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The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10 -mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM–CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor.

The angiotensin-converting enzyme (ACE) inhibitory activity and the concentration of the 2 ACE-inhibiting tripeptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) were studied during cheese ripening in 7 Swiss cheese varieties. The semi-hard cheeses Tilsiter, Appenzeller 1/4 fat, Tête de Moine, and Vacherin fribourgeois and the extra-hard and hard cheeses Berner Hobelkäse, Le Gruyère, and Emmentaler were investigated. Three loaves of each variety manufactured in different cheese factories were purchased at the beginning of commercial ripeness and investigated at constant intervals until the end of the usual sale period. Good agreement was found between ACE-inhibitory activity and the total concentration of VPP and IPP at advanced ripening stages. In most of the investigated varieties ACE-inhibitory activity and the concentration of the 2 tripeptides initially increased during the study period. A decline in the concentration of VPP and IPP was obtained toward the end of the investigated period for Tilsiter and Gruyère. The ratio of VPP/IPP decreased during ripening in all varieties with the exception of Emmentaler. However, large variations were observed among the cheese varieties as well as the individual loaves of the same variety. Chemical characterization of the investigated cheeses revealed that qualitative differences in the proteolysis pattern, not quantitative differences in the degree of proteolysis, are responsible for the observed variations in the concentrations of VPP and IPP. The presence of Lactobacillus helveticus in the starter culture was associated with elevated concentrations of VPP and IPP. The results of the present study show that concentrations of VPP and IPP above 100mg/kg are attainable in semi-hard cheese varieties after ripening periods of about 4 to 7 mo and that stable concentrations of the 2 antihypertensive tripeptides can be expected over several weeks of cheese ripening.

The contents of the 2 antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) were determined in 101 samples from 10 different Swiss cheese varieties using HPLC with subsequent triple mass spectrometry. In the category of extra hard and hard cheeses, the Protected Denomination of Origin cheeses Berner Alpkäse and Berner Hobelkäse, L’Etivaz à rebibes, Le Gruyère, Sbrinz, Emmentaler (organic and conventional) and in the category of semihard cheeses, the varieties Tilsiter, Appenzeller 14 fat and full fat, Tête de Moine, and Vacherin fribourgeois were screened in the study. The average concentration of the sum of VPP and IPP in the screened cheese varieties varied to a large extent, and substantial variations were obtained for individual samples within the cheese varieties. The lowest average concentration of the 2 tri-petides was found in L’Etivaz à rebibes (n = 3) at 19.1mg/kg, whereas Appenzeller 14 fat (n = 4) contained the greatest concentration at 182.2mg/kg. In individual samples, the total concentration of VPP and IPP varied between 1.6 and 424.5mg/kg. With the exception of a 10-yr-old cheese, VPP was always present at greater concentrations than IPP. Milk pretreatment, cultures, scalding conditions, and ripening time were identified as the key factors influencing the concentration of these 2 naturally occurring bioactive peptides in cheese. The results of the present study show that various traditional cheese varieties contain, on average, similar concentrations of the 2 antihypertensive peptides to the recently developed fermented milk products with blood pressure–lowering property. This may serve as a basis for the development of a functional cheese with blood pressure–lowering property.

Purpose To report outcomes of deep sclerectomy (DS) with intraoperative mitomycin C (MMC) application in eyes with previous failed glaucoma surgery (GS) and/or cataract extraction (CE). Patients and methods Single-surgeon case series of 82 eyes of 82 patients undergoing DS with MMC. The patients had previous CE with IOL and/or conjunctival GS and treated intraocular pressure (IOP) >18 mm Hg. MMC (0.2 mg/ml) was applied for 2–3 min before scleral flap dissection. Complete success was defined as IOP between 6 and 21 mm Hg or a reduction of 20% from baseline without medications. Reoperation for glaucoma or related complications, or loss of light perception vision was considered as failure. Results Mean follow-up was 57.7±22.4 months with 78% of patients completing the 3-year follow-up. Mean IOP decreased from 24.0 mm Hg (22.3–25.6, 95% confidence intervals) to 13.4 mm Hg (12.0–14.2) at 3 years after surgery ( P <0.001). There was a significant decrease in the number of glaucoma medications from 2.0±1 preoperatively, to 0.3±0.7, 3 years after surgery. Kaplan–Meier cumulative success rates were 85.6% at 1 year, 80.0% at 2 years, and 76% at 3 years. At 3 years, IOP was maintained <19 and 15 mm Hg in 83 and 70% of eyes, respectively. Fourteen eyes (17.1%) had complications. Delayed hypotony (IOP <6 mm Hg) was the commonest complication in five eyes (6.1%). Conclusion DS with MMC appears to be a safe and effective surgical procedure for eyes with previous intraocular surgery.

Summary Background Mental health stigma (MHS) places a burden on those affected that far exceeds psychosocial harms. Contact-based anti-stigma work has been found effective for several target groups. For medical students however, its efficacy remains unclear. Aim The purpose of this study was to examine the efficacy of contact-based, trialogic anti-stigma training for medical students. Methods A randomized controlled trial (RCT) was conducted, controlling for standard clinical placement in psychiatry. External validity was maximized by including all students ( n  = 204) who started their 6‑week obligatory psychiatry course during the study period between March and July 2018. Assessments were conducted at the beginning of each of the two covered terms and immediately postintervention. Results Students who received the anti-stigma training displayed significantly less stigmatizing attitudes after the intervention, measured using the MICA (Mental Illness—Clinicians’ Attitudes) scale as primary outcome. Analogous findings were noted for social distance and stereotypes , whereas these could not be observed for emotional reactions . All significant changes were independent of gender and age. Conclusion The positive results underpin the research in this field and point towards the inclusion of comparable interventions in regular student curricula. Given the limitation of a missing late follow-up, however, further research regarding the persistence of stigma reduction is needed.

Consumption of CLA by lactating women affects the composition of their milk, but the pattern of the different CLA isomers is still unknown. We determined the effects of short maternal supplementation with CLA‐rich Alpine butter on the occurrence of FA and CLA isomers in human milk. In an open randomized controlled study with a two‐period cross‐over design, milk FA and CLA isomer concentrations were measured on postpartum days >‐20 in two parallel groups of lactating women before, during, and after consumption of defined quantities of Alpine butter or margarine with comparable fat content (10 d of butter followed by 10 d of margarine for one group, and vice versa in the other). In the 16 women who completed the study (8/group), Alpine butter supplementation, increased the C16 and C18 FA, the sum of saturated FA, the 18∶1 trans FA, and the trans FA with CLA. The CLA isomer 18∶2 c9, t11 increased by 19.7%. Significant increases were also found for the isomers t9,t111, t7,c9,t11,c13, and t8,c10 18∶2. The remaining nine of the total 14 detectable isomers showed no changes, and concentrations were <5 mg/100g fat. A breastfeeding mother can therefore modulate the FA/CLA supply of her child by consuming Alpine butter. Further studies will show whether human milk containing this FA and CLA isomer pattern acts as a functional food for newborns.