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Purpose: Socioeconomic status has been related to resting blood pressure (BP) levels at different stages of life. However, the association of childhood socioeconomic status (SES) and adulthood exercise BP is largely unknown. Therefore, we studied the association of childhood SES with adulthood maximal exercise BP., Materials and Methods: This investigation consisted of 373 individuals (53% women) participating in the Cardiovascular Risk in Young Finns Study who had data concerning family SES in childhood (baseline in 1980, at age of 6-18 years) and exercise BP response data in adulthood (follow-up in adulthood in 27-29 years since baseline). A maximal cardiopulmonary exercise test with BP measurements was performed by participants, and peak exercise BP was measured., Results: In stepwise multivariable analysis including childhood risk factors and lifestyle factors (body mass index, systolic BP, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, insulin, fruit consumption, vegetable consumption, and physical activity), lower family SES in childhood was associated with higher maximal exercise BP in adulthood (β value ± SE, 1.63 ± 0.77, p  = 0.035). The association remained significant after further adjustment with participants SES in adulthood (β value ± SE, 1.68 ± 0.65, p  = 0.011) and after further adjustment with adulthood body-mass index, systolic BP, maximal exercise capacity, and peak heart rate in exercise (β value ± SE, 1.25 ± 0.56, p  = 0.027)., Conclusions: These findings suggest that lower childhood family SES is associated with higher maximal exercise BP in adulthood.

Background: Despite some recent advances, pancreatic ductal adenocarcinoma (PDAC) remains a growing oncological challenge. New drugs capable of targeting more than one oncogenic pathway may be one way to improve patient outcomes. This study characterizes the effectiveness of Metavert a first-in-class dual inhibitor of GSK3-β and histone deacetylase in treating PDAC as a single agent or in combination with standard cytotoxics., Methods: Thirty-six Patient-Derived Organoids (hPDOs) characterised by RNASeq and whole exome sequencing were treated with Metavert alone or in combination with standard cytotoxics. Transcriptomic signatures (TS) representing sensitivity to Metavert alone or sensitivity to Metavert + irinotecan (IR) were evaluated in 47 patient samples, chemo-naïve in 26 and post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14, both=2) with companion multiplexed immunofluorescence and RNASeq data., Results: Metavert combined with gemcitabine, irinotecan, 5FU, oxaliplatin, and paclitaxel was synergistic in the hPDOs. Basal-subtype hPDOs were more sensitive to Metavert alone whereas the Metavert+IR combination exhibited synergy in Classical-subtype hPDOs with increased apoptosis and autophagy. hPDO-derived TS evaluated in PDAC tissues demonstrated that Metavert-TS Hi samples were enriched for mRNA splicing and DNA repair processes; they were associated with Basal-like tissues but also with GATA6 +ve -chemo-naïve samples and were higher following gemcitabine but not FOLFIRINOX treatment. In contrast, Metavert+IR-TS HI samples were enriched for TP53 pathways; they were associated with Classical-like pretreatment samples and with GATA6 +ve /KRT17 +ve hybrid cell types following FOLFIRINOX, but not gemcitabine treatment, and were unrelated to transcriptional subtypes., Conclusions: Metavert as a single agent and in combination with irinotecan offers novel strategies for treating pancreatic cancer., Competing Interests: Declaration of competing interest ME and SP are involved in clinical development of Metavert with Avenzoar Pharmaceuticals. The remaining authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background & Aims: As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach., Methods: We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level., Results: We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition., Conclusions: Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Elevated blood pressure (BP) in childhood has been associated with increased adulthood BP. However, BP and its change from childhood to adulthood and the risk of exaggerated adulthood exercise BP response are largely unknown. Therefore, we studied the association of childhood and adulthood BP with adulthood exercise BP response., Materials and Methods: This investigation consisted of 406 individuals participating in the ongoing Cardiovascular Risk in Young Finns Study (baseline in 1980, at age of 6-18 years; follow-up in adulthood in 27-29 years since baseline). In childhood BP was classified as elevated according to the tables from the International Child Blood Pressure References Establishment Consortium, while in adulthood BP was considered elevated if systolic BP was ≥120 mmHg or diastolic BP was ≥80 mmHg or if use of antihypertensive medications was self-reported. A maximal cardiopulmonary exercise test with BP measurements was performed by participants in 2008-2009, and exercise BP was considered exaggerated (EEBP) if peak systolic blood pressure exceeded 210 mmHg in men and 190 mmHg in women., Results: Participants with consistently high BP from childhood to adulthood and individuals with normal childhood but high adulthood BP had an increased risk of EEBP response in adulthood (relative risk [95% confidence interval], 3.32 [2.05-5.40] and 3.03 [1.77-5.17], respectively) in comparison with individuals with normal BP both in childhood and adulthood. Interestingly, individuals with elevated BP in childhood but not in adulthood also had an increased risk of EEBP [relative risk [95% confidence interval], 2.17 [1.35-3.50])., Conclusions: These findings reinforce the importance of achieving and sustaining normal blood pressure from childhood through adulthood.

