ZNF432 stimulates PARylation and inhibits DNA resection to balance PARPi sensitivity and resistance.

Zinc finger (ZNF) motifs are some of the most frequently occurring domains in the human genome. It was only recently that ZNF proteins emerged as key regulators of genome integrity in mammalian cells. In this study, we report a new role for the Krüppel-type ZNF-containing protein ZNF432 as a novel poly(ADP-ribose) (PAR) reader that regulates the DNA damage response. We show that ZNF432 is recruited to DNA lesions via DNA- and PAR-dependent mechanisms. Remarkably, ZNF432 stimulates PARP-1 activity in vitro and in cellulo. Knockdown of ZNF432 inhibits phospho-DNA-PKcs and increases RAD51 foci formation following irradiation. Moreover, purified ZNF432 preferentially binds single-stranded DNA and impairs EXO1-mediated DNA resection. Consequently, the loss of ZNF432 in a cellular system leads to resistance to PARP inhibitors while its overexpression results in sensitivity. Taken together, our results support the emerging concept that ZNF-containing proteins can modulate PARylation, which can be embodied by the pivotal role of ZNF432 to finely balance the outcome of PARPi response by regulating homologous recombination.

Efficacy of maintaining low-tidal volume mechanical ventilation as compared to resting lung strategy during coronary artery bypass graft cardiopulmonary bypass surgery: A post-hoc analysis of the MECANO trial.

STUDY OBJECTIVE: To compare a low-tidal-volume with positive end-expiratory pressure strategy (VENT strategy) to a resting-lung-strategy (i.e., no-ventilation (noV) strategy) during cardiopulmonary bypass for coronary artery bypass graft surgery on the incidence of postoperative pulmonary complications. DESIGN: Post-hoc analysis of the MECANO trial which was a prospective single-center, blind, randomized, parallel-group controlled trial. SETTING: Tertiary care cardiac surgery center. PATIENTS: Patients who underwent isolated on-pump coronary bypass surgery were randomized either to VENT or noV group. INTERVENTION: During the cardiopulmonary bypass phase of the cardiac surgery procedure, mechanical ventilation in the VENT group consisted of a tidal volume of 3 mL/kg, a respiratory rate of 5 per minute and a positive end-expiratory pressure of 5 cmH2O. Patients in the noV group received no ventilation during this phase. MEASUREMENTS: Primary composite outcome combining death, early respiratory failure, ventilation support beyond day 2 and reintubation. MAIN RESULTS: In this post-hoc analysis, we retained 725 patients who underwent isolated CABG surgery, from the 1501 patients included in the original study. There were 352 in the VENT group and 373 patients in the noV group. Post-hoc comparison yielded no differences in baseline characteristics between these two groups. The primary outcome occurred less frequently in the VENT group than in the noV group, with 44 (12.5%) and 76 (20.4%) respectively (odds-ratio (OR) = 0.56 (0.37-0.84), p = 0.004). There were fewer early respiratory dysfunctions and prolonged respiratory support in the VENT group (respectively, OR = 0.34 (0.12-0.96) p = 0.033 and OR = 0.51 (0.27-0.94) p = 0.029). Complications related to mechanical ventilation were similar in the two groups. CONCLUSIONS: In this post-hoc analysis, maintaining low-tidal ventilation compared to a resting-lung strategy was associated with fewer pulmonary postoperative complications in patients who underwent isolated CABG procedures.

Occupational Exposures and Esophageal Cancer: Prog Study.

Esophageal cancer is the sixth most common cause of cancer death worldwide. In France, Brittany is one of the regions most seriously affected. This increased incidence is usually linked to high rates of alcohol overconsumption and smoking, established risk factors for esophageal cancer, but the region has special occupational exposures. We aim to describe the occupational exposures of patients with esophageal cancer. Between June and October 2020, we conducted a monocentric descriptive study in a French Teaching Hospital and identified 37 eligible patients. We gathered data through a systematic individual interview for each participant and by an analysis of their medical file. We were able to include 36 patients; most were men (n = 27, 75.0%) and smokers (n = 25, 69.4%), 21 (58.3%) presented an adenocarcinoma esophageal cancer, 13 (36.1%) a squamous cell cancer, and 2 other types. On occupational exposure, patients declared respectively high exposure by manipulating asbestos materials for 11 (30.6%) patients, regularly in contact with benzene by handling fuel in 7 cases (19.4%), chlorinated solvents in 4 cases (11.1%), pesticides in 4 cases, and ionizing radiation exposure in 3 patients (8.3%). Our findings support the creation of a large-scale study to explore the impact of occupational exposures, particularly exposure to asbestos and hydrocarbons.

