Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.

BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.

Paid maternal leave is associated with infant brain function at 3 months of age.

The first months of life are critical for establishing neural connections relevant for social and cognitive development. Yet, the United States lacks a national policy of paid family leave during this important period of brain development. This study examined associations between paid leave and infant electroencephalography (EEG) at 3 months in a sociodemographically diverse sample of families from New York City (N = 80; 53 males; 48% Latine; data collection occurred 05/2018-12/2019). Variable-centered regression results indicate that paid leave status was related to differences in EEG power (ps < .02, R2 s > .12). Convergent results from person-centered latent profile analyses demonstrate that mothers with paid leave were 7.39 times as likely to have infants with EEG profiles characterized by increased higher-Hz power (95% CI, 1.9-36.9), potentially reflecting more mature patterns of brain activity.

Maternal heart rate variability at 3-months postpartum is associated with maternal mental health and infant neurophysiology.

Previous research has demonstrated a critical link between maternal mental health and infant development. However, there is limited understanding of the role of autonomic regulation in postpartum maternal mental health and infant outcomes. In the current study, we tested 76 mother-infant dyads from diverse socioeconomic backgrounds when infants were 3-months of age. We recorded simultaneous ECG from dyads while baseline EEG was collected from the infant; ECG heart rate variability (HRV) and EEG theta-beta ratio and alpha asymmetry were calculated. Dyadic physiological synchrony was also analyzed to better understand the role of autonomic co-regulation. Results demonstrated that lower maternal HRV was associated with higher self-reported maternal depression and anxiety. Additionally, mothers with lower HRV had infants with lower HRV. Maternal HRV was also associated with higher infant theta-beta ratios, but not alpha asymmetry. Exploratory analyses suggested that for mother-infant dyads with greater physiological synchrony, higher maternal HRV predicted increased infant theta-beta ratio via infant HRV. These findings support a model in which maternal mental health may influence infant neurophysiology via alterations in autonomic stress regulation and dyadic physiological co-regulation.

Malignant Epithelial Tumors of the Ovary: Pathogenesis and Imaging.

Epithelial ovarian neoplasms (EON) constitute the majority of ovarian cancers. Among EON, high-grade serous carcinoma (HGSC) is the most common and most likely to present at an advanced stage. Radiologists should recognize the imaging features associated with HGSC, particularly at ultrasound and MR imaging. Computed tomography is used for staging and to direct care pathways. Peritoneal carcinomatosis is common and does not preclude surgical resection. Other less common malignant EON have varied appearances, but share a common correlation between the amount of vascularized solid tissue and the likelihood of malignancy.

Framing matters but varies: a semantic network analysis of media representations of post-Fukushima food imports across three Chinese societies.

There is a remarkable gap between scientific experts and the nonscientific public regarding the safety of food imported from nuclear-contaminated areas in Japan. How socio-scientific issues such as post-Fukushima food imports are framed in media discourse may have effects on the way people perceive and reason about potential threats, and, in turn, influence government-initiated policies and regulations. In this study, semantic network analysis is performed to examine the diverse media representations of post-Fukushima food imports across information-seeking sources (mass media and search-based media) and three Chinese societies (Hong Kong, Mainland China, and Taiwan). We found that media representation of the crisis differs across sources and sociopolitical contexts. It is also discussed how these channel-specific and contextual factors may affect public opinion. This knowledge can enhance regulatory authorities' informed decision-making about food safety issues, guide crisis professionals' communication efforts, and call for a more context-sensitive approach to public health crisis management.

A combined gene expression and functional study reveals the crosstalk between N-Myc and differentiation-inducing microRNAs in neuroblastoma cells.

MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical role in neuroblastoma tumorigenesis. MYCN regulates neuroblastoma cell differentiation, which is one of the mechanisms underlying its oncogenic function. We recently identified a group of differentiation-inducing microRNAs. Given the demonstrated inter-regulation between MYCN and microRNAs, we speculated that MYCN and the differentiation-inducing microRNAs might form an interaction network to control the differentiation of neuroblastoma cells. In this study, we found that eight of the thirteen differentiation-inducing microRNAs, miR-506-3p, miR-124-3p, miR-449a, miR-34a-5p, miR-449b-5p, miR-103a-3p, miR-2110 and miR-34b-5p, inhibit N-Myc expression by either directly targeting the MYCN 3'UTR or through indirect regulations. Further investigation showed that both MYCN-dependent and MYCN-independent pathways play roles in mediating the differentiation-inducing function of miR-506-3p and miR-449a, two microRNAs that dramatically down-regulate MYCN expression. On the other hand, we found that N-Myc inhibits the expression of multiple differentiation-inducing microRNAs, suggesting that these miRNAs play a role in mediating the function of MYCN. In examining the published dataset collected from clinical neuroblastoma specimens, we found that expressions of two miRNAs, miR-137 and miR-2110, were significantly anti-correlated with MYCN mRNA levels, suggesting their interactions with MYCN play a clinically-relevant role in maintaining the MYCN and miRNA expression levels in neuroblastoma. Our findings altogether suggest that MYCN and differentiation-inducing miRNAs form an interaction network that play an important role in neuroblastoma tumorigenesis through regulating cell differentiation.