Racial disparities in the transgenerational transmission of low birthweight risk

Objective: To examine the association of maternal low birthweight (LBW) with infant LBW and infant LBW subgroups (i.e. moderate and very LBW), overall and among non-Hispanic (NH) white and NH black mothers.

Design: We conducted a population-based cohort study in Allegheny County, Pennsylvania, using linked birth record data of NH white and NH black mother-infant pairs (N?=?6,633) born in 1979–1998 and 2009–2011, respectively. The exposure of interest was maternal LBW (birthweight <2500 grams) while the outcomes were infant LBW and LBW subgroups – moderate LBW (1,500–2,499 grams) or very LBW (<1,500 grams). Logistic regression (binomial and multinomial) models were used to estimate adjusted Odds Ratios (ORs), Relative Risk Ratios (RRRs), and related 95% confidence intervals (CI). Stratified analyses were conducted to assess effect modification by mothers’ race.

Results: Maternal LBW was associated with 1.53 (95%CI: 1.15–2.02) and 1.75 (95%CI: 1.29–2.37) –fold increases in risk of infant LBW and MLBW, respectively, but not VLBW (RRR?=?0.86; 95%CI: 0.44–1.70). In race-stratified models, maternal LBW-infant LBW associations were observed among NH blacks (OR?=?1.88; 95%CI: 1.32–2.66) and not among NH whites (OR?=?1.03; 95%CI: 0.62–1.73) (P for interaction?=?0.07). Among NH blacks, maternal LBW was associated with a 2.18 (95%CI: 1.49, 3.20) –fold increase in risk of infant MLBW, but not VLBW (RRR?=?1.12; 95%CI: 0.54, 2.35). Among NH whites, LBW subgroup analyses could not be performed due to small numbers of VLBW infants among LBW mothers.

Conclusion: Mothers who were LBW at their own birth were more likely to have MLBW infants. Maternal race modified associations of maternal LBW with infant LBW, particularly infant MLBW. Further research is needed in this area to understand the potential mechanisms involved in the transgenerational transmission of LBW risk and race-specific differences in the transmission.     

Diffusion MRI changes in the anterior subventricular zone following chemoradiation in glioblastoma with posterior ventricular involvement

Journal of Neuro-Oncology - There is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which...     

The impact of patient characteristics on enzalutamide pharmacokinetics and how this relates to treatment toxicity and efficacy in metastatic prostate cancer patients

The aim of the study is to investigate the influence of patient characteristics, age and body mass index (BMI), on pharmacokinetics of enzalutamide, and to study the relationships between drug exposure and enzalutamide efficacy and toxicity, in mCRPC patients. Data were collected in a longitudinal cohort study (ANDROPS) and a prospective observational study (ILUMINATE), both in mCRPC patients treated with enzalutamide. To investigate the influence of age and BMI on exposure, enzalutamide and N-desmethylenzalutamide levels were compared by ANOVA. To investigate the relation of exposure versus time to progression (TTP), the sum plasma levels were divided into quartiles and compared by Kaplan–Meier analysis. To assess the relation of exposure with fatigue, plasma levels in patients experiencing fatigue vs. no fatigue were compared by and independent t test. Data of 68 mCRPC patients were included for analysis. Plasma levels were not different for age or BMI. No difference in TTP between both studies was observed (383 days (95% CI 287–859), and 567 days (95% CI 351–NR), p = 0.36). Kaplan–Meier analysis of quartiles of sum levels showed no difference for TTP. Fatigue was reported by 22 patients, no difference in sum plasma levels was observed between patients with and without fatigue. We observed that age and BMI did not influence systemic exposure in patients treated with enzalutamide. No relation of exposure with efficacy or fatigue was observed. Further research using enzalutamide at a lower dose is needed to understand the relation of enzalutamide exposure and fatigue.     

Evolving insights: how DNA repair pathways impact cancer evolution

Viewing cancer as a large, evolving population of heterogeneous cells is a common perspective. Because genomic instability is one of the fundamental features of cancer, this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation, development, metastasis, and relapse. With the increased mutation rate and abundant diversity of the gene pool, this heterogeneity leads to cancer evolution, which is the major obstacle in the clinical treatment of cancer. Cells rely on the integrity of DNA repair machineries to maintain genomic stability, but these machineries often do not function properly in cancer cells. The deficiency of DNA repair could contribute to the generation of cancer genomic instability, and ultimately promote cancer evolution. With the rapid advance of new technologies, such as single-cell sequencing in recent years, we have the opportunity to better understand the specific processes and mechanisms of cancer evolution, and its relationship with DNA repair. Here, we review recent findings on how DNA repair affects cancer evolution, and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.     

Finite Mixture Models with Student t Distributions: an Applied Example

Prevention Science - The use of finite mixture modeling (FMM) to identify unobservable or latent groupings of individuals within a population has increased rapidly in applied prevention research....     

The relative risk of noncervical high-risk human papillomavirus-related (pre)malignancies after recurrent cervical intraepithelial neoplasia grade 3: A population-based study

Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long-lasting increased risk for noncervical high-risk human papillomavirus (hrHPV)-related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post-treatment. Cases of noncervical hrHPV-related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18–76) and 31,594 person-years of follow-up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV-related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32–106.58). The IRR was 2.48 (95% CI 1.87–3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow-up and prophylactic hrHPV vaccination are warranted.     

Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma

The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.