Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.

The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.

The impact of interventions to promote healthier ready-to-eat meals (to eat in, to take away or to be delivered) sold by specific food outlets open to the general public: a systematic review.

INTRODUCTION: Ready-to-eat meals sold by food outlets that are accessible to the general public are an important target for public health intervention. We conducted a systematic review to assess the impact of such interventions. METHODS: Studies of any design and duration that included any consumer-level or food-outlet-level before-and-after data were included. RESULTS: Thirty studies describing 34 interventions were categorized by type and coded against the Nuffield intervention ladder: restrict choice = trans fat law (n = 1), changing pre-packed children's meal content (n = 1) and food outlet award schemes (n = 2); guide choice = price increases for unhealthier choices (n = 1), incentive (contingent reward) (n = 1) and price decreases for healthier choices (n = 2); enable choice = signposting (highlighting healthier/unhealthier options) (n = 10) and telemarketing (offering support for the provision of healthier options to businesses via telephone) (n = 2); and provide information = calorie labelling law (n = 12), voluntary nutrient labelling (n = 1) and personalized receipts (n = 1). Most interventions were aimed at adults in US fast food chains and assessed customer-level outcomes. More 'intrusive' interventions that restricted or guided choice generally showed a positive impact on food-outlet-level and customer-level outcomes. However, interventions that simply provided information or enabled choice had a negligible impact. CONCLUSION: Interventions to promote healthier ready-to-eat meals sold by food outlets should restrict choice or guide choice through incentives/disincentives. Public health policies and practice that simply involve providing information are unlikely to be effective.

Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling.

Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared with mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the interleukin (IL)-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling.

A systematic review of the effectiveness of individual, community and societal-level interventions at reducing socio-economic inequalities in obesity among adults.

BACKGROUND: Socioeconomic inequalities in obesity are well established in high-income countries. There is a lack of evidence of the types of intervention that are effective in reducing these inequalities among adults. OBJECTIVES: To systematically review studies of the effectiveness of individual, community and societal interventions in reducing socio-economic inequalities in obesity among adults. METHODS: Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence (both experimental and observational) of interventions at an individual, community and societal level that might reduce inequalities in obesity among adults (aged 18 years or over) in any setting and country. Studies were included if they reported a body fatness-related outcome and if they included a measure of socio-economic status. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. RESULTS: The 'best available' international evidence was provided by 20 studies. At the individual level, there was evidence of the effectiveness of primary care delivered tailored weight loss programmes among deprived groups. Community based behavioural weight loss interventions and community diet clubs (including workplace ones) also had some evidence of effectiveness-at least in the short term. Societal level evaluations were few, low quality and inconclusive. Further, there was little evidence of long term effectiveness, and few studies of men or outside the USA. However, there was no evidence to suggest that interventions increase inequalities. CONCLUSIONS: The best available international evidence suggests that some individual and community-based interventions may be effective in reducing socio-economic inequalities in obesity among adults in the short term. Further research is required particularly of more complex, multi-faceted and societal-level interventions.

Unbiased pattern detection in microarray data series.

MOTIVATION: Following the advent of microarray technology in recent years, the challenge for biologists is to identify genes of interest from the thousands of genetic expression levels measured in each microarray experiment. In many cases the aim is to identify pattern in the data series generated by successive microarray measurements. RESULTS: Here we introduce a new method of detecting pattern in microarray data series which is independent of the nature of this pattern. Our approach provides a measure of the algorithmic compressibility of each data series. A series which is significantly compressible is much more likely to result from simple underlying mechanisms than series which are incompressible. Accordingly, the gene associated with a compressible series is more likely to be biologically significant. We test our method on microarray time series of yeast cell cycle and show that it blindly selects genes exhibiting the expected cyclic behaviour as well as detecting other forms of pattern. Our results successfully predict two independent non-microarray experimental studies.

Epithelioma cuniculatum (carcinoma cuniculatum) of the thumb: a case report and literature review.

Epithelioma cuniculatum is a rare, slow growing, but locally destructive, low-grade epithelioma of squamous cell origin. The first case of this tumor occurring on the thumb is reported. Treatment of this case is discussed, the literature reviewed, and controversy surrounding the naming of this tumor is examined.

