BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression.

Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.

The effect of aging on the chaperone concentrations in the hepatic, endoplasmic reticulum of male rats: the possible role of protein misfolding due to the loss of chaperones in the decline in physiological function seen with age.

The endoplasmic reticulum (ER) chaperones are highly conserved proteins that catalyze the posttranslational processing of all secretory and membrane proteins. Our studies suggest that chaperone declines are one of the two central defects in Alzheimer's disease. We propose that similar declines in other organ systems underlie the physiological deficits of aging. Rats were maintained in a colony from age 21 days to death. Animals were killed at regular intervals, and hepatic, ER chaperone contents were determined by immunoblotting. ERp55, ERp57, ERp72, BiP, and calnexin constitutive levels declined 30%-50% with age. Calreticulin was unaffected. BiP (also known as GRP78), ERp55, and ERp57 showed marked swings with peaks occurring in midwinter and midsummer. This cyclics declined 73% with age. Considering the role of the ER chaperones in membrane and secretory protein posttranslational processing, these data support the concept that their loss could lead to many of the physiological declines associated with aging.

Population-based case-control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk.

The aryl hydrocarbon receptor (AhR) is a key regulator of the transcriptional expression for the cytochrome P450 1 (CYP1) genes. CYP1A2 is one of the major CYP1 enzymes that catalyse 2-hydroxylation of estrogen, a hormone that plays a critical role in the etiology of breast cancer. In this study, we investigated whether two common polymorphisms in these two genes, CYP1A2*1F and AhR Lys554Arg, were associated with breast cancer risk in 1090 cases and 1183 controls, a subset of the population-based case-control study, the Shanghai Breast Cancer Study. Caffeine tests were performed in vivo in a subset of 236 study subjects to investigate the relationship of these two polymorphisms with CYP1A2 activity. For the AhR gene, the A (Lys) allele was associated with a decreased risk of breast cancer. Using the genotype GG as reference, odds ratios of 0.82 [95% confidence interval (CI)=0.69-0.99] for the AG genotype and 0.76 (95% CI=0.58-1.01) for the AA genotype (P for trend=0.018) were obtained. However, no association was observed between CYP1A2 genotypes and breast cancer risk, although the CYP1A2*1F polymorphism was found to be related to CYP1A2 activity. The geometric mean values for the caffeine metabolites ratio were 2.90, 2.30, and 1.95 for CC, AC, and AA genotypes, respectively (P for trend=0.024). In conclusion, the results from our study suggest that the AhR Lys554Arg polymorphism may be a genetic susceptibility factor for breast cancer, whereas CYP1A2*1F, which is a potentially functional single nucleotide polymorphism, may not be related to breast cancer risk.

In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.

The beta-amyloids (abetas) are the major components of the plaque observed in the brains of patients with Alzheimer's disease. The conundrum is that although they are produced in everyone during the posttranslational processing in the endoplasmic reticulum (ER) of the amyloid precursor protein (APP), deposits are only observed in the elderly. Our work suggests that normals have a carrier protein(s) keeping them in solution. Based on immunoblotting studies of cerebrospinal fluid (CSF) from normals, we find that the bulk of the abetas are bound to the ER chaperones, ERp57 and calreticulin, suggesting that these may be carrier proteins which prevent aggregation of the abetas and that the deposits are due to faulty ER posttranslational processing of APP with the failure to form this complex. If membrane protein synthesis is similarly affected, it could explain the neuronal dysfunction characteristic of Alzheimer's disease.

Within-person variability of urinary 6beta-hydroxycortisol to urinaryl ratios in Caucasian women.

Cortisol is metabolized to 6beta-hydroxycortisol by human cytochrome p450-3A4 (CYP3A4), an important enzyme involved in the metabolism of a variety of exogenous and endogenous compounds. Both cortisol and 6beta-hydroxycortisol are excreted in urine, and the ratio of these steroids has been proposed as an indicator of CYP3A4 activity. We evaluated within-person variability of this biomarker in 10 healthy Caucasian women, aged 23-58 years. Each study participant was asked to provide a fasting morning urine sample once a week consecutively for 8 weeks. Urinary cortisol and 6beta-hydroxycortisol were determined by immunoassay kits purchased from the DiaSorin (Stillwater, MN) and the Stabiligen (Nancy, France), respectively. The coefficients of variation (CV) of urinary 6beta-hydroxycortisol to cortisol ratios from study participants ranged from 16.7 to 51.4% (mean, 31.1%) over the study period. The level of the ratio measured in any single urine sample was correlated reasonably well with the average of the ratios over the 8-week study period from the same woman, with the mean correlation coefficient of 0.79. These results indicated that urinary 6beta-hydroxycortisol to cortisol ratios measured in a spot urine sample may reflect the level of this biomarker over a relatively longer time period in Caucasian women, and thus, it can be used in epidemiologic studies as a biomarker to evaluate the association between CYP3A4 activity and disease risk.