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Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73 m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs).Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR 1.73 m2. Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively −4% and −10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs.Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI.

Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs). Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR <60 mL/min/1.73m². The inclusion criteria for this study were the use of OADs and the availability of data on weight, height and serum creatinine. We compared data for three BMI subgroups (group 1 <30 kg/m²; group 2 30-34.9 kg/m²; group 3 =35 kg/m²). Inappropriate prescriptions (contraindicated or over-dosed drugs) were assessed with regard to the summary of product characteristics and the patient's kidney function estimated with the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the 2021 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) equation, the European Kidney Function Consortium (EKFC) equation, their deindexed estimates, and the Cockcroft-Gault (CG) formula. The impact of deindexing the equations was evaluated by assessing 1) the difference between the indexed and deindexed eGFRs, and 2) the difference in the proportion of patients with at least one inappropriate OAD prescription between the indexed and deindexed estimates. Results: At baseline, 694 patients were receiving OADs. The median BMI was 30.7 kg/m², the mean BSA was 1.98m², and 90% of patients had a BSA >1.73m². Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively -4% and -10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs. Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI. [ABSTRACT FROM AUTHOR]

Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells’ fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment.

Background The association between hypo- and/or hypermagnesaemia and cardiovascular (CV) outcomes or mortality has shown conflicting results in chronic kidney disease (CKD) and has been conducted on total magnesium (tMg) levels. Thus, the objectives of the present study were to (i) describe the serum ionized Mg (iMg) concentration in patients at various CKD stages, (ii) measure the correlation between iMg and tMg concentrations, (iii) identify their associated factors and (iv) determine whether serum tMg and/or iMg concentrations are associated with major adverse cardiovascular events (MACE) and mortality before kidney replacement therapy in CKD patients. Methods Chronic Kidney Disease–Renal Epidemiology and Information Network (CKD-REIN) is a prospective cohort of CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Baseline iMg and tMg serum concentrations were centrally measured. Adjusted cause-specific Cox proportional hazard models were used to estimate hazard ratios (HRs) for first MACE and for mortality. Results Of the 2419 included patients, median age was 68 years, and the mean eGFR was 34.8 mL/min/1.73 m2. Concentrations of serum iMg and tMg were strongly correlated (r = 0.89, P  < .001) and were independently associated with eGFR. The adjusted HR [95% confidence interval (CI)] for MACE associated with the baseline serum tMg level was 1.27 (0.95; 1.69) for patients in Tertile 1 and 1.56 (1.18; 2.06) for patients in Tertile 3, relative to patients in Tertile 2. The HR (95% CI) of death according to serum tMg concentration was increased in Tertile 3 [1.48 (1.11; 1.97)]. The adjusted risk for MACE and mortality (all-cause or CV) associated with the baseline serum iMg level was not significantly different between tertiles. Conclusions Our analysis of a large cohort of patients with moderate-to-advanced CKD demonstrated that individuals with higher serum tMg concentrations, although still within the normal range, had a greater likelihood of MACE and mortality. However, serum iMg levels were not associated with these outcomes. [ABSTRACT FROM AUTHOR]

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient’s treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.

Vascular calcification contributes to cardiovascular morbidity and mortality. A recently developed serum calcification propensity assay is based on the half-transformation time (T50) from primary calciprotein particles (CPPs) to secondary CPPs, reflecting the serum’s endogenous capacity to prevent calcium phosphate precipitation. We sought to identify and review the results of all published studies since the development of the T50-test by Pasch et al. in 2012 (whether performed in vitro, in animals or in the clinic) of serum calcification propensity. To this end, we searched PubMed, Elsevier EMBASE, the Cochrane Library and Google Scholar databases from 2012 onwards. At the end of the selection process, 57 studies were analyzed with regard to the study design, sample size, characteristics of the study population, the intervention and the main results concerning T50. In patients with primary aldosteronism, T50 is associated with the extent of vascular calcification in the abdominal aorta. In chronic kidney disease (CKD), T50 is associated with the severity and progression of coronary artery calcification. T50 is also associated with cardiovascular events and all-cause mortality in CKD patients, patients on dialysis and kidney transplant recipients and with cardiovascular mortality in patients on dialysis, kidney transplant recipients, patients with ischemic heart failure and reduced ejection fraction, and in the general population. Switching from acetate-acidified dialysate to citrate-acidified dialysate led to a longer T50, as did a higher dialysate magnesium concentration. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with a lower serum calcification propensity. Serum calcification propensity is an overall marker of calcification associated with hard outcomes but is currently used in research projects only. This assay might be a valuable tool for screening serum calcification propensity in at-risk populations (such as CKD patients and hemodialyzed patients) and, in particular, for monitoring changes over time in T50.

Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells' fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment. [ABSTRACT FROM AUTHOR]

It is recognized that cellular senescence is triggered by DNA damage as a protective mechanism against tumorigenesis. Here the authors show that DNA single-strand breaks of oxidative origin can induce a transient senescent state followed by the emergence of clonal transformed cells.

Abstract Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.

Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen supply and exposure to chemo/radiotherapy, which forces them to develop adaptive mechanisms such as the Unfolded Protein Response (UPR). It is now well documented that the UPR, a homeostatic mechanism, is induced at different stages of cancer progression in response to intrinsic (oncogenic activation) or extrinsic (microenvironment) perturbations. This review will discuss the role of the UPR in HNSCC as well as in the key processes that characterize the physiology of HNSCC. The role of the UPR in the clinical context of HNSCC will also be addressed.

Vascular calcification contributes to cardiovascular morbidity and mortality. A recently developed serum calcification propensity assay is based on the half-transformation time (T50) from primary calciprotein particles (CPPs) to secondary CPPs, reflecting the serum's endogenous capacity to prevent calcium phosphate precipitation. We sought to identify and review the results of all published studies since the development of the T50-test by Pasch et al. in 2012 (whether performed in vitro, in animals or in the clinic) of serum calcification propensity. To this end, we searched PubMed, Elsevier EMBASE, the Cochrane Library and Google Scholar databases from 2012 onwards. At the end of the selection process, 57 studies were analyzed with regard to the study design, sample size, characteristics of the study population, the intervention and the main results concerning T50. In patients with primary aldosteronism, T50 is associated with the extent of vascular calcification in the abdominal aorta. In chronic kidney disease (CKD), T50 is associated with the severity and progression of coronary artery calcification. T50 is also associated with cardiovascular events and all-cause mortality in CKD patients, patients on dialysis and kidney transplant recipients and with cardiovascular mortality in patients on dialysis, kidney transplant recipients, patients with ischemic heart failure and reduced ejection fraction, and in the general population. Switching from acetate-acidified dialysate to citrate-acidified dialysate led to a longer T50, as did a higher dialysate magnesium concentration. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with a lower serum calcification propensity. Serum calcification propensity is an overall marker of calcification associated with hard outcomes but is currently used in research projects only. This assay might be a valuable tool for screening serum calcification propensity in at-risk populations (such as CKD patients and hemodialyzed patients) and, in particular, for monitoring changes over time in T50. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cl.2005.09.002 Byline: Kim Mens (a), Andy Kellens (b), Frederic Pluquet (c), Roel Wuyts (c) Abstract: Intensional views and relations have been proposed as a way of actively documenting high-level structural regularities in the source code of a software system. By checking conformance of these intensional views and relations against the source code, they supposedly facilitate a variety of software maintenance and evolution tasks. In this paper, by performing a case study on three different versions of the SmallWiki application, we critically analyze in how far the model of intensional views and its current generation of tools provide support for co-evolving high-level design and source code of a software system. Author Affiliation: (a) Departement d'Ingenierie Informatique (INGI), Universite catholique de Louvain (UCL), Place Sainte Barbe 2, B-1348 Louvain-la-Neuve, Belgium (b) Departement Informatica (DINF), Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussel, Belgium (c) Department d'Informatique, Universite Libre de Bruxelles (ULB), Boulevard du Triomphe - CP212, B-1050 Bruxelles, Belgium Article History: Received 12 September 2005

The micropattern gaseous detector Micromegas has been developed for several years in Saclay and presents good performance for neutron detection. A prototype for neutron imaging has been designed and new results obtained in thermal neutron beams are presented. Based on previous results demonstrating a good 1D spatial resolution, a tomographic image of a multiwire cable has been performed using a 1D Micromegas prototype. The number of pillars supporting the micromesh is too large and leads to local losses of efficiency that distort the tomographic reconstruction. Nevertheless, this first tomographic image achieved with this kind of detector is very encouraging. The next worthwhile development for neutron imaging is to achieve a bi-dimensional detector, which is presented in the second part of this study. The purpose of measurements was to investigate various operational parameters to optimize the spatial resolution. Through these measurements the optimum spatial resolution has been found to be around 160 [micro]m (standard deviation) using Micromegas operating in double amplification mode. Several 2D imaging tests have been carried out. Some of these results have revealed fabrication defects that occurred during the manufacture of Micromegas and that are limiting the full potential of the present neutron imaging system. Index Terms--Micromegas, neutron, radiation detector, tomography.

