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Abstract Background The authors examined factors associated with nutritional resilience/vulnerability among preschoolers in the Gaza Strip in 2007, where political violence and deprivation are widespread. Methods This cross-sectional study was carried out in 2007 using random sampling of kindergartens in order to select 350 preschoolers. Binary logistic regression was used to compare resilient (adequate nutrition) and vulnerable (stunted) groups with those with moderate nutrition. Results Approximately 37% of the subjects demonstrated nutritional resilience and 15% were vulnerable. Factors associated with nutritional resilience were child younger age, normal birth weight, actively hand- or spoon-feeding when the child was below two years, and residential stability in the past two years. The only factor associated with nutritional vulnerability was lower total score on the mother's General Health Questionnaire, which we interpret as a marker of maternal mental health. Conclusions Children with low-birth weight and older children had worse nutritional resiliency outcomes. Further, poorer outcomes for children were associated with lower maternal mental health status, as well as increased family residential instability. Our results add to the large literature on the pervasive effects of violence and instability on children and underscore the need for resources for early intervention and for the urgent resolution of the Palestinian and other armed conflicts.

Rationale: Sleep-disordered breathing (SDB) has been associated with total and cardiovascular mortality, but an association with cancer mortality has not been studied. Results from in vitro and animal studies suggest that intermittent hypoxia promotes cancer tumor growth.Objectives: The goal of the present study was to examine whether SDB is associated with cancer mortality in a community-based sample.Methods: We used 22-year mortality follow-up data from the Wisconsin Sleep Cohort sample (n = 1,522). SDB was assessed at baseline with full polysomnography. SDB was categorized using the apnea-hypopnea index (AHI) and the hypoxemia index (percent sleep time below 90% oxyhemoglobin saturation). The hazards of cancer mortality across levels of SDB severity were compared using crude and multivariate analyses.Measurements and Main Results: Adjusting for age, sex, body mass index, and smoking, SDB was associated with total and cancer mortality in a dose-response fashion. Compared with normal subjects, the adjusted relative hazards of cancer mortality were 1.1 (95% confidence interval [CI], 0.5-2.7) for mild SDB (AHI, 5-14.9), 2.0 (95% CI, 0.7-5.5) for moderate SDB (AHI, 15-29.9), and 4.8 (95% CI, 1.7-13.2) for severe SDB (AHI ≥ 30) (P-trend = 0.0052). For categories of increasing severity of the hypoxemia index, the corresponding relative hazards were 1.6 (95% CI, 0.6-4.4), 2.9 (95% CI, 0.9-9.8), and 8.6 (95% CI, 2.6-28.7).Conclusions: Our study suggests that baseline SDB is associated with increased cancer mortality in a community-based sample. Future studies that replicate our findings and look at the association between sleep apnea and survival after cancer diagnosis are needed. [ABSTRACT FROM AUTHOR]

Rationale: Cerebrovascular regulation is impaired in patients with moderate to severe obstructive sleep apnea; however, it is unknown whether this impairment exists in individuals with less severe sleep-disordered breathing.Objectives: To test the hypothesis that cerebrovascular responses to hypercapnia are attenuated in a nonclinical population-based cohort.Methods: A rebreathing test that raised end-tidal CO₂ tension by 10 mm Hg was performed during wakefulness in 373 participants of the Wisconsin Sleep Cohort.Measurements and Main Results: We measured cerebral flow velocity (transcranial Doppler ultrasound); heart rate (electrocardiogram); blood pressure (photoplethysmograph); ventilation (pneumotachograph); and end-tidal CO₂ (expired gas analysis). Cerebrovascular CO₂ responsiveness was quantified as the slope of the linear relationship between flow velocity and end-tidal CO₂ during rebreathing. Linear regression analysis was performed using cerebrovascular CO₂ responsiveness as the outcome variable. Main independent variables were the apnea-hypopnea index and the mean level of arterial oxygen saturation during sleep. We observed a positive correlation between cerebrovascular CO₂ responsiveness and the mean level of oxygen saturation during sleep that was statistically significant in unadjusted analysis and after adjustment for known confounders and the increase in arterial pressure during rebreathing. Each 5% decrease in Sa(O₂) during sleep predicted a decrease in cerebrovascular reactivity of 0.4 ± 0.2 cm/second/mm Hg P(ET)CO₂. In contrast, the negative correlation between cerebrovascular CO₂ responsiveness and apnea-hypopnea index was statistically significant only in the unadjusted analysis.Conclusions: Hypercapnic vasodilation in the cerebral circulation is blunted in individuals with sleep-disordered breathing. This impairment is correlated with hypoxemia during sleep. [ABSTRACT FROM AUTHOR]