Purpose: High pulse wave velocity (PWV), a marker of increased arterial stiffness, and an exaggerated exercise blood pressure (EEBP) response during an exercise test have both been related to an increased risk of hypertension and cardiovascular events. Contradictory results have been published about the association between these two parameters, and their relation in healthy young adults is unknown. Materials and methods: This study consisted of 209 young adults (mean age 38 years) who participated in the ongoing Cardiovascular Risk in Young Finns Study between 2007 and 2009. We measured resting PWV with impedance cardiography in 2007, and participants performed a maximal cardiopulmonary exercise test with blood pressure (BP) measurements at rest, during exercise and during recovery in 2008-2009. Results: High PWV (≥age- and sex-specific median) at baseline was associated with EEBP (SBP >210 mmHg for men and >190 mmHg for women) an average of 14 months later and with systolic BP during different stages of exercise from rest to peak and recovery (during peak exercise, β ± SE was 4.1 ± 1.1, p  < 0.001). The association between high PWV and systolic BP remained after adjustment for traditional cardiovascular risk factors and other exercise parameters (during peak exercise, β ± SE was 2.3 ± 1.1, p  = 0.04). Conclusions: Increased arterial stiffness predicts EEBP during a maximal exercise test in young adults during all stages of exercise from rest to peak and recovery. PWV could provide an additional tool for EEBP risk evaluation.

Background: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a multicenter randomized controlled trial that reported beneficial effects on cognition for a 2-year multimodal intervention (diet, exercise, cognitive training, vascular risk monitoring) versus control (general health advice). This study reports exploratory analyses of brain MRI measures., Methods: FINGER targeted 1260 older individuals from the general Finnish population. Participants were 60-77 years old, at increased risk for dementia but without dementia/substantial cognitive impairment. Brain MRI scans were available for 132 participants (68 intervention, 64 control) at baseline and 112 participants (59 intervention, 53 control) at 2 years. MRI measures included regional brain volumes, cortical thickness, and white matter lesion (WML) volume. Cognition was assessed at baseline and 1- and 2-year visits using a comprehensive neuropsychological test battery. We investigated the (1) differences between the intervention and control groups in change in MRI outcomes (FreeSurfer 5.3) and (2) post hoc sub-group analyses of intervention effects on cognition in participants with more versus less pronounced structural brain changes at baseline (mixed-effects regression models, Stata 12)., Results: No significant differences between the intervention and control groups were found on the changes in MRI measures. Beneficial intervention effects on processing speed were more pronounced in individuals with higher baseline cortical thickness in Alzheimer's disease signature areas (composite measure of entorhinal, inferior and middle temporal, and fusiform regions). The randomization group × time × cortical thickness interaction coefficient was 0.198 (p = 0.021). A similar trend was observed for higher hippocampal volume (group × time × hippocampus volume interaction coefficient 0.1149, p = 0.085)., Conclusions: The FINGER MRI exploratory sub-study did not show significant differences between the intervention and control groups on changes in regional brain volumes, regional cortical thicknesses, or WML volume after 2 years in at-risk elderly without substantial impairment. The cognitive benefits on processing speed of the FINGER intervention may be more pronounced in individuals with fewer structural brain changes on MRI at baseline. This suggests that preventive strategies may be more effective if started early, before the occurrence of more pronounced structural brain changes., Trial Registration: ClinicalTrials.gov, NCT01041989 . Registered January 5, 2010.

