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.     

In Utero Exposure to Benzo[a]pyrene Induces Ovarian Mutations at Doses That Deplete Ovarian Follicles in Mice

Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are ubiquitous environmental contaminants formed during incomplete combustion of organic materials. Our prior work showed that transplacental exposure to BaP depletes ovarian follicles and increases prevalence of epithelial ovarian tumors later in life. We used the MutaMouse transgenic rodent model to address the hypothesis that ovarian mutations play a role in tumorigenesis caused by prenatal exposure to BaP. Pregnant MutaMouse females were treated with 0, 10, 20, or 40 mg/(kg day) BaP orally on gestational days 7–16, covering critical windows of ovarian development. Female offspring were euthanized at 10 weeks of age; some ovaries with oviducts were processed for follicle counting; other ovaries/oviducts and bone marrow were processed for determination of lacZ mutant frequency (MF). Mutant plaques were pooled within dose groups and sequenced to determine the mutation spectrum. BaP exposure caused highly significant dose-related decreases in ovarian follicles and increases in ovarian/oviductal and bone marrow mutant frequencies at all doses. Absence of follicles, cell packets, and epithelial tubular structures were observed with 20 and 40 mg/(kg day) BaP. Depletion of ovarian germ cells was inversely associated with ovarian MF. BaP induced primarily G > T and G > C transversions and deletions in ovaries/oviducts and bone marrow cells and produced a mutation signature highly consistent with that of tobacco smoking in human cancers. Overall, our results show that prenatal BaP exposure significantly depletes ovarian germ cells, causes histopathological abnormalities, and increases the burden of ovarian/oviductal mutations, which may be involved in pathogenesis of epithelial ovarian tumors. Environ. Mol. Mutagen. 60:410–420, 2019. © 2018 Her Majesty the Queen in Right of Canada     

Non-response for health-related quality of life outcomes in ICU patients: A systematic review of the reporting in randomised trials

Background

Health-related quality of life (HRQoL) is frequently assessed in randomised clinical trials (RCTs) in the intensive care unit (ICU), but data are limited regarding the proportions of patients without responses or not surviving to HRQoL follow-up and the handling of this. We aimed to describe the extent and pattern of missing HRQoL data in intensive care trials and describe how these data and deaths were handled statistically.

Methods

We conducted a systematic review and meta-analysis following a published protocol. We searched PubMed, EMBASE, CINAHL and Cochrane Library for RCTs involving adult ICU patients reporting HRQoL as an outcome and excluded RCTs unobtainable in full text. We performed risk of bias assessment independently and in duplicate.

Results

We included 196 outcomes from 88 RCTs published in the years 2002–2022; the numbers of patients alive and eligible to respond HRQoL were reported in 76% of trials. At follow-up, median 27% (interquartile range 14%–39%) of patients had died, and median 20% (9%–38%) of survivors did not respond across outcomes. Analyses of 80% of outcomes were restricted to complete cases only. The handling of non-survivors in analyses were reported for 46% of outcomes, with 26% of all outcomes reported as including non-survivors (using the value zero or the worst possible score).

Conclusion

For HRQoL outcomes in ICU trials, we found that mortality at time of follow-up was high and non-response among survivors frequent. The reporting and statistical handling of these issues were insufficient, which may have biased results.