The fructose-bisphosphate, Aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair.

Glucose metabolism and DNA repair are fundamental cellular processes frequently dysregulated in cancer. In this study, we define a direct role for the glycolytic Aldolase A (ALDOA) protein in DNA double-strand break (DSB) repair. ALDOA is a fructose biphosphate Aldolase that catalyses fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), during glycolysis. Here, we show that upon DNA damage induced by ionising radiation (IR), ALDOA translocates from the cytoplasm into the nucleus, where it partially co-localises with the DNA DSB marker γ-H2AX. DNA damage was shown to be elevated in ALDOA-depleted cells prior to IR and following IR the damage was repaired more slowly. Consistent with this, cells depleted of ALDOA exhibited decreased DNA DSB repair via non-homologous end-joining and homologous recombination. In support of the defective repair observed in its absence, ALDOA was found to associate with the major DSB repair effector kinases, DNA-dependent Protein Kinase (DNA-PK) and Ataxia Telangiectasia Mutated (ATM) and their autophosphorylation was decreased when ALDOA was depleted. Together, these data establish a role for an essential metabolic protein, ALDOA in DNA DSB repair and suggests that targeting ALDOA may enable the concurrent targeting of cancer metabolism and DNA repair to induce tumour cell death.

Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics.

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Proportionate reduction in uncertainty of late onset infection in pre-term infants by neutrophil CD64 measurement.

OBJECTIVE: Establish how neutrophil CD64 performs as a marker of definite infection in pre-term infants in comparison to C reactive protein (CRP) and procalcitonin (PCT). METHODS: A total of 38 pre-term infants with suspected late onset infection had CD64 measured by flow cytometry. Proportionate reduction in uncertainty (PRU) curves were generated for CD64 counts at various threshold values. RESULTS: PRU curves reduced the residual uncertainty of the presence of infection by up to 64%. CONCLUSIONS: The CD64 appears to be a useful point of care test (POCT) for further defining the likelihood of infection and performs better than CRP or PCT at helping to rule in infection.

Deaths in preterm infants: changing pathology over 2 decades.

OBJECTIVE: To establish how cause of death for live-born preterm infants (24-31 weeks gestation) has changed in a single large UK population over 2 decades. STUDY DESIGN: This was an interrogation of a population-based survey of >680, 000 live births (between 1988 and 2008) for deaths in the first postnatal year. We collected cause of death grouped into major etiologies: respiratory, infection, malformation, necrotizing enterocolitis (NEC), and other. Data were analyzed in three 7-year epochs and 2 gestational groups (<27 and 28-31 weeks). Numbers, rates per 1000 live births, and proportional contributions to each epoch were analyzed. RESULTS: A total of 1504 deaths occurred. The infants who died had a median gestational age of 26 weeks (IQR, 25-28 weeks) and a median birth weight of 880 g (IQR, 700-1170 g). The number of deaths decreased with each later epoch (from 671 to 473 and then to 360), as did the proportion of deaths from respiratory causes (64% to 62% and then to 49%). The proportion of deaths occurring after 40 weeks postmenstrual age remained stable across the 3 epochs (8.8%, 8%, and 8%). Deaths from infection and NEC increased with time (from 11% to 13% and then to 21%), as did median time to death (from 2.7 to 3.8 days). CONCLUSION: Infection and NEC are increasingly prevalent causes of death in preterm infants.