RESUMO
Birt-Hogg-Dubé (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells and found that long-term folliculin (FLCN) knockdown was required to increase their tumorigenic potential, forming larger spheroids in non-adherent conditions. Transcriptomic and proteomic analysis uncovered links between FLCN, cell cycle control and the DNA damage response (DDR) machinery. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). A FLCN interactome screen uncovered FLCN binding to DNA-dependent protein kinase (DNA-PK). This novel interaction was reversed in an irradiation-responsive manner. Knockdown of FLCN in HK2 cells caused a marked elevation of γH2AX and RB1 phosphorylation. Both CCND1 and RB1 phosphorylation remained raised during DNA damage, showing an association with defective cell cycle control with FLCN knockdown. Furthermore, Flcn-knockdown C. elegans were defective in cell cycle arrest by DNA damage. This work implicates that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.
RESUMO
OBJECTIVE: This study aims to determine the effect of infant-mother separation following a short-stay (≤72 hours) admission to a Level 5 neonatal unit versus no admission on infant-feeding outcomes at hospital discharge. DESIGN: Retrospective cohort study. SETTING: An Australian Level 5 neonatal unit within a tertiary referral hospital. PARTICIPANTS: Mothers and their infants born between 1 January 2018 and 31 December 2020 had a short-stay admission to the neonatal unit or no admission. All participants met admission criteria to the postnatal ward and were discharged home at ≤72 hours (n=12 540). Postnatal ward admission criteria included ≥36 weeks' gestation and birth weight ≥2.2 kg. MAIN OUTCOME MEASURES: Infant feeding at discharge from hospital. Multivariate logistic regression analysis was conducted, adjusting for confounders associated with known breastfeeding issues. These included age, ethnicity, parity, obesity, socioeconomic score, hypertensive disorders of pregnancy, diabetes, infant gestation and birthweight centile, caesarean section birth, postpartum haemorrhage and skin-to-skin contact. RESULTS: Of the 12 540 live births meeting inclusion criteria, 1000 (8%) infants were admitted to the neonatal unit. The primary reasons for admission were suspicion of sepsis (24%), maternal diabetes (19%) and jaundice (16%). We found a reduction in full breast feeding at hospital discharge in cases of a short admission to the neonatal unit compared with no admission (aOR 0.40; 95% CI 0.34 to 0.47; p<0.001). We identified that women of different ethnicities had differing levels of risk for formula supplementation at hospital discharge. The ethnic grouping least likely to be fully breast feeding at discharge was Southeast Asian women (aOR 0.47; 95% CI 0.39 to 0.57; p<0.001). CONCLUSIONS: Identifying mother-infant dyads at risk of non-exclusive breast feeding at hospital discharge will help target resources for practice improvement.
