Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.     

Impact of overweight and obesity on US renal cell carcinoma incidence trends (1995-2018)

In the United States, renal cell carcinoma (RCC) incidence and the prevalence of obesity, an established risk factor for RCC, have been increasing for several decades. RCC is more common among older individuals. We sought to quantify the contribution of excess adiposity to the rising incidence of RCC among individuals 60 years or older. National Institutes of Health-American Association of Retired Persons Diet and Health Study data (n = 453 859 participants, enrolled in 1995-1996, age at enrollment 50-71 years) were used to estimate multivariable-adjusted hazard ratios (HRs) for RCC across body mass index categories and HRs associated with smoking. Population attributable fractions (PAFs) were calculated using estimated HRs and annual overweight/obesity prevalence from the National Health Interview Survey (1985-2008). PAF estimates were combined with RCC incidence from Surveillance, Epidemiology and End Results-13 to calculate annual percent changes in RCC incidence attributable (and unrelated) to overweight/obesity. We found that between 1995 and 2018, among individuals aged 60 years and older, PAF for overweight/obesity increased from 18% to 29% for all RCCs. In comparison, the PAF for smoking declined from 12% to 9%. RCC incidence increased 1.8% per year (95% confidence interval [CI] 1.5%-2.1%) overall, while RCC incidence attributable to overweight/obesity increased 3.8% per year (95%CI 3.5%-4.2%) and RCC incidence unrelated to overweight/obesity increased 1.2% per year (95% CI 0.9%-1.4%). In conclusion, overweight/obesity appears to have contributed importantly to the rising incidence of RCC in the United States since the mid-1990s. Public health interventions focused on reducing overweight and obesity could help substantially in curbing this trend.     

Drug‐induced photosensitivity: culprit drugs,potential mechanisms and clinical consequences

Drug‐induced photosensitivity, the development of phototoxic or photoallergic reactions due to pharmaceuticals and subsequent exposure to ultraviolet or visible light, is an adverse effect of growing interest. This is illustrated by the broad spectrum of recent investigations on the topic, ranging from molecular mechanisms and culprit drugs through epidemiological as well as public health related issues to long‐term photoaging and potential photocarcinogenic consequences. The present review summarizes the current state of knowledge on the topic while focusing on culprit drugs and long‐term effects. In total, 393 different drugs or drug compounds are reported to have a photosensitizing potential, although the level of evidence regarding their ability to induce photosensitive reactions varies markedly among these agents. The pharmaceuticals of interest belong to a wide variety of drug classes. The epidemiological risk associated with the use of photosensitizers is difficult to assess due to under‐reporting and geographical differences. However, the widespread use of photosensitizing drugs combined with the potential photocarcinogenic effects reported for several agents has major implications for health and safety and suggests a need for further research on the long‐term effects.     

Major Cardiac–Psychiatric Drug–Drug Interactions: a Systematic Review of the Consistency of Drug Databases

Cardiovascular Drugs and Therapy - Major depressive disorder (MDD) and anxiety disorders (AD) are both highly prevalent among individuals with arrhythmia, ischemic heart disease, heart failure,...     

Associations of nadir haemoglobin level and red blood cell transfusion with mortality and length of stay in surgical specialties: a retrospective cohort study

Few studies have investigated if, and how, red cell transfusion and anaemia interact. We analysed 60,955 admissions to three metropolitan hospitals in Western Australia between 2008 and 2017 to determine whether the relationship between red cell transfusion and outcomes in surgical patients differed by lowest (nadir) level of haemoglobin. At levels above 100 g.l⁻¹, in-hospital, 30-day and 1-year mortality were higher with transfusion, the adjusted odds ratios (ORs) (95%CI) being 8.80 (4.43–17.45) p < 0.001 and 3.68 (1.93–7.02) p < 0.001 and the adjusted hazard ratio (95%CI) being 1.83 (1.28–2.61) p = 0.001, respectively. Likewise, between 90 g.l⁻¹ and 99 g.l⁻¹, in-hospital, 30-day and 1-year mortality were higher with transfusion, the adjusted odds ratio (95%CI) being 3.76 (2.23–6.34) p < 0.001 and 1.96 (1.23–3.12) p < 0.001 and the adjusted hazard ratio (95%CI) being 1.34 (1.05–1.70) p = 0.017, respectively. Length of stay was longer with transfusion at nadir haemoglobin levels above 100 g.l⁻¹ and in the following ranges: 90–99 g.l⁻¹, 80–89 g.l⁻¹, 70–79 g.l⁻¹ and 60–69 g.l⁻¹, the adjusted rate ratio (95%CI) being 1.38 (1.25–1.53) p < 0.001, 1.18 (1.10–1.27) p < 0.001, 1.17 (1.13–1.22) p < 0.001, 1.07 (1.02–1.12) p = 0.003 and 1.24 (1.13–1.36) p < 0.001, respectively. Mortality was higher with red cell transfusion at haemoglobin levels greater than 90 g.l⁻¹, whereas at all levels below 90 g.l⁻¹ mortality was not significantly higher or lower. Length of stay was longer with transfusion at nadir haemoglobin levels of 60 g.l⁻¹ or above. Our results suggest that nadir haemoglobin modified the relationship between red cell transfusion and outcomes and adds to the evidence recommending caution before transfusing red cells.     

It is more than Interference: Examining the neurohemodynamic correlates of the flanker task with functional near‐infrared spectroscopy

Previous functional near‐infrared spectroscopy studies using the Eriksen flanker task, in contrast to functional magnetic resonance imaging studies, revealed the quite puzzling finding of an inverted conflict effect, that is, greater middle and superior frontal activation in response compatible than in response incompatible trials. However, since neither prior functional near‐infrared spectroscopy studies nor most previous functional magnetic resonance imaging studies separated between an identical and a compatible condition, it is hard to pinpoint whether this discrepancy occurs on the level of stimulus processing or response generation. By assigning two letters to both left (D, F) and right (J, K) hand reactions, we were able to separate identical (e.g., JJJ) and compatible (e.g., JKJ) conditions that solely differ in their stimulus congruency. Replicating prior functional magnetic resonance imaging findings, we found the standard conflict effect at the transition of superior and middle frontal gyrus, when comparing the activation in compatible trials to that in incompatible trials. Both changes in oxygenated and deoxygenated hemoglobin thus pointed to more effortful processing in incompatible trials. Interestingly, however, identical trials showed the highest activation in this region, according to both changes in oxygenated and deoxygenated blood. A finding that mirrors and extends prior functional near‐infrared spectroscopy findings, which only regarded oxygenated blood. We argue that this pattern of results does not reflect the standard conflict effect. We rather assume that other processes like perceptual familiarity or strategic readjustment might be at play.     

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