Incorporation of intracisternally administered L-[methyl-3H]methionine and S-adenosyl-L-[methyl-3H]-methionine into rat brain phospholipids.

The incorporation of intracisternally injected L-[methyl-3H]methionine [( 3H]Met) or S-adenosyl-L-[methyl-3H]methionine (Ado[3H]Met) into rat brain AdoMet and phospholipid pools was examined. When [3H]Met was administered, both AdoMet and phospholipid pools were labeled. However, exogenously injected Ado[3H]Met did not serve as a substrate for phospholipid-N-methyltransferases. It was concluded that only Ado[3H]Met formed in situ was utilized to methylate phospholipids and that this process was initiated on the cytoplasmic side of the membrane. The apparent biological half-life in brainstem of phosphatidyl-N-monomethylethanolamine and phosphatidyl-N,N-dimethylethanolamine formed from [3H]Met was 1.4 and 1.7 days, respectively. The half-life of phosphatidylcholine could not be determined due to interference from peripheral sources.

Beta-adrenergic coupled phospholipid methylation. A possible role in withdrawal from chronic ethanol.

Phospholipid methylation was studied in rat brain cortex preparations. Adrenergic agonists stimulated methylation in a dose-dependent manner. The effect was stereospecific and the order of potency of agonists was isoproterenol greater than norepinephrine greater than or equal to epinephrine. The stimulation could be blocked by propranolol. It was concluded that adrenergic stimulation of phospholipid methylation in these preparations involved a beta-adrenergic receptor and that this response was dependent upon an intact membrane environment. Neither adenosine nor histamine stimulated methylation. In fact, histamine appeared to inhibit methylation. Cleavage of phosphatidylcholine to lyso-phosphatidylcholine occurred in the presence of either adrenergic agonists or histamine, indicating an involvement of phospholipase A2. Norepinephrine-sensitive methylation in cortex homogenates from rats withdrawn from chronic ethanol administration was double that of controls by 72 hr after the final ethanol dose. Furthermore, basal methylation exhibited a decreasing trend during this period.

Phenylethanolamine-N-methyltransferase:alcohol and the mechanism of action.

Mixed-solvent systems of methanol and other alcohols and water were used to study the properties of bovine phenylethanolamine-N-methyltransferase. The presence of methanol decreased the binding affinity of the enzyme for its amine substrate but did not alter the maximum velocity. The change in binding was accompanied by an alkaline shift in the pK of an ionizable group in the active site. The well-known property of enzyme inhibition by substrate was also alleviated. Increasing the pH of the medium, in the presence or absence of methanol, increased the maximum velocity but did not alter substrate inhibition. It is proposed that substrate inhibition is due in part to the ionic state of a single unidentified ionizable group in the active site of the enzyme and to a slow release of product. Evidence that an essential, pH-dependent sulfhydryl modulates product release is presented. The properties of phenylethanolamine-N-methyl-transferase are quite responsive to changes in pH, ionic strength, and water content so that the enzyme may well be regulated at the microenvironmental level.

Beneficial effect of indomethacin on acid-induced esophagitis in cats.

Acid-induced esophageal injury in the cat, produced by infusion of 0.1 N HCl (1 ml/min for 30 min) on 4 consecutive days, has been shown previously to adversely affect lower esophageal sphincter (LES) pressure. We studied the role of prostaglandins in acid-induced esophagitis and the associated LES hypotension by simultaneous treatment of some animals with indomethacin (150 micrograms/kg intravenous), a specific inhibitor of prostaglandin synthesis, either during production of esophagitis or during recovery. LES pressures and esophageal histology were compared to control groups which received acid alone. Indomethacin treatment resulted in more rapid healing of the esophageal inflammation and prevented or promptly corrected the esophagitis-associated LES hypotension. These studies provide further evidence that prostaglandins play an important role in the pathogenesis of acid-induced esophagitis and LES hypotension and raise the possibility that indomethacin, a prostaglandin synthetase inhibitor, may be of benefit in prevention or therapy of esophagitis.

Somatostatin effects on lower esophageal sphincter function.