AIM: To describe changes in leisure time and occupational physical activity status in an urban Mediterranean population-based cohort, and to evaluate sociodemographic, health-related and lifestyle correlates of such changes. METHODS: Data for this study come from the Cornellè Health Interview Survey Follow-Up Study, a prospective cohort study of a representative sample (n = 2500) of the population. Participants in the analysis reported here include 1246 subjects (567 men and 679 women) who had complete data on physical activity at the 1994 baseline survey and at the 2002 follow-up. We fitted Breslow-Cox regression models to assess the association between correlates of interest and changes in physical activity. RESULTS: Regarding leisure time physical activity, 61.6% of cohort members with 'sedentary' habits in 1994 changed their status to 'light/moderate' physical activity in 2002, and 70% who had 'light/moderate' habits in 1994 did not change their activity level. Regarding occupational physical activity, 74.4% of cohort members who were 'active' did not change their level of activity, and 64.3% of participants with 'sedentary' habits in 1994 changed to 'active' occupational physical activity. No clear correlates of change in physical activity were identified in multivariate analyses. CONCLUSION: While changes in physical activity are evident in this population-based cohort, no clear determinants of such changes were recognised. Further longitudinal studies including other potential individual and contextual determinants are needed to better understand determinants of changes in physical activity at the population level. [ABSTRACT FROM AUTHOR]

Background: Narrowing of the small arterioles has been hypothesized to contribute to the pathogenesis of hypertension, but prospective clinical data are lacking.Objective: To examine the relation of retinal arteriolar narrowing to incident hypertension in healthy middle-aged persons.Design: Prospective cohort study.Setting: The population-based Atherosclerosis Risk in Communities Study, conducted in 4 U.S. communities.Participants: 5628 persons 49 to 73 years of age without preexisting hypertension.Measurements: Diameters of retinal vessels were measured from digitized retinal photographs. A summary arteriole-to-venule ratio was computed as an indicator of generalized arteriolar narrowing; a lower ratio indicated greater narrowing. Areas of focal arteriolar narrowing were defined from photographs by using a standard protocol. Incident hypertension, defined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or use of antihypertensive medication, was identified from the cohort.Results: After 3 years of follow-up, 811 (14.4%) persons had developed hypertension. The incidence of hypertension was higher in persons with lower arteriole-to-venule ratios (incidence of 8.9%, 12.3%, 13.7%, 14.3%, and 22.3%, comparing decreasing quintiles of the ratio) and in persons with focal arteriolar narrowing than in those without focal arteriolar narrowing (25.1% vs. 13.0%). After the authors controlled for the average systolic and diastolic blood pressures over the preceding 6 years, body mass index, waist-to-hip ratio, and other risk factors, the odds of developing hypertension were approximately 60% higher in persons with lower arteriole-to-venule ratios (odds ratio, 1.62 [95% CI, 1.21 to 2.18] comparing lowest to highest quintile; P = 0.006 for trend) and focal arteriolar narrowing (odds ratio, 1.61 [CI, 1.27 to 2.04]; P < 0.001).Conclusions: Smaller retinal arteriolar diameters are independently associated with incident hypertension, which suggests that arteriolar narrowing may be linked to the occurrence and development of hypertension. [ABSTRACT FROM AUTHOR]