[89Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B-targeted Therapy in Triple-negative Breast Cancer.

There is a need for prognostic markers to select patients most likely to benefit from antibody-drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 ± 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2-4 weeks after treatment with CDX-011 (Spearman ρ = -0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.

Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease.

INTRODUCTION: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry. MATERIAL AND METHODS: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients. RESULTS: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18-59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases. The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints. CONCLUSION: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition.

Generation of parametric Ki images for FDG PET using two 5-min scans.

PURPOSE: The net uptake rate constant (Ki ) derived from dynamic imaging is considered the gold standard quantification index for FDG PET. In this study, we investigated the feasibility and assessed the clinical usefulness of generating Ki images for FDG PET using only two 5-min scans with population-based input function (PBIF). METHODS: Using a Siemens Biograph mCT, 10 subjects with solid lung nodules underwent a single-bed dynamic FDG PET scan and 13 subjects (five healthy and eight cancer patients) underwent a whole-body dynamic FDG PET scan in continuous-bed-motion mode. For each subject, a standard Ki image was generated using the complete 0-90 min dynamic data with Patlak analysis (t* = 20 min) and individual patient's input function, while a dual-time-point Ki image was generated from two 5-min scans based on the Patlak equations at early and late scans with the PBIF. Different start times for the early (ranging from 20 to 55 min with an increment of 5 min) and late (ranging from 50 to 85 min with an increment of 5 min) scans were investigated with the interval between scans being at least 30 min (36 protocols in total). The optimal dual-time-point protocols were then identified. Regions of interest (ROI) were drawn on nodules for the lung nodule subjects, and on tumors, cerebellum, and bone marrow for the whole-body-imaging subjects. Quantification accuracy was compared using the mean value of each ROI between standard Ki (gold standard) and dual-time-point Ki , as well as between standard Ki and relative standardized uptake value (SUV) change that is currently used in clinical practice. Correlation coefficients and least squares fits were calculated for each dual-time-point protocol and for each ROI. Then, the predefined criteria for identifying a reliable dual-time-point Ki estimation for each ROI were empirically determined as: (1) the squared correlation coefficient (R2 ) between standard Ki and dual-time-point Ki is larger than 0.9; (2) the absolute difference between the slope of the equality line (1.0) and that of the fitted line when plotting standard Ki versus dual-time-point Ki is smaller than 0.1; (3) the absolute value of the intercept of the fitted line when plotting standard Ki versus dual-time-point Ki normalized by the mean of the standard Ki across all subjects for each ROI is smaller than 10%. Using Williams' one-tailed t test, the correlation coefficient (R) between standard Ki and dual-time-point Ki was further compared with that between standard Ki and relative SUV change, for each dual-time-point protocol and for each ROI. RESULTS: Reliable dual-time-point Ki images were obtained for all the subjects using our proposed method. The percentage error introduced by the PBIF on the dual-time-point Ki estimation was smaller than 1% for all 36 protocols. Using the predefined criteria, reliable dual-time-point Ki estimation could be obtained in 25 of 36 protocols for nodules and in 34 of 36 protocols for tumors. A longer time interval between scans provided a more accurate Ki estimation in general. Using the protocol of 20-25 min plus 80-85 or 85-90 min, very high correlations were obtained between standard Ki and dual-time-point Ki (R2  = 0.994, 0.980, 0.971 and 0.925 for nodule, tumor, cerebellum, and bone marrow), with all the slope values with differences ≤0.033 from 1 and all the intercept values with differences ≤0.0006 mL/min/cm3 from 0. The corresponding correlations were much lower between standard Ki and relative SUV change (R2  = 0.673, 0.684, 0.065, 0.246). Dual-time-point Ki showed a significantly higher quantification accuracy with respect to standard Ki than relative SUV change for all the 36 protocols (p < 0.05 using Williams' one-tailed t test). CONCLUSIONS: Our proposed approach can obtain reliable Ki images and accurate Ki quantification from dual-time-point scans (5-min per scan), and provide significantly higher quantification accuracy than relative SUV change that is currently used in clinical practice.

Efficacy of parasternal block to decrease intraoperative opioid use in coronary artery bypass surgery via sternotomy: a randomized controlled trial.

OBJECTIVE: This study aims to assess the effect of a preoperative parasternal plane block (PSB) on opioid consumption required to maintain hemodynamic stability during sternotomy for coronary artery bypass graft surgery. METHODS: This double-blind, randomized, placebo-controlled trial prospectively enrolled 35 patients scheduled for coronary artery bypass graft surgery under general anesthesia with propofol and remifentanil. Patients were randomized to receive preoperative PSB using either ropivacaine (PSB group) or saline solution (placebo group) (1:1 ratio). The primary endpoint was the maximal effect-site concentration of remifentanil required to maintain heart rate and blood pressure within the recommended ranges during sternotomy. RESULTS: Median maximum concentration of remifentanil necessary to maintain adequate hemodynamic status during sternotomy was significantly reduced in PSB group (4.2 (2.5-6.0) ng/mL) compared with placebo group (7.0 (5.2-8.0) ng/mL) (p=0.02). Mean maximum concentration of propofol used to control depth of anesthesia was also reduced (3.9±1.1 µg/mL vs 5.0±1.5 µg/mL, PSB vs placebo, respectively; p=0.02). This reduction in propofol consumption during sternotomy enabled a more adequate level of sedation to be maintained in patients (minimum patient state index was 11.7±8.7 in placebo group and 18.3±6.8 in PSB group; p=0.02). PSB reduced postoperative inflammatory response by limiting concentrations of proinflammatory cytokines IL-8, IL-18, IL-23, IL-33 and MCP-1 measured in the first 7-day after surgery (p<0.05). CONCLUSIONS: Preoperative PSB reduced the maximum concentrations of remifentanil and propofol required to maintain hemodynamic stability and depth of anesthesia during sternotomy. TRIAL REGISTRATION NUMBER: NCT03734159.Sébastien Bloc, M.D.1,2; Brieuc P. Pérot, Ph.D.3; Hadrien Gibert, M.D.1; Jean-Dominique Law Koune, M.D.1; Yannick Burg, M.D.1; Didier Leclerc, M.D.1; Anne-Sophie Vuitton, M.D.1; Christophe De La Jonquière, M.D.1; Marine Luka, L.S.3; Thierry Waldmann, M.D.4; Nicolas Vistarini, M.D.4; Stéphane Aubert, M.D.4; Mickaël M. Ménager, Ph.D.3; Messaouda Merzoug, Ph.D.2; Cécile Naudin, Ph.D.2; Pierre Squara, M.D.2,5.

The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE).

This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.

Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE).

Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.

Seafarers' Occupational Noise Exposure and Cardiovascular Risk. Comments to Bolm-Audorff, U.; et al. Occupational Noise and Hypertension Risk: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2020, 17, 6281.

A German team published a new meta-analysis on the topic, "Occupational noise and hypertension risk: A systematic review and meta-analysis" in the International Journal of Environmental Research and Public Health [...].

Low Tidal Volume Mechanical Ventilation Against No Ventilation During Cardiopulmonary Bypass in Heart Surgery (MECANO): A Randomized Controlled Trial.