The Sloan Digital Sky Survey (SDSS)(1) is an astrophysics project to produce a three dimensional map of a quarter of the Universe. We present a description of the SDSS prototype, the Drift Scan Camera (DSC) online system,(2) which is operational and currently being deployed. We also present the status of the development of the SDSS online system. The hardware and software architectures for both systems are provided

Abstract Background The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. Methods We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm3) and fever (temperature > 38.3°C). Results The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm3. Conclusion Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population.

Abstract Background Dengue and Dengue hemorrhagic fever have emerged as some of the most important mosquito-borne viral diseases in the tropics. The mechanisms of pathogenesis of Dengue remain elusive. Recently, virus-induced apoptosis mediated by the Unfolded Protein Response (UPR) has been hypothesised to represent a crucial pathogenic event in viral infection. In an attempt to evaluate the contribution of the UPR to virus replication, we have characterized each component of this signalling pathway following Dengue virus infection. Results We find that upon Dengue virus infection, A549 cells elicit an UPR which is observed at the level of translation attenuation (as visualized by the phosphorylation of eIF2alpha) and activation of specific pathways such as nuclear translocation of ATF-6 and splicing of XBP-1. Interestingly, we find that specific serotype of virus modulate the UPR with different selectivity. In addition, we demonstrate that perturbation of the UPR by preventing the dephosphorylation of the translation initiation factor eIF2alpha using Salubrinal considerably alters virus infectivity. Conclusion This report provides evidence that Dengue infection induces and regulates the three branches of the UPR signaling cascades. This is a basis for our understanding of the viral regulation and conditions beneficial to the viral infection. Furthermore, modulators of UPR such as Salubrinal that inhibit Dengue replication may open up an avenue toward cell-protective agents that target the endoplasmic reticulum for anti-viral therapy.

Senescence is a complex cellular state, which can be considered as a stress response phenotype. However, the mechanisms through which cells acquire and maintain this phenotype are not fully understood. In this paper, it is argued that the unfolded protein response (UPR) may represent a signalling platform that is associated with the major senescence hallmarks. [ABSTRACT FROM AUTHOR]

Many cancers respond to initial treatment but most of them relapse due to the persistence of dormant tumor cells. Determining the exact nature of the dormant state is crucial to develop therapies aiming to eradicate the dormant cells. Here, we argue that therapy-induced senescence of cancer cells could be an alternative form of dormancy. [ABSTRACT FROM AUTHOR]

Inhibition of p53-mediated apoptosis by endoplasmic reticulum (ER) stress is demonstrated. Findings suggest that inactivation of p53 is a protective mechanism used by cells to adapt to ER stress.

Activating transcription factor 6 alpha (referred to as ATF6 hereafter) is an endoplasmic reticulum (ER)‐resident glycoprotein and one of the three sensors of the unfolded protein response (UPR). Upon ER stress, ATF6 is exported to the Golgi complex where it is cleaved by the S1P and S2P proteases thus releasing ATF6 cytosolic fragment and leading to the transcription of ATF6 target genes. In this study, we performed a phenotypic small‐interfering RNA (siRNA) screening to better characterize the ER mechanisms involved in ATF6 activation upon ER stress. This revealed that silencing of ER‐degradation‐enhancing alpha‐mannosidase‐like protein‐1 (EDEM1) increased the bioavailability of ER stress‐induced ATF6 export to the Golgi complex through the stabilization of the natively unstable ATF6 protein. Moreover, we characterized a somatic variant of EDEM1 (N198I) found in hepatocellular carcinoma that alters ATF6 signaling and might provide a selective advantage to the transforming cells. Hence, our work confirms the natively unstable nature of ATF6 and links this property to potentially associated pro‐oncogenic functions. The unfolded protein response (UPR) is a cellular stress response that is triggered by protein misfolding in the ER. A key protein involved in 'sensing' ER stress and activating UPR genes is the transcription factor ATF6. The molecular mechanisms underpinning this role remain largely elusive. Here, Chevet and co‐authors used an siRNA‐based screen to uncover functional relationships between ATF6 and mediators of ER protein quality control (ERQC). They show that silencing of an ERQC component, EDEM1, leads to enhanced activation of ATF6, providing new insight into its regulation in the ER. Intriguingly, characterisation of a mutant variant of EDEM1 linked to hepatocellular carcinoma indicates that alteration of ATF6 signalling could promote oncogenesis. [ABSTRACT FROM AUTHOR]