Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.     

Studies on the radioiodination of very low density lipoprotein obtained from different mammalian species

Very low density lipoprotein (VLDL) isolated from human, pig and rat serum showed marked differences in labelling patterns when radioiodinated under similar conditions, with greater amounts of ¹²⁵ I-labelled iodine being incorporated into the lipid moieties of pig and rat VLDL than into human VLDL. The effect (on their biological behaviour) of introducing increasing amounts of iodine into the lipoproteins was tested for both human and rat VLDL with preparations containing iodine:protein (I/P) ratios varying from < 0.5 to 12. After injection into rats and analysis of disappearance curves, only minor differences in catabolic rates were observed between different preparations. Thus, rat VLDL, with I/P ratios varying from < 0.5–12 showed fast and slow exponential components varying in half life ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) between 40–63 min and 10–11 h, respectively, while human VLDL with comparable I/P ratios, had a fast component varying from ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) 50–78 min and a slower component ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) of 10.5–12.5 h The plasma disappearance of human VLDL, labelled by the lactoperoxidase method, was also characterised by two exponential components with mean half lives of 67 min and 11 h, respectively, suggesting similarity in the biological behaviour of human VLDL labelled both enzymatically and with iodine monochloride. The results also indicated similarity in the catabolism of rat and human VLDL by the rat, suggesting that this animal is a suitable model for studying VLDL metabolism.     

Faecal immunochemical test outside colorectal cancer screening?

Faecal immunochemical tests (FITs) are the most widely colorectal cancer (CRC) diagnostic biomarker available. Many population screening programmes are based on this biomarker, with the goal of reducing CRC mortality. Moreover, in recent years, a large amount of evidence has been produced on the use of FIT to detect CRC in patients with abdominal symptoms in primary healthcare as well as in surveillance after adenoma resection. The aim of this review is to highlight the available evidence on these two topics. We will summarize the evidence on diagnostic yield in symptomatic patients with CRC and significant colonic lesion and the different options to use this (thresholds, brands, number of determinations, prediction models and combinations). We will include recommendations on FIT strategies in primary healthcare proposed by regulatory bodies and scientific societies and their potential effects on healthcare resources and CRC prognosis. Finally, we will show information regarding FIT-based surveillance as an alternative to endoscopic surveillance after high-risk polyp resection. To conclude, due to the coronavirus disease 2019 pandemic, FIT-based strategies have become extremely relevant since they enable a reduction of colonoscopy demand and access to the healthcare system by selecting individuals with the highest risk of CRC.     

Das Verhalten des elastischen Gewebes in den Aortenklappen bei Blutdrucksteigerung

Ohne ZusammenfassungMit 6 Textabbildungen.     

Duration of participation of correctional volunteers as a function of personal and situational variables

From a population of 302 volunteers in a volunteers in probation program, 85 females and 25 males returned questionnaires which measured a variety of personal and situational variables. Based upon their duration of service, volunteers were classified as Committed (having served the desired six months or more), Partially Committed (having served less than six months), and Uncommitted (having failed to complete the orientation session). A multivariate F-test did not differentiate among the groups for the personal variables, but the multivariate F for the situational variables was significant. Specifically, Committed volunteers were significantly more satisfied with the orientation process and with the volunteer agency staff support, felt they received more help from probation officers, and reported spending significantly less time with administrative tasks as compared with Partially Committed volunteers. These results indicate the relative importance of situational variables over personal variables, and the importance of support from the volunteer and probation agencies.     

Characterization of mGluR5R,a novel,metabotropic glutamate receptor 5-related gene

We report here the isolation of a novel gene termed mGluR5R (mGluR5-related). The N-terminus of mGluR5R is highly similar to the extracellular domain of metabotropic glutamate receptor 5 (mGluR5) whereas the C-terminus bears similarity to the testis-specific gene, RNF18. mGluR5R is expressed in the human CNS in a coordinate fashion with mGluR5. Although the sequence suggests that mGluR5R may be a secreted glutamate binding protein, we found that when expressed in HEK293 cells it was membrane associated and not secreted. Furthermore, mGluR5R was incapable of binding the metabotropic glutamate receptor class I selective agonist, quisqualate. Although mGluR5R could not form disulfide-mediated covalent homodimers, it was able to form a homomeric complex, presumably through noncovalent interactions. mGluR5R also formed noncovalent heteromeric associations with an engineered construct of the extracellular domain of mGluR5 as well as with full-length mGluR5 and mGluR1alpha. The ability of mGluR5R to associate with mGluR1alpha and mGluR5 suggests that it may be a modulator of class I metabotropic glutamate receptor function.