Metastatic signature in lung cancer is associated with sensitivity to anti‐integrin αV monoclonal antibody intetumumab

Intetumumab is a fully human monoclonal antibody that inhibits α_v integrins. It has been shown in in vitro assays to effectively inhibit cell viability, metastasis, and adhesion of human cancer cells and endothelial cells. However, the response to Intetumumab varies in different tumor cell lines. To understand the growth inhibition mechanism of Intetumumab and to identify a molecular signature that can predict sensitivity, we focused on lung cancer cell lines and performed a series of proliferation assays. We then assessed the global gene expression profiles, DNA copy number variations, and microRNA profiles from a total of 23 lung cancer lines. The results revealed that lung cancer sensitivity to Intetumumab is associated with several chromosomal alterations, particularly genetic loss at chromosome arm 19p, which resulted in gene expression changes. We identified a genetic signature that can be used to predict Intetumumab sensitivity for lung cancer cell lines. Independently, microRNA analysis revealed a panel of signature microRNAs that includes several markers of epithelial to mesenchymal transition and tumor metastasis such as miR‐200 family and miR‐205. Both the genetic and microRNA signatures provide insights into the potential mechanism of Intetumumab activity and serve as the first step to develop a patient stratification strategy for Intetumumab therapy in lung cancer. © 2014 Wiley Periodicals, Inc.     

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA,and their analogs

5F‐PY‐PICA and 5F‐PY‐PINACA are pyrrolidinyl 1‐(5‐fluoropentyl)ind (az)ole‐3‐carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F‐PY‐PICA, 5F‐PY‐PINACA, and analogs featuring variation of the 1‐alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (LC–QTOF–MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB₁) or type 2 (hCB₂), all analogs showed minimal affinity for CB₁ (pK_i < 5), although several demonstrated moderate CB₂ binding (pK_i 5.45–6.99). In fluorescence‐based membrane potential assays using AtT20‐hCB₁ or ‐hCB₂ cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB₁, although several showed slightly higher relative efficacy at hCB₂. Expansion of the pyrrolidine ring of 5F‐PY‐PICA to an azepane ( 8 ) conferred the greatest hCB₂ affinity (pK_i 6.99) and activity (pEC₅₀ 7.54, E_max 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F‐PY‐PICA and 5F‐PY‐PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.     

Digit ratio (2D:4D) and hand preference for writing in the BBC Internet Study

The ratio of the length of the second to the fourth digit (2D:4D) may be negatively correlated with prenatal testosterone. Hand preference has been linked with prenatal testosterone and 2D:4D. Here we show that 2D:4D is associated with hand preference for writing in a large internet sample (n>170,000) in which participants self-reported their finger lengths. We replicated a significant association between right 2D:4D and writing hand preference (low right 2D:4D associated with left hand preference) as well as a significant correlation between writing hand preference and the difference between left and right 2D:4D or Dr-l (low Dr-l associated with left hand preference). A new significant correlation between left 2D:4D and writing hand preference was also shown (high left 2D:4D associated with left hand preference). There was a clear interaction between writing hand preference and 2D:4D: The left 2D:4D was significantly larger than the right 2D:4D in male and female left-handed writers, and the right hand 2D:4D was significantly larger than the left hand 2D:4D in male and female right-handed writers.     

There's more to flow-mediated dilation than nitric oxide

Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary.     

Differences in outcomes between cholecalciferol and ergocalciferol supplementation in veterans with inflammatory bowel disease

Aim: Vitamin D deficiency is a global health issue associated with increased health‐care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitamin D deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitamin D level were included. Initial and follow‐up vitamin D values were recorded. The type of vitamin D supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitamin D were divided into separate inpatient and outpatient categories. Results: Veterans (n = 108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitamin D level were studied. There were differences in follow‐up vitamin D levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitamin D3 were less likely to use laboratory, pharmacy, radiology and fee‐based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health‐care costs and expenses in patients with inflammatory bowel disease. Geriatr Gerontol Int 2012; 12: 475–480.     

Impairment‐ and activity/participation‐directed interventions in progressive language impairment: Clinical and theoretical issues

Abstract

The most salient and discussed features of agrammatism are the omission and substitution of grammatical morphemes, whether bound or free, in speech production. Cross-linguistic studies have shown that language-specific features determine the pattern of omissions and substitutions found; morphological markers are almost never omitted if the resulting form is a non-word; substitutions are mis-selections from existing paradigms. In the present paper we investigate the ways in which agrammatism is manifested in Algerian Arabic, a Semitic language where simple (Ø-prefixed and Ø-suffixed) words are described as consisting of three morphemes: the discontinuous consonantal root, the discontinuous vocalic base and a CV template or skeleton (McCarthy 1975). Our findings are comparable to those previously reported, in that the three agrammatic subjects who participated in this study do omit and substitute free-standing and bound grammatical markers, and never produce non-words. More specifically, their performance is characterized by omissions of linear bound morphemes in prefixed and suffixed words, as well as substitutions of morphologically complex forms by simpler and more frequent ones. An interpretation of the subjects' performance in the light of current linguistic and psycholinguistic theories on the lexicon is proposed.