Purpose: Fatty liver is an expanding health concern associated with metabolic disturbances and increased risk of cardiovascular disease. Experimental studies in animals have shown associations between fatty liver and cardiorespiratory fitness but limited data exist in humans. The aim of this study was to analyze the links between cardiorespiratory fitness and fatty liver in a population-based sample of adults., Methods: Participants were 463 adults (48% men) from the Cardiovascular Risk in Young Finns Study. Cardiorespiratory fitness was measured with a cycle ergometer exercise test as peak oxygen uptake (V˙O2peak [mL·kg·min]) in 2008 to 2009. Hepatic ultrasonographic imaging was performed in 2011 to determine fatty liver., Results: Cardiorespiratory fitness was associated with lower risk of fatty liver (1 mL·kg·min increase in V˙O2peak: risk ratio, 0.90; 95% confidence interval, 0.88-0.93, P < 0.0001; adjusted for age and sex). This association remained significant after further adjustments with physical activity, adiposity, smoking, alcohol consumption, serum lipids, insulin, glucose, and C-reactive protein. Participants who were obese (waist circumference, >80 cm in women and >94 cm in men) but fit (V˙O2peak in the upper age- and sex-specific median) had lower prevalence of fatty liver than participants who were obese and unfit (below median), (11.7% vs 34.8%, P = 0.0003)., Conclusions: In a population-based sample of adults, cardiorespiratory fitness is strongly, inversely and independently related with the risk of fatty liver. Importantly, the association is evident also among obese.

In standard forensic DNA analysis, single base mutations within short tandem repeats (STR) mostly escape detection. In this study, high-resolution DNA melting (HRM) is compared to minisequencing and Sanger sequencing as to determine the most suitable method for detection of a G to C mutation within a repetitive DNA sequence, the STR system DXS10161. It shows an ATG/ATC polymorphism surrounded by a variable number of (TATC) and (ATCT) motifs. Neutral base changes like G:C to C:G result in very low differences in the melting temperature (T m) of the PCR amplicons. By enhanced resolution of fluorescence vs. temperature in HRM, the technique showed to be suitable for detecting a G to C transversion in this repetitive DNA sequence context. Compared to minisequencing, HRM is more time- and cost-effective. Results were confirmed by Sanger sequencing.

Background: Novel parameters derived from peak maximal oxygen uptake (VO2) and exercise arterial blood pressure, such as peak circulatory power (CP) and exercise cardiac power (ECP), can be used in the risk assessment of cardiovascular disease and stroke. However, the determinants of these factors are poorly characterized in the general population., Methods: We assessed peak arterial blood pressure, CP and ECP with standardized cardiopulmonary exercise test (CPET) on 281 female and 257 male participants of the Cardiovascular Risk in Young Finns Study. The subjects were aged 30-47 years. Peak VO2 as well as systolic and diastolic arterial blood pressures were measured to calculate peak mean arterial pressure, CP and ECP. These parameters were assessed for correlation with sex, age, height, weight, waist-to-hip ratio, smoking, physical activity index (PAI), fasting insulin and glucose levels as well as the use of antihypertensive treatment., Results: Sex, age and weight explained 36% of the variation in peak systolic blood pressure, and these factors in combination with height and the use of antihypertensive treatment explained 13% of the variation in peak diastolic blood pressure. Sex, height, weight, waist-to-hip ratio, PAI and smoking explained 49% - 52% of the variation in peak CP. Sex, age, height, weight, waist-to-hip ratio, PAI, smoking and insulin levels explained 21% - 49% of variation in ECP., Conclusions: Subject demographics and lifestyle-related factors should be taken into account when exercise blood pressure response, CP and ECP are used to evaluate patients' cardiac function in CPET.