Clinical studies have suggested that sleep apnea is associated with impaired brachial artery flow-mediated dilation, a surrogate of endothelial dysfunction. We examined this question among older participants in the baseline examination of the Sleep Heart Health/Cardiovascular Health Study cohort (n = 1,037, age 68 years or older, 56% female). Indices of sleep apnea, derived from 12-channel home polysomnography, were the apnea-hypopnea index (average number of apneas/hypopneas per hour) and the hypoxemia index (percentage of time below 90% O2 saturation). Baseline arterial diameter and percentage of flow-mediated dilation were measured by ultrasound. Sleep apnea measures were associated with baseline diameter and the percentage of flow-mediated dilation, although these associations were weakened after adjustment for other cardiovascular risk factors, particularly body mass index. However, a statistically significant linear association between the hypoxemia index and baseline diameter was observed even after adjustment for body mass index and other confounders (p < 0.01). The associations were stronger among participants who were younger than 80 years and among those who with hypertension. This study adds to the growing body of evidence linking sleep apnea with vascular dysfunction in older subjects. Whether these relationships are entirely independent of obesity is unclear. This association might be one of the mechanisms explaining the relationship between sleep apnea, hypertension, and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to determine whether depressive symptoms predict type 2 diabetes.Research Design and Methods: We analyzed data on depressive symptoms (including recent fatigue, sleep disturbance, feelings of hopelessness, loss of libido, and increased irritability) in a longitudinal, biracial cohort study of 11,615 initially nondiabetic adults aged 48-67 years, who were subsequently followed for 6 years for the development of type 2 diabetes.Results: At baseline, depressive symptoms were positively associated with BMI, fasting insulin, systolic blood pressure, caloric intake, physical inactivity, and current smoking (all P < 0.05). In prospective analyses, after adjusting for age, race, sex, and education, individuals in the highest quartile of depressive symptoms had a 63% increased risk of developing diabetes compared with those in the lowest quartile (relative hazard [RH] 1.63, 95% CI 1.31-2.02). This relation persisted after adjustment for stress-associated lifestyle factors (smoking, physical activity, caloric intake, and adiposity) (1.28, 1.02-1.60) and metabolic covariates (fasting insulin and glucose, lipids, blood pressure, and adiposity) (1.38, 1.10-1.73).Conclusions: In this cohort, depressive symptoms predicted incident type 2 diabetes. This relation is only partially explained by demographic, metabolic, and lifestyle factors. Possible neuroendocrine mediators of the stress-obesity-diabetes relationship require further evaluation in prospective cohort studies that use an established tool to assess depression and incorporate neurohormonal measurements. [ABSTRACT FROM AUTHOR]

The authors examined the association between lung function, as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity, and the 10-year incidence of coronary heart disease among 14,480 participants in the Atherosclerosis Risk in Communities Study (1987-1998). Separate proportional hazards models were used for FEV1 and forced vital capacity, with gender-specific lung function quartiles and lung function x gender interaction terms. An association between lung function and coronary heart disease was observed in both genders and was stronger among women. After adjustment for age, race, study center, height, height squared, smoking, and cardiovascular disease risk factors, the hazard ratios for the first (lowest), second, and third quartiles of FEV1 were 3.70 (95% confidence interval (CI): 2.19, 6.24), 2.54 (95% CI: 1.49, 4.32), and 2.25 (95% CI: 1.31, 3.87) for women and 1.51 (95% CI: 1.07, 2.13), 1.59 (95% CI: 1.15, 2.20), and 1.52 (95% CI: 1.10, 2.09) for men. After stratification by smoking status, associations were observed in each smoking group for women, while those in men were weaker and less consistent. Similar results were obtained for forced vital capacity. This analysis indicates an association between lung function and incident coronary heart disease that may be stronger in women than in men. [ABSTRACT FROM AUTHOR]

