management of halitosis. Based on this review, transient (average of 2 weeks) dosing with probiotics (mainly Lactobacillus strains) has a moderate effect on halitosis regarding OLT scores, but we could not confirm the effects of probiotics on the VSC reduction. The available evidence is quantitatively and qualitatively insufficient for further recommendations, especially with regard to administration strategies and pretreatment. Future studies should aim for longer follow-up and standardized administration methods to prove or refute the effect of probiotics on halitosis.
PMID: 29168154 [PubMed - as supplied by publisher]
Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial.
Osteoporos Int. 2017 Nov 22;:
Authors: Bilezikian JP, Hattersley G, Fitzpatrick LA, Harris AG, Shevroja E, Banks K, Leder BZ, Zanchetta JR, Hans D
In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score.
INTRODUCTION: Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS).
METHODS: This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 μg), subcutaneous teriparatide (20 μg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed.
RESULTS: After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 μg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p < 0.05 for each). The TBS in the placebo group declined by 1.08%. The TBS increase in each treatment group was significantly higher than placebo at 24 weeks (p < 0.0001 for each) after adjustment for age, BMI, and baseline TBS. A dose-response was observed at 24 weeks across the three doses of abaloparatide-SC and placebo (p = 0.02). The increase in TBS in the abaloparatide-SC 80 μg group was significantly greater than TPTD (p < 0.03).
CONCLUSIONS: These results are consistent with an effect of abaloparatide-SC to improve lumbar spine skeletal microarchitecture, as assessed by TBS.
PMID: 29167971 [PubMed - as supplied by publisher]
Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial.
JAMA Psychiatry. 2017 Nov 22;:
Authors: Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Corlett PR, Rothman DL, Mason G, Qiu M, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman JA
Importance: Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate.
Objective: To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies.
Design, Setting, and Participants: This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016.
Interventions: Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions.
Main Outcomes and Measures: Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection.
Results: Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups.
Conclusions and Relevance: These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures.
Trial Registration: clinicaltrials.gov Identifier: NCT02134951.
PMID: 29167877 [PubMed - as supplied by publisher]
Pharmacological interventions for preventing acute mountain sickness: a network meta-analysis and trial sequential analysis of randomized clinical trials.
Ann Med. 2017 Nov 23;:1-9
Authors: Sridharan K, Sivaramakrishnan G
BACKGROUND: Individuals ascending to high altitude are at a risk of getting acute mountain sickness (AMS). The present study is a network meta-analysis comparing all the interventions available to prevent AMS.
METHODS: Electronic databases were searched for randomized clinical trials evaluating the use of drugs to prevent AMS. Incidence of AMS was the primary outcome and incidence of severe AMS, paraesthesia (as side effect of acetazolamide use), headache and severe headache, and oxygen saturation were the secondary outcomes. Odds ratio [95% confidence interval] was the effect estimate for categorical outcomes and weighted mean difference for oxygen saturation. Random effects model was used to derive the direct and mixed treatment comparison pooled estimates. Trial sequential analysis and grading of the evidence for key comparisons were carried out.
RESULTS: A total of 24 studies were included. Acetazolamide at 125, 250 and 375 mg twice daily, dexamethasone and ibuprofen had statistically significant lower incidence of AMS compared to placebo. All the above agents except ibuprofen were also observed to significantly reduce the incidence of severe AMS. Acetazolamide alone or in combination with Ginkgo biloba were associated with lower incidence of headache, but higher risk of paraesthesia. Acetazolamide at 125 mg and 375 mg twice daily significantly reduce the incidence of severe headache as like ibuprofen. Trial sequential analysis indicates that the current evidence is adequate for the incidence of AMS only for acetazolamide 125 and 250 mg twice daily. Similarly, the strength of evidence for acetazolamide 125 and 250 mg twice daily was moderate while it was either low or very low for all other comparisons.
CONCLUSIONS: Acetazolamide at 125, 250 and 375 mg twice daily, ibuprofen and dexamethasone significantly reduce the incidence of AMS of which adequate evidence exists only for acetazolamide 125 and 250 mg twice daily therapy. Acetazolamide 125 mg twice daily could be the best in the pool considering the presence of enough evidence for preventing AMS and associated with lower incidence of paraesthesia. Key messages Acetazolamide 125, 250 and 375 mg twice daily, dexamethasone and ibuprofen reduce the incidence of AMS in high altitudes. Adequate evidence exists supporting the use of acetazolamide 125 mg and 250 mg twice daily for preventing AMS of which acetazolamide 125 mg twice daily could be the best.
PMID: 29166795 [PubMed - as supplied by publisher]