Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

What are the benefits of preemptive versus non-preemptive kidney transplantation? A systematic review and meta-analysis

Opting for a preemptive kidney transplant (PKT) can help avoid costs and morbidity associated with dialysis. However, while multiple studies have shown clinical benefits of PKT, other studies have not demonstrated this, leading to controversy in the literature regarding the exact benefits of PKT. Therefore, this study aimed to determine the clinical outcomes of PKT versus non-preemptive kidney transplantation (nPKT) in adult patients. Multiple databases were searched up to May 4, 2022. Independent reviewers selected studies for inclusion and extracted relevant data. Risk of bias was assessed using the Downs and Black checklist. Eighty-seven studies including 859,715 adult kidney transplant patients were included the review. The risk of patient death (relative risk [95% confidence interval] 0.74 [0.60–0.91]) was significantly lower in PKT versus nPKT patients for living donor (LD) transplants, whereas the risk of overall graft loss was significantly lower in PKT compared to nPKT patients for both LD (0.72 [0.62–0.83]) as well as deceased donor (DD) transplants (0.80 [0.69–0.92]). The evidence suggests that LD PKT patients have a lower risk of patient death and graft loss compared to nPKT patients, and DD PKT patients have a lower risk of graft loss than nPKT patients.</p

COVID-19 length of hospital stay: a systematic review and data synthesis.

BACKGROUND: The COVID-19 pandemic has placed an unprecedented strain on health systems, with rapidly increasing demand for healthcare in hospitals and intensive care units (ICUs) worldwide. As the pandemic escalates, determining the resulting needs for healthcare resources (beds, staff, equipment) has become a key priority for many countries. Projecting future demand requires estimates of how long patients with COVID-19 need different levels of hospital care. METHODS: We performed a systematic review of early evidence on length of stay (LoS) of patients with COVID-19 in hospital and in ICU. We subsequently developed a method to generate LoS distributions which combines summary statistics reported in multiple studies, accounting for differences in sample sizes. Applying this approach, we provide distributions for total hospital and ICU LoS from studies in China and elsewhere, for use by the community. RESULTS: We identified 52 studies, the majority from China (46/52). Median hospital LoS ranged from 4 to 53 days within China, and 4 to 21 days outside of China, across 45 studies. ICU LoS was reported by eight studies-four each within and outside China-with median values ranging from 6 to 12 and 4 to 19 days, respectively. Our summary distributions have a median hospital LoS of 14 (IQR 10-19) days for China, compared with 5 (IQR 3-9) days outside of China. For ICU, the summary distributions are more similar (median (IQR) of 8 (5-13) days for China and 7 (4-11) days outside of China). There was a visible difference by discharge status, with patients who were discharged alive having longer LoS than those who died during their admission, but no trend associated with study date. CONCLUSION: Patients with COVID-19 in China appeared to remain in hospital for longer than elsewhere. This may be explained by differences in criteria for admission and discharge between countries, and different timing within the pandemic. In the absence of local data, the combined summary LoS distributions provided here can be used to model bed demands for contingency planning and then updated, with the novel method presented here, as more studies with aggregated statistics emerge outside China

W(h)ither the academy? An exploration of the role of university social work in shaping the future of social work in Europe

A controversial proposal to pilot the training of child protection social workers through an intensive work-based route in England is being supported and funded by the UK Government. Frontline, the brainchild of a former teacher, locates social work training within local authorities (‘the agency’) rather than university social work departments (‘the academy’) and has stimulated debate amongst social work academics about their role in shaping the direction of the profession. As a contribution to this debate, this paper explores the duality of social work education, which derives its knowledge from both the academic social sciences and the experience of practice within social work agencies. While social work education has traditionally been delivered by the academy, this paper also explores whether the delivery of training in the allied professions of probation and nursing by ‘the agency’ is equally effective. Finally, this paper explores the Helsinki model which achieves a synergy of ‘academy’ and ‘agency’. It suggests that there are alternative models of social work education, practice and research which avoid dichotomies between the ‘academy’ and the ‘agency’ and enable the profession to be shaped by both social work academics and practitioners