BACKGROUND: Postoperative pulmonary complications are common after cardiac surgery and have been related to lung collapse during cardiopulmonary bypass (CPB). No consensus exists regarding the effects of maintaining mechanical ventilation during CPB to decrease these complications. RESEARCH QUESTION: To determine whether maintaining low-tidal ventilation (3 mL/kg 5 times/min, with positive end expiratory pressure of 5 cm H2O) during CPB (ventilation strategy) was superior to a resting-lung strategy with no ventilation (no ventilation strategy) regarding postoperative pulmonary complications, including mortality. STUDY DESIGN AND METHODS: In a randomized controlled trial, patients undergoing cardiac surgery at a single center from May 2017 through August 2019 were randomized to the ventilation or no ventilation strategy during CPB (1:1 ratio). Apart from the CPB phase, perioperative ventilation procedures were standardized. RESULTS: The study included 1,501 patients (mean age, 68.8 ± 10.3 years; 1,152 (76.7%) men; mean EuroSCORE II, 2.3 ± 2.7). Seven hundred fifty-six patients were in the ventilation strategy group, and no differences existed in baseline characteristics and types of procedures between the two groups. An intention-to-treat analysis yielded no significant difference between the ventilation and no ventilation groups regarding incidence of the primary composite outcome combining death, early respiratory failure, ventilation support beyond day 2, and reintubation, with 112 of 756 patients (14.8%) in the ventilation group vs 133 of 745 patients (17.9%) in the no ventilation group (OR, 0.80; 95% CI, 0.61-1.05; P = .11). Strict per-protocol analyses of 1,338 patients (89.1%) with equally distributed preoperative characteristics yielded similar results (OR, 0.81; 95% CI, 0.60-1.09; P = .16). Post hoc analysis of the subgroup who underwent isolated coronary artery bypass graft procedures (n = 725) showed that the ventilation strategy was superior to the no ventilation strategy regarding the primary outcome (OR, 0.56; 95% CI, 0.37-0.84; P = .005). INTERPRETATION: Among patients undergoing cardiac surgery with CPB, continuation of low tidal volume ventilation was not superior to no ventilation during CPB with respect to postoperative complications, including death, early respiratory failure, ventilation support beyond day 2, and reintubation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03098524; URL: www.clinicaltrials.gov.

A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE).

Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs' knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.

[11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis.

PURPOSE: As stereotactic radiosurgery (SRS) and immunotherapy are increasingly used to treat brain metastases, incidence of radiation necrosis (RN) is consequently rising. Differentiating tumor regrowth (TR) from RN is vital in management but difficult to assess using MRI. We hypothesized that tumor methionine levels would be elevated given increased metabolism and high amino acid uptake, whereas RN would increase inflammation marked by upregulated translocator protein (PBR-TSPO), which can be quantified with specific PET tracers. PROCEDURES: We performed a feasibility study to prospectively evaluate [11C]methionine and [11C]PBR28 using PET in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate TR from RN. RESULTS: Sequential imaging with dual tracers was well-tolerated. [11C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [11C]PBR28 was only accurate in 3/7 lesions. Tumor PBR-TSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [11C]PBR28-PET. CONCLUSION: Sequential use of PET tracers is safe and effective. [11C]Methionine was a reliable TR marker, but [11C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging.

Assessment of population-based input functions for Patlak imaging of whole body dynamic 18F-FDG PET.

BACKGROUND: Arterial blood sampling is the gold standard method to obtain the arterial input function (AIF) for quantification of whole body (WB) dynamic 18F-FDG PET imaging. However, this procedure is invasive and not typically available in clinical environments. As an alternative, we compared AIFs to population-based input functions (PBIFs) using two normalization methods: area under the curve (AUC) and extrapolated initial plasma concentration (CP*(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated CP*(0). The aim of this study was to validate IDIF and PBIF for FDG oncological WB PET studies by comparing to the gold standard arterial blood sampling. METHODS: The Feng 18F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0-60 min) or CP*(0), estimated from an exponential fit. CP*(0) is also described as the ratio of the injected dose (ID) to initial distribution volume (iDV). iDV was modeled using the subject height and weight, with coefficients that were estimated in 23 subjects. In 12 oncological patients, we computed IDIF (from the aorta) and PBIFs with scaling by the AUC of the IDIF from 4 time windows (15-45, 30-60, 45-75, 60-90 min) (PBIFAUC) and estimated CP*(0) (PBIFiDV). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak Ki values. RESULTS: The IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and Ki comparison, 30-60 min was the most accurate time window for PBIFAUC; later time windows for scaling underestimated Ki (- 6 ± 8 to - 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIFAUC(30-60), and PBIFiDV were 0.91, 0.94, and 0.90, respectively. The bias of Ki was - 9 ± 10%, - 1 ± 8%, and 3 ± 9%, respectively. CONCLUSIONS: Both PBIF scaling methods provided good mean performance with moderate variation. Improved performance can be obtained by refining IDIF methods and by evaluating PBIFs with test-retest data.

