Non-maturation and post-maturation venous stenosis are the primary causes of failure within arteriovenous fistulae (AVFs). Although the exact mechanisms triggering failure remain unclear, abnormal ...hemodynamic profiles are thought to mediate vascular remodelling and can adversely impact on fistula patency.
The review aims to clarify the role of shear stress on outward remodelling during maturation and evaluate the evidence supporting theories related to the localisation and development of intimal hyperplasia within AVFs.
A systematic review of studies comparing remodelling data with hemodynamic data obtained from computational fluid dynamics of AVFs during and after maturation was conducted.
Outward remodelling occurred to reduce or normalise the level of shear stress over time in fistulae with a large radius of curvature (curved) whereas shear stress was found to augment over time in fistulae with a small radius of curvature (straight) coinciding with minimal to no increases in lumen area. Although this review highlighted that there is a growing body of evidence suggesting low and oscillating shear stress may stimulate the initiation and development of intimal medial thickening within AVFs. Further lines of evidence are needed to support the disturbed flow theory and outward remodelling findings before surgical configurations and treatment strategies are optimised to conform to them. This review highlighted that variation between the time of analysis, classification of IH, resolution of simulations, data processing techniques and omission of various shear stress metrics prevented forming pooling of data amongst studies.
Standardised measurements and data processing techniques are needed to comprehensively evaluate the relationship between shear stress and intimal medial thickening. Advances in image acquisition and flow quantifications coupled with the increasing prevalence of longitudinal studies commencing from fistula creation offer viable techniques and strategies to robustly evaluate the relationship between shear stress and remodelling during maturation and thereafter.
The Harbour of All This Sea and Realm offers an overview of the Lusignan, Genoese and Venetian history of the main port city of Cyprus, a Mediterranean crossroads. The essays contribute to the ...understanding of Famagusta’s social and administrative structure, as well as the influences on its architectural, artisan, and art historical heritage from the thirteenth to sixteenth centuries. We read of crusader bishops from central France, metalworkers from Asia Minor, mercenaries from Genoa, refugees from Acre, and traders from Venice. The themes of the city’s diasporas and cultural hybridity permeate and unify the essays in this collaborative effort.
We report that two oncogenes coamplified on chromosome 3q26, PRKCI and SOX2, cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (LSCC). Protein kinase Cι (PKCι) phosphorylates ...SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog (Hh) acyltransferase (HHAT) that catalyzes the rate-limiting step in Hh ligand production. PKCι-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKCι, SOX2, and HHAT and require PKCι-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKCι and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis.
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•PRKCI and SOX2 are coamplified and coordinately overexpressed in LSCC tumors•PKCι transcriptionally regulates expression of Hedgehog acyltransferase (HHAT)•PKCι directly phosphorylates and recruits SOX2 to the HHAT promoter•PKCι and SOX2 activate autocrine Hh signaling to maintain LSCC stem-like cells
Justilien et al. find a functional link between proteins encoded by PRKCI and SOX2 that are often coamplified in lung squamous cell carcinoma. PKCι phosphorylates SOX2, enabling it to increase HHAT expression that, in turn, activates cell-autonomous Hedgehog signaling to sustain a stem-like phenotype.
Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these ...myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.
The 'EF-hand' Ca2+-binding motif plays an essential role in eukaryotic cellular signalling, and the proteins containing this motif constitute a large and functionally diverse family. The EF-hand is ...defined by its helix-loop-helix secondary structure as well as the ligands presented by the loop to bind the Ca2+ ion. The identity of these ligands is semi-conserved in the most common (the 'canonical') EF-hand; however, several non-canonical EF-hands exist that bind Ca2+ by a different co-ordination mechanism. EF-hands tend to occur in pairs, which form a discrete domain so that most family members have two, four or six EF-hands. This pairing also enables communication, and many EF-hands display positive co-operativity, thereby minimizing the Ca2+ signal required to reach protein saturation. The conformational effects of Ca2+ binding are varied, function-dependent and, in some cases, minimal, but can lead to the creation of a protein target interaction site or structure formation from a molten-globule apo state. EF-hand proteins exhibit various sensitivities to Ca2+, reflecting the intrinsic binding ability of the EF-hand as well as the degree of co-operativity in Ca2+ binding to paired EF-hands. Two additional factors can influence the ability of an EF-hand to bind Ca2+: selectivity over Mg2+ (a cation with very similar chemical properties to Ca2+ and with a cytoplasmic concentration several orders of magnitude higher) and interaction with a protein target. A structural approach is used in this review to examine the diversity of family members, and a biophysical perspective provides insight into the ability of the EF-hand motif to bind Ca2+ with a wide range of affinities.
Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends life span in multiple species. However, ...it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes, and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.
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• DR tends to have no effect but otherwise reduces mitochondrial ROS production.•DR tends to have no effect but otherwise increases endogenous antioxidants.•DR often reduces oxidative damage to macromolecules.•DR tends to increase redox antioxidants like glutathione.•DR during aging is more likely to affect oxidative stress parameters.
Purpose
Be Well Communities™ is MD Anderson’s signature place-based approach for cancer prevention and control, working with communities to promote wellness and address modifiable risk factors for ...cancer. The purpose of this paper is to describe implementation of the planning phase of the Be Well Communities model in Acres Homes which began in 2019.
Methods
A community advisory group (Steering Committee) including residents, non-profit organizations, health care partners, city and county agencies, plus other stakeholders, was convened and aligned through a structured process to develop shared goals, foster multisector collaboration, as measured by a stakeholder survey administered twice, and enhance community capacity to improve health outcomes through development of a Community Action Plan.
Results
Clear, achievable goals were developed, multisector collaboration was enhanced, and more than 400 h of capacity building support led to a Community Action Plan initially focused on healthy eating and active living, including 15 evidence-based interventions led by 18 organizations. The majority (93%) of the Steering Committee reports that this plan reflects community priorities and will reach the residents most in need.
Conclusion
By listening and developing trust, the Be Well Communities team successfully worked with Acres Homes residents and organizations to enhance community capacity to address health inequities in one of Houston’s most diverse and historic communities.
Fanconi anemia (FA) is a DNA repair disorder associated with a high risk of cancer and bone marrow failure. Patients with FA may present with certain dysmorphic features, such as radial ray ...abnormalities, short stature, typical facies, bone marrow failure, or certain solid malignancies. Some patients may be recognized due to exquisite sensitivity after exposure to cancer therapy. FA is diagnosed by increased chromosomal breakage after exposure to clastogenic agents. It follows autosomal recessive and X-linked inheritance depending on the underlying genomic alterations. Recognizing patients with FA is important for therapeutic decisions, genetic counseling, and optimal clinical management.
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