The objective of the study was to determine which component of an anger-prone personality more strongly predicts coronary heart disease (CHD) risk. Proneness to anger, as assessed by the Spielberger Trait Anger Scale, is composed of two distinct subcomponents-anger-temperament and anger-reaction. Participants were 12,990 middle-aged Black men and women and White men and women from the Atherosclerosis Risk in Communities Study who were followed for the occurrence of acute myocardial infarction (MI)/fatal CHD, silent MI, or cardiac revascularization procedures (average = 53 months; maximum = 72 months) through December 31, 1995. Among normotensive persons, a strong, angry temperament (tendency toward quick, minimally provoked, or unprovoked anger) was associated with combined CHD (acute MI/fatal CHD, silent MI, or cardiac revascularization procedures) (multivariate-adjusted hazard ratio = 2.10, 95% confidence interval: 1.34, 3.29) and with 'hard' events (acute MI/fatal CHD) (multivariate adjusted hazard ratio = 2.28, 95% confidence interval: 1.29, 4.02). CHD event-free survival among normotensives who had a strong, angry temperament was not significantly different from that of hypertensives at either level of anger. These data suggest that a strong, angry temperament rather than anger in reaction to criticism, frustration, or unfair treatment places normotensive, middle-aged persons at increased risk for cardiac events and may confer a CHD risk similar to that of hypertension. [ABSTRACT FROM AUTHOR]

Associations between sleep-disordered breathing and cardiovascular disease (CVD) may be mediated by higher cardiovascular risk factor levels in those with sleep-disordered breathing. The authors examined these relations in the Sleep Heart Health Study, a multiethnic cohort of 6,440 men and women over age 40 years conducted from October 1995 to February 1998 and characterized by home polysomnography. In 4,991 participants who were free of self-reported CVD at the time of the sleep study, moderate levels of sleep-disordered breathing were common, with a median Respiratory Disturbance Index (RDI) of 4.0 (interquartile range, 1.25-10.7). The level of RDI was associated cross-sectionally with age, body mass index, waist-to-hip ratio, hypertension, diabetes, and lipid levels. These relations were more pronounced in those under age 65 years than in those over age 65. Women under age 65 years with RDI in the higher quartiles were more obese than men with similar RDI. Although the pattern of associations was consistent with greater obesity in those with higher RDI, higher body mass index did not explain all of these associations. If sleep-disordered breathing is shown in future follow-up to increase the risk for incident CVD events, part of the risk is likely to be due to the higher cardiovascular risk factors in those with higher RDI. [ABSTRACT FROM AUTHOR]

Context: Sleep-disordered breathing (SDB) and sleep apnea have been linked to hypertension in previous studies, but most of these studies used surrogate information to define SDB (eg, snoring) and were based on small clinic populations, or both.Objective: To assess the association between SDB and hypertension in a large cohort of middle-aged and older persons.Design and Setting: Cross-sectional analyses of participants in the Sleep Heart Health Study, a community-based multicenter study conducted between November 1995 and January 1998.Participants: A total of 6132 subjects recruited from ongoing population-based studies (aged > or = 40 years; 52.8% female).Main Outcome Measures: Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas per hour of sleep, with apnea defined as a cessation of airflow and hypopnea defined as a > or = 30% reduction in airflow or thoracoabdominal excursion both of which are accompanied by a > or = 4% drop in oxyhemoglobin saturation) [corrected], obtained by unattended home polysomnography. Other measures include arousal index; percentage of sleep time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication.Results: Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing SDB measures, although some of this association was explained by body mass index (BMI). After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol intake and smoking, the odds ratio for hypertension, comparing the highest category of AHI (> or = 30 per hour) with the lowest category (< 1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03-1.83; P for trend = .005). The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (> or = 12% vs < 0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified analyses, associations of hypertension with either measure of SDB were seen in both sexes, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring.Conclusion: Our findings from the largest cross-sectional study to date indicate that SDB is associated with systemic hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds. [ABSTRACT FROM AUTHOR]

Pathologic findings and cross-sectional epidemiologic studies suggest that past infection with Chlamydia pneumoniae is associated with clinical and subclinical atherosclerotic disease, although evidence from prospective studies is still scarce. The association between chronic infection by C. pneumoniae and incident coronary heart disease (CHD) was investigated in a case-cohort study conducted among participants in the Atherosclerosis Risk in Communities Study who were free of CHD at the baseline examination (1986-1989). Levels of C. pneumoniae immunoglobulin G (IgG) antibodies in serum collected at baseline from 246 incident cases of CHD identified during follow-up (median, 3.3 years; maximum, 5 years) were compared with those from a stratified sample of the baseline cohort (n = 550). Among incident CHD cases, 65% had IgG antibody titers > or =1:64, compared with 55% of noncases (compared with negative IgG titers, the relative hazard of CHD was 1.6 (p < 0.01)). In multivariate analyses controlling for other risk factors (age, gender, smoking, serum cholesterol, hypertension, diabetes mellitus, and educational level), the above estimates were substantially reduced and became statistically nonsignificant (relative hazard = 1.2). A significantly increased CHD hazard associated with IgG antibody titers > or =1:64 was observed among nonsmokers, even after adjustment for other risk factors. Overall, these results do not provide strong support for the hypothesis that C. pneumoniae infection is a risk factor for clinical CHD. Studies with longer follow-up periods will be necessary to determine whether C. pneumoniae infection is involved as an etiologic factor in earlier phases of atherogenesis. [ABSTRACT FROM AUTHOR]