The effect of somatostatin (GH-RIH) infusion (2 microgram/min) on lower esophageal sphincter pressure (LESP) responses to various stimuli was evaluated in adult male baboons. GH-RIH infusion did not affect basal LESP, but did cause a significant suppression of mean immunoreactive insulin (IRI) to 5.8% of basal values (P less than 0.05). Pentagastrin IV caused dose-related increases in LESP that were unaffected by GH-RIH. Abdominal compression caused a threefold rise in LESP (P less than 0.005) both without and with GH-RIH. However, atropine (20 microgram/kg iv bolus) completely blocked this cholinergic LES pressure response. Intragastric alkali as well as intragastric glycine caused significant increases in LESP (P less than 0.05). These LESP responses to alkali and to glycine were totally abolished by GH-RIH. In conclusion, GH-RIH infusion in the baboon does not affect basal LESP, LES smooth muscle response to exogenous stimulation, nor a cholinergically mediated LES response. GH-RIH does inhibit the response of LESP both to intragastric alkali and to glycine by the apparent suppression of a hormonally mediated mechanism.

Effects of vasoactive intestinal polypeptide (VIP) on lower esophageal sphincter in awake baboons: comparison with glucagon and secretin.

The effects of vasoactive intestinal polypeptide (VIP), glucagon, and secretin on lower esophageal sphincter pressure were investigated in awake baboons. The three hormones were compared with respect to effect on (1) resting lower esophageal sphincter pressure and (2) maximal stimulatory response to pentagastrin. VIP was shown to reduce resting and pentagastrin-stimulated lower esophageal sphincter pressure with significantly greater potency than either secretin or glucagon. For reduction of resting lower esophageal sphincter pressure, the potency ratio of VIP to secretin was 16:1 and of VIP to glucagon was 32:1 (P less than 0.05). For inhibition of pentagastrin-stimulated sphincter pressure, the potency ratio of VIP to secretin was 32:1 and of VIP to glucagon was 64:1 (P less than 0.02). This demonstration of significantly increased potency of VIP over known inhibitory hormones strengthens the suggestion that VIP may have a physiologic role in the control of lower esophageal sphincter function.

Histaminergic pharmacology of primate lower esophageal sphincter.

We have studied the lower esophageal sphincter (LES) response to exogenous histamine and to H1- and H2-blocking agents in the awake baboon. Increasing intravenous bolus doses of histamine produce an increase in LES pressure with a maximum response at a dose of 12 microgram/kg. H1-receptor blockade with chlorpheniramine over a wide dose range did not alter basal LES pressure but did abolish the response of the LES to exogenous histamine. H2-receptor blockade with cimetidine at doses markedly inhibiting gastric acid secretion (2 mg/kg.h) did not alter basal LES pressure or the response of the LES to exogenous histamine. In addition, cimetidine did not alter the response of the LES to pentagastrin and bethanechol. Although histamine and histamine receptors are important in gastric secretion, they appear to have no identifiable role in the maintenance of basal LES smooth muscle tone in the baboon. These results demonstrate the presence of a stimulatory H1 receptor on baboon LES smooth muscle, but provide no evidence for the presence of an H2-inhibitory receptor. As opposed to the parietal cell, the LES response to pentagastrin and bethanechol does not require a H2 receptor.

Muscle function and structure of the esophagus of the baboon (Papio anubis).

A baboon (Papio anubis) was used as a model for the study of the physiology of the esophagus. This model closely resembles the human being phylogenetically and physiologically. Base-line lower esophageal sphincter pressure and peristaltic amplitude are similar to that of man. In addition, the anatomic transition from striated to smooth muscle is identical to that of the human esophagus. The sphincter-depressing effect of ketamine anesthesia was demonstrated.

Inhibition of dopamine beta-hydroxylase by 4-hydroxypyrazole: ethanol-pyrazole effects on serum dopamine beta-hydroxylase in vivo.

Chronic pyrazole treatment caused a 40% decrease in rat serum dopamine beta-hydroxylase (DBH) activity. Ethanol given simultaneously with pyrazole prevented the inhibition. 4-Hydroxypyrazole, the major metabolite of pyrazole, competitively inhibited both rat serum DBH and partially purified bovine adrenal DBH in vitro. In vivo, 4-hydroxypyrazole caused large decreases in rat serum (53-84%) and adrenal (97%) DBH activity but had no effect on brain enzyme. The decrease in rat serum DBH after chronic pyrazole treatment and the pyrazole-induced changes in physiological parameters, such as body weight and temperature, may be due to the formation of 4-hydroxypyrazole.