CNS Maturation Process in Children and Adolescents in the Northern Region of the Russian Federation and Its Reflection in the Dynamics of Integral EEG Parameters

Neuroscience and Behavioral Physiology - We present here results from analysis of the formation of brain bioelectrical activity in children and adolescents living in the northern region of Russia...     

Correction to: “Living with COVID”—implications for immunosuppressed and immunocompromised

Clinical Rheumatology -     

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.     

Bodily obsessions: intrusiveness of organs in somatic obsessive–compulsive disorder

Medicine, Health Care and Philosophy - In this paper, I will provide a phenomenological analysis of somatic obsessions at times present in obsessive–compulsive disorder. I will compare two...     

Sinensetin attenuates oxygen–glucose deprivation/reperfusion-induced neurotoxicity by MAPK pathway in human cerebral microvascular endothelial cells

Sinensetin is a polymethoxylated flavone with anti-inflammatory and anti-oxidative activities. This work aimed to explore the function and mechanism of sinensetin in oxygen and glucose deprivation/reperfusion (OGD/R)-induced neurotoxicity. The overlapping target genes of cerebral stroke and sinensetin were determined according to GeneCards and ParmMapper tools and were subjected to Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Human cerebral microvascular endothelial cells (HCMECs) were stimulated with OGD/R. Neurotoxicity was investigated by Cell Counting Kit-8, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) level, qRT-PCR, and TUNEL analysis. The proteins (p38, JNK, and ERK) in mitogen-activated protein kinase (MAPK) signaling were measured using Western blotting. Total of 50 overlapping target genes of cerebral stroke and sinensetin were predicted. Pathway analysis showed they might be involved in the MAPK pathway. Sinensetin attenuated OGD/R-induced neurotoxicity by mitigating viability reduction, LDH release, ROS generation, inflammatory response, and apoptosis in HCMECs. Sinensetin weakened OGD/R-induced activation of the MAPK pathway via decreasing the phosphorylation of p38, JNK, and ERK. The pathway inhibitors mitigated the activation of the MAPK signaling, and sinensetin exacerbated this effect. The inhibitors reversed OGD/R-induced neurotoxicity in HCMECs, and sinensetin contributed to this role. Overall, sinensetin prevents OGD/R-induced neurotoxicity through decreasing the activation of MAPK pathway.