Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some well‐validated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta?Mouse lung epithelial cells (FE1 cell assay) and a regulatory‐compliant in vivo Big Blue® mouse test. Consistent with previous reports, an additional six‐well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.     

The effect of caffeine abstinence on sleep among habitual caffeine users with poor sleep

Caffeine is the most widely used psychoactive substance in the world and is known to disrupt healthy sleep. However, very few studies have directly tested the effect of caffeine abstinence on sleep, and these have yielded inconsistent findings. The purpose of the present study was to examine changes in sleep following caffeine abstinence and examine the extent to which characteristics of habitual caffeine use moderated this change. Participants included 66 healthy, young adults with habitual caffeine use and poor sleep. During the 2‐week baseline, sleep was assessed using wrist actigraphy and daily caffeine use was assessed with bedtime diaries. Eligible participants then completed 1 week of caffeine abstinence, during which sleep was measured with wrist actigraphy. Multilevel models found no significant differences between either mean levels or growth trajectories of total sleep time or sleep efficiency between baseline and caffeine abstinence. Mean levels of sleep onset latency also did not differ between baseline and caffeine abstinence. A small but significant quadratic effect was observed, such that sleep onset latency decreased during the first few days of caffeine abstinence, then increased to levels above baseline. Characteristics of caffeine use did not moderate changes in sleep between baseline and caffeine abstinence. These data suggest that abstaining from caffeine may not result in long‐term sleep improvement for habitual caffeine users, which contradicts the common sleep health recommendation. The present findings encourage more rigorous investigation of the effectiveness of caffeine restriction on sleep.     

The Course of Eating Disorders Involving Bingeing and Purging Among Adolescent Girls: Prevalence,Stability, and Transitions

Purpose

To quantify eating disorder (ED) stability and diagnostic transition among a community-based sample of adolescents and young adult females in the United States.

Associations of common SNPs in the SORT1, GCKR,LPL, APOA1, CETP,LDLR, APOE genes with lipid trait levels in an Algerian population sample

Genome-wide association studies have identified many lipid-associated loci primarily in European and Asian populations. In view of the differences between ethnic groups in terms of the frequency and impact of these variants, our objective was to evaluate the relationships between eight lipid-associated variants (considered individually and in combination) and fasting serum triglyceride, total cholesterol, HDL- and LDL-cholesterol levels in an Algerian population sample (ISOR study, n = 751). Three SNPs (in SORT1, CETP and GCKR) were individually associated with lipid level variations. Moreover, the risk allele scores for total cholesterol, triglyceride and LDL-C levels (encompassing between three and six SNPs) were associated with their corresponding lipid traits. Our study is the first to show that some of the lipid-associated loci in European populations are associated with lipid traits in Algerians. Although our results will have to be confirmed in other North African populations, this study contributes to a better understanding of genetic susceptibility to lipid traits in Algeria.