Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

Background: Mantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL. Methods: The effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition. Results: In this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples. Conclusion: Our data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Effects of Caloric Restriction on Spatial Object Recognition Memory, Hippocampal Neuron Loss and Neuroinflammation in Aged Rats

Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear. Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity

Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.The study was supported by research funding from the Spanish Ministry of Economy and Competitiveness through the Plan Estatal de Investigación Científica y Técnica y de Innovación (MINECO) RTI2018-094584-B-I00 [to DC] and was cofunded by the European Regional Development Fund [ERDF] and the CERCA program from Generalitat de Catalunya, Centro de Investigación Biomédica en Cáncer [CIBERONC] [CB16/12/00334 and CB16/12/00225] and Generalitat de Catalunya Suport Grups de Recerca [2017 SGR 1009]. This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 306240. NG is a recipient of a predoctoral fellowship from AGAUR, L.R. is a recipient of a postdoctoral fellowship from AGAUR (PERIS), ILO is a recipient of the PhD4MD program and HPA is a recipient of a predoctiral fellowship from Spanish Ministry of Economy and Competitiveness (FPU

Can we save a marine species affected by a highly infective, highly lethal, waterborne disease from extinction?

Anthropogenic drivers and global warming are altering the occurrence of infectious marine diseases, some of which produce mass mortalities with considerable ecosystemic and economic costs. The Mediterranean Sea is considered a laboratory to examine global processes, and the fan mussel Pinna nobilis a sentinel species within it. Since September 2016, fan mussels suffer a die-off, very likely provoked by the protozoan Haplosporidium pinnae. Population dynamic surveys, rescue programmes, larvae collector installation and protection of infected adults from predators, have increased knowledge about the factors conditioning the spread of the die-off; previous model simulations indicate that water temperature and salinity seem to be related to the manifestation of the disease, which at the end are strongly influenced by climate change and anthropogenic actions. The absence of natural recruitment implies that fan mussel populations are not recovering, but the survival of populations living in paralic environments provides an opportunity to study the disease and its conditioning factors. The fan mussel disease outbreak provides a case example for how climate change may mediate host-protozoan dynamics and poses several questions: are we witnessing the potential extinction of a sentinel species? Can we avoid it by applying active measures? If so, which measures will be more effective? How many other more overlooked species might experience a massive and unnoticed die-off before it is too late to implement any preservation action? This is especially relevant because the loss of keystone species can drive to community effects that influence marine ecosystem processes.This research was partially funded by the Spanish Ministry for the Ecological Transition, project 28-5310 “Rescate de 215 ejemplares de nacra (Pinna nobilis) y su mantenimiento en 5 centros especializados en el marco del Proyecto UFE IP-PAF INTEMARES (LIFE15 IPE ES 012)”, “Gestión integrada, innovadora y participativa de la Red Natura 2000 en el medio marino español” as well as those agreements and contracts with the participating entities (IFAPA, IRTA, IEO) derived from this project, and by the Prince Albert II of Monaco Foundation to project BF/HEM 15-1662, “The study, protection and possible breeding of pen shell (Pinna nobilis) in the Boka Kotorska Bay”. Maite Vázquez-Luis was supported by the postdoctoral contract, Juan de la Cierva-Incorporación (IJCI-2016-29329) of Ministerio de Ciencia, Innovación y Universidades. G. Catanese was supported by a research contract from the INIA-CCAA (DOC INIA 8/2013) MINECO programme. The M. López-Sanmartín contract is co-financed by the State Plan for Scientific and Technical Research and Innovation 2013–2016, MINECO, ref. PTA215-11709-I

Pla de salut de Catalunya 2002-2005: estratègies de salut per a l'any 2010

Planificació sanitària; Sistema sanitari; Línies estratègiquesPlanificación sanitaria; Sistema sanitario; Líneas estratégicasHealth planning; Sanitary system; Strategic linesEn aquest document, que inclou a la vegada els objectius per a l’any 2010 i el Pla de salut 2002-2005, es defineixen les polítiques de salut que se seguiran a Catalunya durant el primer decenni del segle XXI, els objectius generals, de salut i de disminució de risc a assolir l’any 2010 i els objectius operacionals a aconseguir l’any 2005

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat