Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells.

BACKGROUND: Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells. METHODS: The effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells. RESULTS: We show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively. CONCLUSIONS: These results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.

Prenatal diagnosis of Silver-Russell syndrome with 8q12 deletion including the PLAG1 gene: a case report and review.

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder. A retrospective analysis predicted that the live birth prevalence of SRS in Estonia is 1:15,886 [Yakoreva et al., Eur J Hum Genet, 2019, 27(11), 1649-1658]. The most common causative genetic mechanism in the proband is loss of paternal methylation in the imprinted control region 1 (ICR1) at 11p15.5 chromosome. A few studies suggested that inherited or de novo loss-of-function alterations of the PLAG1 gene, including the whole-gene deletion and intragenic pathogenic variants, could cause a rare type of SRS. To date, less than 20 unrelated PLAG1-related SRS cases have been reported, and the clinical information about these cases is limited. We report the first prenatal case of SRS with 8q12 deletion (including the PLAG1 gene). The fetus presented with intrauterine growth retardation, small for gestational age, relative macrocephaly at birth, and a protruding forehead. Unlike classical SRS cases, the fetus had micrognathia and did not show body asymmetry. We hope that the literature review in this study provides new insights into genotype-phenotype relationships of PLAG1-related SRS.

Association between maternal gestational weight gain and preterm birth according to body mass index and maternal age in Quzhou, China.

The aim of this study is to investigate the association between maternal gestational weight gain (GWG) and preterm birth according to pre-pregnancy body mass index (BMI) and maternal age. We did a cohort, hospital-based study in Quzhou, South China, from 1 Jan 2018 to 30 June 2019. We selected 4274 singleton live births in our analysis, 315 (7.4%) of which were preterm births. In the overall population, excess GWG was significantly associated with a decreased risk of preterm birth compared with adequate GWG (adjusted OR 0.81 [95% CI 0.72-0.91]), and the risk varied by increasing maternal age and pre-pregnancy BMI. Interestingly, underweight women who older than 35 years with excess GWG had significantly increased odds of preterm birth compared with adequate GWG in underweight women aged 20-29 years (2.26 [1.06-4.85]) and normal weight women older than 35 years (2.23 [1.13-4.39]). Additionally, low GWG was positively and significantly associated with preterm birth overall (1.92 [1.47-2.50]). Among normal weight women category, compared with adequate GWG women aged 20-29 years did, those older than 20 years with low GWG, had significantly higher odds of preterm birth, which increased with maternal age (1.80 [1.16-2.79] in 20-29 years, 2.19 [1.23-3.91] in 30-34 years, 3.30 [1.68-6.46] in ≫ 35 years). In conclusion, maternal GWG was significantly associated with the risk of preterm birth, but the risk varied by pre-pregnancy BMI and maternal age.