The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation.

Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chaperonin T-complex-protein-1-ring (TRiC) or Cytosolic Chaperonin containing TCP-1 (CCT) to assist folding of newly synthesized polypeptides. The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels. Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation. We mapped the interaction of prefoldin with pVHL at the exon2-exon3 junction encoded region. Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations. Our results link the prefoldin complex with pVHL folding and this may impact VHL diseases progression.

Temporary and permanent unfitness of occupational divers. Brest Cohort 2002-2019 from the French National Network for Occupational Disease Vigilance and Prevention (RNV3P).

BACKGROUND: In France, the monitoring of professional divers is regulated. Several learned societies (French Occupational Medicine Society, French Hyperbaric Medicine Society and French Maritime Medicine Society) have issued follow-up recommendations for professional divers, including medical follow-up. Medical decisions could be temporary unfitness for diving, temporary fitness with monitoring, a restriction of fitness, or permanent unfitness. The aim of study was to point out the causes of unfitness in our centre. MATERIALS AND METHODS: The divers' files were selected from the French National Network for Occupational Disease Vigilance and Prevention (RNV3P). Only files with a special medical decision were selected, between 2002 and 2019. RESULTS: Three hundred and ninety-six professional divers are followed-up in our centre and 1371 medical decisions were delivered. There were 29 (7.3%) divers with a special medical decision, during 42 (3.1%) medical visit. Twelve (3.0%) had a permanent unfitness. The leading cause of unfitness was pulmonary diseases: emphysema (3), chronic obstructive pulmonary disorder (2), asthma (2). Sixteen (4.0%) divers had temporary unfitness. The leading causes were cardiovascular (4 times) and neurological (6 times). Twelve (3.0%) divers had had at least one decompression sickness. CONCLUSIONS: Judgments of permanent unfitness for diving were rare (3.0% of divers), but were because of life-threatening disease. Medical follow-up of occupational divers was justified to decrease the risk of fatal event during occupational dives.

[Better screening for work-related cancers: The experience of Brest University Hospital Occupational Disease Center inpatient service]. / Améliorer le repérage des cancers professionnels : bilan de la consultation de pathologie professionnelle de liaison du centre hospitalier universitaire de Brest.

INTRODUCTION: An in-patient clinical service has been set up in March 2016 in the Occupational Diseases Center of Brest University Hospital, France, to seek for work-relatedness of diseases in patients hospitalized into the oncology and hematology departments. We present here data after two years of existence. METHODS: All cases of cancers or malignant hematological diseases (ICD-10 codes C00 to C97 and D37 to D48) seen between March 1, 2016, and March 1, 2018, have been identified. We present sociodemographic data, occupational exposures, occupation, business sector, and tobacco consumption. The causation level between the disease and each of the occupational exposures has been rated as strong, intermediate, weak or null by the occupational medicine specialist of the Occupational Diseases Center. RESULTS: Among the 196 patients encountered, there are 127 work-related diseases and 82 of these had one occupational exposure rated as strong or intermediate. The most frequent occupational hazards were asbestos (48 cases) and ionizing radiation (23 cases). The most frequent business sectors were metallurgy, mechanical engineering, and agriculture. Lung cancer was the most frequently reported disease (49 cases). DISCUSSION: . We identified well-known couples with occupational exposures and diseases, such as asbestos and lung cancer. We also identified a link between pesticides and leukemias. This in-patient clinical service is helpful to identify work-related exposures and in helping patients to get compensated.

Body Mass Index and Age Effects on Brain 11ß-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study.

CONTEXT: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11ß-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE: We analyzed positron emission tomography (PET) scans with an 11ß-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 µg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 µg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. RESULTS: Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. CONCLUSIONS: In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11ß-HSD1 in the brain and correlation of increased 11ß-HSD1 levels in the brain with advancing age.