Entanglement in bipartite generalized coherent states

Entanglement in a class of bipartite generalized coherent states is discussed. It is shown that a positive parameter can be associated with the bipartite generalized coherent states so that the states with equal value for the parameter are of equal entanglement. It is shown that the maximum possible entanglement of 1 bit is attained if the positive parameter equals $\sqrt{2}$. The result that the entanglement is one bit when the relative phase between the composing states is $\pi$ in bipartite coherent states is shown to be true for the class of bipartite generalized coherent states considered.Comment: 10 pages, 4 figures; typos corrected and figures redrawn for better clarit

Risk-Driven Design Processes: Balancing Efficiency with Resilience in Product Design

Current design methods and approaches focus on increasing the efficiency of the product design system by, for example, eliminating waste and focusing on value creation. However, continuing failures in the development of complex, large scale products and systems point towards weaknesses in the existing approaches. We argue that product development organizations are hindered by the many uncertainties that are inherent in the process. Common management heuristics ignore uncertainty and thus overly simplify the decision making process. Creating transparency regarding uncertainties and the associated risks (i.e. effect of uncertainties on design objectives) is not seen as an explicit priority. Consequently organizations are unable to balance risk and return in their development choices. Product development processes do not emphasize reduction of risks, particularly those risks that are apparent early in the process. In addition, the resilience of the PD system, i.e. its ability to deliver on-target results under uncertainty, is not deliberately designed to match the level of residual uncertainty. This chapter introduces the notion of Risk-Driven Design and its four principles of 1. Creating transparency regarding design risks; 2. Risk-driven decision making; 3. Minimizing uncertainty; and 4. Creating resilience.Massachusetts Institute of Technology. Lean Advancement InitiativeCenter for Clean Water and Clean Energy at MIT and KFUP

Matrix-free calcium in isolated chromaffin vesicles

Isolated secretory vesicles from bovine adrenal medulla contain 80 nmol of Ca2+ and 25 nmol of Mg2+ per milligram of protein. As determined with a Ca2+-selective electrode, a further accumulation of about 160 nmol of Ca2+/mg of protein can be attained upon addition of the Ca2+ ionophore A23187. During this process protons are released from the vesicles, in exchange for Ca2+ ions, as indicated by the decrease of the pH in the incubation medium or the release of 9-aminoacridine previously taken up by the vesicles. Intravesicular Mg2+ is not released from the vesicles by A23 187, as determined by atomic emission spectroscopy. In the presence of N H Q , which causes the collapse of the secretory vesicle transmembrane proton gradient (ApH), Ca2+ uptake decreases. Under these conditions A23 187-mediated influx of Ca2+ and efflux of H+ cease at Ca2+ concentrations of about 4 pM. Below this concentration Ca2+ is even released from the vesicles. At the Ca2+ concentration at which no net flux of ions occurs the intravesicular matrix free Ca2+ equals the extravesicular free Ca2+. In the absence of NH4C1 we determined an intravesicular pH of 6.2. Under these conditions the Ca2+ influx ceases around 0.15 pM. From this value and the known pH across the vesicular membrane an intravesicular matrix free Ca2+ concentration of about 24 pM was calculated. This is within the same order of magnitude as the concentration of free Ca2+ in the vesicles determined in the presence of NH4C1. Calculation of the total Ca2+ present in the secretory vesicles gives an apparent intravesicular Ca2+ concentration of 40 mM, which is a factor of lo4 higher than the free intravesicular concentration of Ca2+. It can be concluded, therefore, that the concentration gradient of free Ca2+ across the secretory vesicle membrane in the intact chromaffin cells is probably small, which implies that less energy is required to accumulate and maintain Ca2+ within the vesicles than was previously anticipated

Implementation of a quantum algorithm to solve Bernstein-Vazirani's parity problem without entanglement on an ensemble quantum computer

Bernstein and Varizani have given the first quantum algorithm to solve parity problem in which a strong violation of the classical imformation theoritic bound comes about. In this paper, we refine this algorithm with fewer resource and implement a two qubits algorithm in a single query on an ensemble quantum computer for the first time