The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, ...and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.
Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, ...and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors. The purpose of this review is to summarize current knowledge about the role of these cell cycle regulators in the development of native and graft atherosclerosis that has arisen from animal studies, histological examination of specimens from human patients, and genetic studies.
Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are ...apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiometabolic conditions. Clonal hematopoiesis typically arises from somatic mutations that confer a competitive advantage to a mutant hematopoietic stem cell, leading to its clonal expansion in the stem cell population and its progeny of blood leukocytes. Human sequencing studies and experiments in mice suggest that clonal hematopoiesis, at least when driven by certain mutations, contributes to accelerated atherosclerosis development. However, the epidemiology, biology and clinical implications of this phenomenon remain incompletely understood. Here, we review the current understanding of the connection between clonal hematopoiesis and atherosclerosis, and highlight knowledge gaps in this area of research.
The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs.
This was a ...multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated.
A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months 95% confidence interval (CI) 4.8-14.1. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively.
Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201).
NCT01280201.
The purpose of this investigation was to design and validate a multidimensional scale with the potential to measure perceived discrimination in different stigmatized groups. The study was carried out ...in Spain with a sample of 1,016 participants belonging to five stigmatized groups: Latin American immigrants, Romanian immigrants, people with HIV, gays and lesbians. Confirmatory factor analysis validated the existence of four dimensions in the scale: blatant group discrimination, subtle group discrimination, blatant individual discrimination, and subtle individual discrimination. In accordance with the literature, the scale presents positive relations with the stigma consciousness scale (Pinel in J Pers Soc Psychol 76:114–128, 1999) and negative relations with two measures of psychological well-being, affect balance and self-acceptance. Likewise, the results indicate that the perception of subtle individual discrimination is more negatively associated with participants' psychological well-being.
Hippocampal plasticity (e.g. neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to ...drug‐seeking behavior, bred Low‐Responders (bLR) and bred High‐Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time‐points of the cocaine sensitization process; Ki‐67 for newly born cells, NeuroD for cells born partway, and 5‐bromo‐2′‐deoxyuridine for older cells born prior to sensitization. Results show that: (i) bHRs exhibited greater psychomotor response to cocaine than bLRs; (ii) acute cocaine did not alter cell proliferation in bLR/bHR rats; (iii) chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence; (iv) neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype; (v) cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine; and (vi) cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR vs. bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs, which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine‐induced psychomotor behavioral sensitization.
A new method to measure the top-quark mass in high energetic hadron collisions is presented. We use theoretical predictions calculated at next-to-leading order accuracy in quantum chromodynamics to ...study the (normalized) differential distribution of the
cross section with respect to its invariant mass
. The sensitivity of the method to the top-quark mass together with the impact of various theoretical and experimental uncertainties has been investigated and quantified. The new method allows for a complementary measurement of the top-quark mass parameter and has a high potential to become competitive in precision with respect to established approaches. Furthermore we emphasize that in the proposed method the mass parameter is uniquely defined through one-loop renormalization.
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