Chlamydia pneumoniae protein CPn0809 is a type three secretion system substrate, the exact function of which in infection pathogenesis has remained unknown. In this study, we identified by yeast two-hybrid screening a potential host cell interaction partner of CPn0809, Golgi anti-apoptotic protein (GAAP), a conserved protein found in eukaryotic cells. GAAP gene is expressed at relatively constant levels and its expression remained stable also after C. pneumoniae infection. The interaction between GAAP and C. pneumoniae was suggested by transfection studies. GAAP knock-down by siRNA in infected A549 cells resulted in an increased number of C. pneumoniae genomes and growth of the bacteria as judged by quantitative PCR and inclusion counts, respectively. Silencing of GAAP did not make the A549 cells more susceptible to apoptosis per se, and infection with C. pneumoniae prevented staurosporin-induced apoptosis also in transfected cultures. Taken together, the proposed interaction between C. pneumoniae and GAAP modulates bacterial growth in A549 cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Limited and partly controversial data are available regarding the relationship of arterial pulse wave velocity and childhood cardiovascular risk factors. We studied how risk factors identified in childhood and adulthood predict pulse wave velocity assessed in adulthood. The study cohort consisted of 1691 white adults aged 30 to 45 years who had risk factor data available since childhood. Pulse wave velocity was assessed noninvasively by whole-body impedance cardiography. The number of conventional childhood and adulthood risk factors (extreme quintiles for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, body mass index, and smoking) was directly associated with pulse wave velocity in adulthood (P=0.005 and P<0.0001, respectively). In multivariable regression analysis, independent predictors of pulse wave velocity were sex (P<0.0001), age (P<0.0001), childhood systolic blood pressure (P=0.002) and glucose (P=0.02), and adulthood systolic blood pressure (P<0.0001), insulin (P=0.0009), and triglycerides (P=0.003). Reduction in the number of risk factors (P<0.0001) and a favorable change in obesity status (P=0.0002) from childhood to adulthood were associated with lower pulse wave velocity in adulthood. Conventional risk factors in childhood and adulthood predict pulse wave velocity in adulthood. Favorable changes in risk factor and obesity status from childhood to adulthood are associated with lower pulse wave velocity in adulthood. These results support efforts for a reduction of conventional risk factors both in childhood and adulthood in the primary prevention of atherosclerosis.

Objective: Inflammatory factors modify the risk of coronary heart disease. Pleiotropic cytokine interleukin-10 (IL-10) has been suggested as modifying risk for atherosclerosis. Promoter region genetic polymorphism of IL-10 gene (IL10) is known to be associated with the variation of IL-10 production. We investigated whether single-base exchange polymorphisms -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) at IL10 gene are associated with risk factors and early markers of atherosclerosis in young subjects., Methods and Results: As a part of the Cardiovascular Risk in Young Finns Study, we determined carotid artery compliance (CAC), stiffness index (SI) and Young's elastic modulus (YEM), intima media thickness (IMT), IL10 genotype and atherosclerosis risk parameters for 2260 subjects aged 24-39 years. In male subjects CAC was lower in carriers of IL-10 high- to intermediate-producer haplotype -1082 G; -819 C; -592 C (GCC+, 1.96+/-0.67) than in noncarriers (GCC-, 2.10+/-0.62, %/10 mmHg, mean+/-SD, p=0.0010). An inverse association was observed in SI (GCC+, 5.76+/-2.12 and GCC-, 5.26+/-1.46, p=0.0034) and YEM (GCC+, 347+/-165 and GCC-, 305+/-110, mm Hg.mm, p=0.0005). Associations remained significant when adjusted to age, BMI, smoking and serum lipids as well as fasting glucose and insulin levels. The genetic effect size for these parameters was not significant in women., Conclusions: IL10 promoter region high- to intermediate-producer haplotype GCC associates with decreased arterial elasticity in men. These results are in disconcordance with the supposed antiatheromatous properties of IL-10., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)