Context: Cigarette smoking is a powerful risk factor for incident heart disease and stroke, but the relationship of active and passive smoking with the progression of atherosclerosis has not been described.Objective: To examine the impact of active smoking and exposure to environmental tobacco smoke (ETS) on the progression of atherosclerosis.Design: A longitudinal assessment of the relationship between smoking exposure evaluated at the initial visit and the 3-year change in atherosclerosis.Setting: A population-based cohort of middle-aged adults from 4 communities in the United States.Participants: A total of 10914 participants from the Atherosclerosis Risk in Communities (ARIC) study enrolled between 1987 and 1989.Main Outcome Measure: Change in atherosclerosis from baseline to the 3-year follow-up as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound and adjusted for demographic characteristics, cardiovascular risk factors, and lifestyle variables.Results: Exposure to cigarette smoke was associated with progression of atherosclerosis. Relative to never smokers and after adjustment for demographic characteristics, cardiovascular risk factors, and lifestyle variables, current cigarette smoking was associated with a 50% increase in the progression of atherosclerosis (mean progression rate over 3 years, 43.0 microm for current and 28.7 microm for never smokers, regardless of ETS exposure), and past smoking was associated with a 25% increase (mean progression rate over 3 years, 35.8 microm for past smokers and 28.7 microm for never smokers). Relative to those not exposed to ETS, exposure to ETS was associated with a 20% increase (35.2 microm for those exposed to ETS vs 29.3 microm for those not exposed). The impact of smoking on atherosclerosis progression was greater for subjects with diabetes and hypertension. Although more pack-years of exposure was independently associated with faster progression (P<.001), after controlling for the number of pack-years, the progression rates of current and past smokers did not differ (P=.11).Conclusions: Both active smoking and ETS exposure are associated with the progression of an index of atherosclerosis. Smoking is of particular concern for patients with diabetes and hypertension. The fact that pack-years of smoking but not current vs past smoking was associated with progression of atherosclerosis suggests that some adverse effects of smoking may be cumulative and irreversible. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the effect of age and study period on coronary heart disease (CHD) risk attributable to cardiovascular risk factors. METHODS: A cohort of cardiovascular disease (CVD)-free randomly participants from Girona (Spain) aged 35-74 years recruited in 1995 and 2000 and followed for an average of 6.9 years. A survey conducted in the same area in 2005 was also used for the analysis. Smoking, hypertension, diabetes, sedentary lifestyle, obesity, total cholesterol > or = 240 mg/dl, low-density lipoprotein (LDL) cholesterol > or = 160 mg/dl, and high-density lipoprotein cholesterol <40 mg/dl were the risk factors considered. The composite end-point included myocardial infarction, angina pectoris, and CHD death. RESULTS: LDL cholesterol had the highest potential for CHD prevention between 35 and 74 years [42% (95% Confidence Interval: 23,58)]. The age-stratified analysis showed that the population attributable risk (PAF) for smoking was 64% (30,80) in subjects < 55 years; for those > or = 55 years, the PAF for hypertension was 34% (1,61). The decrease observed between 1995 and 2005 in the population's mean LDL cholesterol level reduced that PAF in all age groups. CONCLUSION: Overall, LDL cholesterol levels had the highest potential for CHD prevention. Periodic PAF recalculation in different age groups may be required to adequately monitor population trends. Copyright © 2010 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether homocyst(e)ine (H(e)) is related to hemostatic factors in a population-based sample without evidence of cardiovascular disease.Methods: A subsample of 660 participants--67 African-American women, 53 African-American men, 201 white women, and 339 white men--was selected from the Atherosclerosis Risk in Communities Study baseline cohort. This was based on carotid intimal-medial wall thickness above the 90th percentile or below the 75th percentile of the population distribution, assessed by B-mode ultrasonography. Unadjusted and multivariable-adjusted associations between fasting plasma H(e) and the hemostatic factors fibrinogen, factor VII:c, factor VIII:c, protein C antigen, hematocrit, platelet count, beta-thromboglobulin (beta-TG), tissue plasminogen activator (tPA), PAI-1, D-dimer, and lipoprotein[a] were examined.Results: Mean age-adjusted H(e) was positively, albeit weakly, correlated with beta-TG, tPA, hematocrit, D-dimer and PAI-1; inversely correlated with protein C; and was higher in smokers, men and African-Americans. In multivariable regression, beta-TG, tPA, and factor VII:c were positively associated with H(e), as well as age, black race, male sex, and current cigarette smoking.Conclusions: These cross-sectional data for a biracial group of middle-aged individuals suggest that H(e) levels falling below values consistent with homocyst(e)inemia are associated with several prothrombotic factors after adjustment for sociodemographic factors. If H(e) change is antecedent to altered hemostasis, FDA-mandated fortification of grain products with folic acid for prevention of fetal neural tube defects may lead to both reduced plasma H(e) levels and improved hemostatic profiles. [ABSTRACT FROM AUTHOR]

Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance., Methods: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi., Results: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively., Conclusions: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option., (© 2024. The Author(s).)

The aim of this study is to describe the anaesthesia management of two patients undergoing carinal resection under veno-venous extracorporeal membrane oxygenation (VV ECMO). In both cases, anaesthesia was induced and then maintained with inhalational agents during pneumonectomy and mediastinoscopy (respectively). Then the jugular and femoral veins were cannulated and VV ECMO was started after heparinization. One of the patients presented bleeding during surgery, which was treated with low-dose vasopressors (norepinephrine) and transfusion of platelets, fresh frozen plasma, and concentrated red blood cells. During VV ECMO, anaesthesia was maintained with target-controlled infusion of propofol. VV ECMO can be expected to improve surgical conditions in tracheal surgery; however, it is still a novel technique in this context. In selected patients, it would guarantee ventilatory support during carinal resection, but it is essential to carefully plan anaesthesia maintenance and prepare for VV ECMO-related complications. This technique should only be used in tertiary centres with experience in VV ECMO management., (Copyright © 2023 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity., Competing Interests: Declaration of interests E.P. is a member of the Cell Stem Cell advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8 + T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity., (© 2024. The Author(s).)

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta., (© 2024. The Author(s).)

Early organogenesis represents a key step in animal development, during which pluripotent cells diversify to initiate organ formation. Here, we sampled 300,000 single-cell transcriptomes from mouse embryos between E8.5 and E9.5 in 6-h intervals and combined this new dataset with our previous atlas (E6.5-E8.5) to produce a densely sampled timecourse of >400,000 cells from early gastrulation to organogenesis. Computational lineage reconstruction identified complex waves of blood and endothelial development, including a new programme for somite-derived endothelium. We also dissected the E7.5 primitive streak into four adjacent regions, performed scRNA-seq and predicted cell fates computationally. Finally, we defined developmental state/fate relationships by combining orthotopic grafting, microscopic analysis and scRNA-seq to transcriptionally determine cell fates of grafted primitive streak regions after 24 h of in vitro embryo culture. Experimentally determined fate outcomes were in good agreement with computationally predicted fates, demonstrating how classical grafting experiments can be revisited to establish high-resolution cell state/fate relationships. Such interdisciplinary approaches will benefit future studies in developmental biology and guide the in vitro production of cells for organ regeneration and repair., Competing Interests: Competing interests J.C.M. has been an employee of Genentech since September 2022., (© 2024. Published by The Company of Biologists Ltd.)

Parkin is an ubiquitin-E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5 month-old) and aged (16 month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality., (© 2023. The Author(s).)