A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS)

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m(2) on days 1 and 2 of cycle 1; 27 mg/m(2) thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients

Gastrin-Releasing Peptide Signaling Plays a Limited and Subtle Role in Amygdala Physiology and Aversive Memory

Links between synaptic plasticity in the lateral amygdala (LA) and Pavlovian fear learning are well established. Neuropeptides including gastrin-releasing peptide (GRP) can modulate LA function. GRP increases inhibition in the LA and mice lacking the GRP receptor (GRPR KO) show more pronounced and persistent fear after single-trial associative learning. Here, we confirmed these initial findings and examined whether they extrapolate to more aspects of amygdala physiology and to other forms of aversive associative learning. GRP application in brain slices from wildtype but not GRPR KO mice increased spontaneous inhibitory activity in LA pyramidal neurons. In amygdala slices from GRPR KO mice, GRP did not increase inhibitory activity. In comparison to wildtype, short- but not long-term plasticity was increased in the cortico-lateral amygdala (LA) pathway of GRPR KO amygdala slices, whereas no changes were detected in the thalamo-LA pathway. In addition, GRPR KO mice showed enhanced fear evoked by single-trial conditioning and reduced spontaneous firing of neurons in the central nucleus of the amygdala (CeA). Altogether, these results are consistent with a potentially important modulatory role of GRP/GRPR signaling in the amygdala. However, administration of GRP or the GRPR antagonist (D-Phe6, Leu-NHEt13, des-Met14)-Bombesin (6–14) did not affect amygdala LTP in brain slices, nor did they affect the expression of conditioned fear following intra-amygdala administration. GRPR KO mice also failed to show differences in fear expression and extinction after multiple-trial fear conditioning, and there were no differences in conditioned taste aversion or gustatory neophobia. Collectively, our data indicate that GRP/GRPR signaling modulates amygdala physiology in a paradigm-specific fashion that likely is insufficient to generate therapeutic effects across amygdala-dependent disorders

Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats

BACKGROUND: There is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats. METHODS: Fasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein-protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM. RESULTS: Fasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up-regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein-protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM. CONCLUSIONS: Non-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM

The impact of natural resource use on bird and reptile communities within multiple-use protected areas: evidence from sub-arid southern Madagascar

Multiple-use protected areas, in which sustainable levels of extractive livelihood activities are permitted, play an increasingly important role in the global protected area estate, and are expected to rise in prevalence. However, we know little about their effectiveness at conserving biodiversity. We surveyed bird and reptile communities in three areas across a forest disturbance gradient resulting from charcoal production and shifting cultivation within a multiple-use protected area in Madagascar’s sub-arid spiny forest. We scored individual species using a Conservation Value Index (CVI; a simple metric based on rarity, threat and distinctiveness), and estimated the total conservation value of each treatment by calculating the sum of frequency-weighted CVI scores across all present species. Bird and reptile community responses to forest disturbance were idiosyncratic. Bird richness was greatest in the moderate-disturbance treatment, but the low-disturbance treatment had the superior conservation value due to higher frequencies of locally-endemic species. Reptile richness was the same in low- and moderate-disturbance treatments, but the conservation value of the latter was greater. The high-disturbance areas had lowest richness and conservation value for both groups. For birds, increasing disturbance levels were accompanied by community turnover from high-value to low-value species, a pattern highlighted by CVI that is masked by assessing species richness alone. Although some endemic species appear to be resilient to degradation, multiple-use protected areas in Madagascar may lose biodiversity since most endemic species are forest-dependent. Stricter protected area models may be more appropriate in areas where much of the high-value biodiversity is sensitive to habitat degradation

The Study of Total IgE Reference Range in Healthy Adults in Tehran, Iran

"nBackground: IgE is an antibody class that regarded as an important factor in the pathogenesis of allergic diseases, asthma, im­mune responses to parasitic infection and it could be responsible for the late- phase allergic response. The objective of this study was to evaluate total IgE in healthy Iranian adults, establishment of reference range of total IgE and assess helpful­ness of this value in clinical diagnosis atopic and allergic diseases."nMethod: Three hundred sixty six healthy adults from blood transfusion volunteers (18 to 60 years) were selected in this study. A specific questionnaire (including demographic factors, smoking status and ...) was filled out for each person. Also, we evaluated effect of race and education on total IgE. These adults had no history of allergic disease. The total serum IgE level using a commercial enzyme immunoassay and CBC (Eosinophil count) was determined in them."nResults: Mean of age was 37.32± 10.93 yrs and 219 cases were males and 147 females. The geometric mean of total IgE was 20.84 IU/ml (2-373 IU/ml) (95% percentile= 250) (95% confidence interval=46.27-62.70). No differences was observed between mean of IgE log in males and females (P= NS) but mean of total IgE log in females is more than males."nConclusion: Normal range of serum total IgE obtained in this study could be helpful for diagnosis of IgE-dependent allergic dis­ease, as reference ranges in Iranian healthy adults