DNA double-strand breaks (DSBs) are common lesions that continually threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including cell death. Misrepair is also fraught ...with danger, especially inappropriate end-joining events, which commonly underlie oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous recombination (HR) and the classical nonhomologous end-joining pathway (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors.
Considerable research and public discourse on family caregiving portrays it as a stressful and burdensome experience with serious negative health consequences. A landmark study by Schulz and Beach ...that reported higher mortality rates for strained spouse caregivers has been widely cited as evidence for the physical health risks of caregiving and is often a centerpiece of advocacy for improved caregiver services. However, 5 subsequent population-based studies have found reduced mortality and extended longevity for caregivers as a whole compared with noncaregiving controls. Most caregivers also report benefits from caregiving, and many report little or no caregiving-related strain. Policy reports, media portrayals, and many research reports commonly present an overly dire picture of the health risks associated with caregiving and largely ignore alternative positive findings. As the pool of traditional family caregivers declines in the coming years, a more balanced and updated portrayal of the health effects of caregiving is needed to encourage more persons to take on caregiving roles, and to better target evidence-based services to the subgroup of caregivers who are highly strained or otherwise at risk. Recommendations are discussed for research that will better integrate and clarify both the negative and potential positive health effects of informal caregiving.
Abstract
Objectives
Social isolation among older adults is an important but under-recognized risk for poor health outcomes. Methods are needed to identify subgroups of older adults at risk for social ...isolation.
Methods
We constructed a typology of social isolation using data from the National Health and Aging Trends Study (NHATS) and estimated the prevalence and correlates of social isolation among community-dwelling older adults. The typology was formed from four domains: living arrangement, core discussion network size, religious attendance, and social participation.
Results
In 2011, 24% of self-responding, community-dwelling older adults (65+ years), approximately 7.7 million people, were characterized as socially isolated, including 1.3 million (4%) who were characterized as severely socially isolated. Multinomial multivariable logistic regression indicated that being unmarried, male, having low education, and low income were all independently associated with social isolation. Black and Hispanic older adults had lower odds of social isolation compared with white older adults, after adjusting for covariates.
Discussion
Social isolation is an important and potentially modifiable risk that affects a significant proportion of the older adult population.
Background
Many older adults living with dementia have not been formally diagnosed. Even when clinicians document the diagnosis, patients and families may be unaware of the diagnosis. Knowledge of ...how individual characteristics affect detection and awareness of dementia is limited.
Objective
To identify characteristics associated with dementia diagnosis and awareness of diagnosis.
Design
Cross-sectional observational study.
Participants
Five hundred eighty-five adults aged ≥ 65 in the National Health and Aging Trends Study who met assessment-based study criteria for probable dementia in 2011 and had 3 years of continuous, fee-for-service Medicare claims prior to 2011.
Main Measures
Using multivariable logistic regression, we compared participants with undiagnosed versus diagnosed dementia (based on Medicare claims) on demographic, social/behavioral, functional, medical, and healthcare utilization characteristics. Among those diagnosed, we compared characteristics of participants unaware versus aware of the diagnosis (based on self or proxy report).
Key Results
Among older adults with probable dementia, 58.7% were either undiagnosed (39.5%) or unaware of the diagnosis (19.2%). In adjusted analyses, individuals who were Hispanic (OR 2.48, 95% CI 1.19, 5.14), had less than high school education (OR 0.54 for at least high school education, 95% CI 0.32, 0.91), attended medical visits alone (OR 1.98, 95% CI 1.11, 3.51), or had fewer functional impairments (OR 0.79 for each impairment, 95% CI 0.69, 0.90) were more likely to be undiagnosed. Similarly, among those diagnosed, having less education (OR 0.42), attending medical visits alone (OR 1.97), and fewer functional impairments (OR 0.72) were associated with unawareness of diagnosis (all
p
s < 0.05).
Conclusions
The majority of older adults with dementia are either undiagnosed or unaware of the diagnosis, suggesting shortcomings in detection and communication of dementia. Individuals who may benefit from targeted screening include racial/ethnic minorities and persons who have lower educational attainment, any functional impairment, or attend medical visits alone.
In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or ...cyclophosphamide-azathioprine), are unknown.
In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate eGFR that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m
of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m
, and no use of rescue therapy). The time to a renal-related event or death was assessed.
A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval CI, 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.
In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).
V(D)J recombination, the mechanism responsible for generating antigen receptor diversity, has the potential to generate aberrant DNA rearrangements in developing lymphocytes. Indeed, the recombinase ...has been implicated in several different kinds of errors leading to oncogenic transformation. Here we review the basic aspects of V(D)J recombination, mechanisms underlying aberrant DNA rearrangements, and the types of aberrant events uncovered in recent genomewide analyses of lymphoid neoplasms.
Angiosarcoma (AS) is a rare neoplasm with limited treatment options and a poor survival rate. Development of effective therapies is hindered by the rarity of this disease. Dogs spontaneously develop ...hemangiosarcoma (HSA), a common, histologically similar neoplasm. Metastatic disease occurs rapidly and despite chemotherapy, most dogs die several months after diagnosis. These features suggest that HSA might provide a tractable model to test experimental therapies in clinical trials. We previously reported whole exome sequencing of 20 HSA cases. Here we report development of a NGS targeted resequencing panel to detect driver mutations in HSA and other canine tumors. We validated the panel by resequencing the original 20 cases and sequenced 30 additional cases. Overall, we identified potential driver mutations in over 90% of the cases, including well-documented (in human cancers) oncogenic mutations in PIK3CA (46%), PTEN (6%), PLCG1(4%), and TP53 (66%), as well as previously undetected recurrent activating mutations in NRAS (24%). The driver role of these mutations is further demonstrated by augmented downstream signaling crucial to tumor growth. The recurrent, mutually exclusive mutation patterns suggest distinct molecular subtypes of HSA. Driver mutations in some subtypes closely resemble those seen in some AS cases, including NRAS, PLCG1, PIK3CA and TP53. Furthermore, activation of the MAPK and PI3K pathways appear to be key oncogenic mechanisms in both species. Together, these observations suggest that dogs with spontaneous HSA could serve as a useful model for testing the efficacy of targeted therapies, some of which could potentially be of therapeutic value in AS.
Caveolae, flask‐like invaginations of the plasma membrane, were discovered nearly 60 years ago. Originally regarded as fixation artifacts of electron microscopy, the functional role for these ...structures has taken decades to unravel. The discovery of the caveolin protein in 1992 (by the late Richard G.W. Anderson) accelerated progress in defining the contribution of caveolae to cellular physiology and pathophysiology. The three isoforms of caveolin (caveolin‐1, ‐2, and ‐3) are caveolae‐resident structural and scaffolding proteins that are critical for the formation of caveolae and their localization of signaling entities. A PubMed search for “caveolae” reveals ~280 publications from their discovery in the 1950s to the early 1990s, whereas a search for “caveolae or caveolin” after 1990, identifies ~7000 entries. Most work on the regulation of biological responses by caveolae and caveolin since 1990 has focused on caveolae as plasma membrane microdomains and the function of caveolin proteins at the plasma membrane. By contrast, our recent work and that of others has explored the localization of caveolins in multiple cellular membrane compartments and in the regulation of intracellular signaling. Cellular organelles that contain caveolin include mitochondria, nuclei and the endoplasmic reticulum. Such intracellular localization allows for a complexity of responses to extracellular stimuli by caveolin and the possibility of novel organelle‐targeted therapeutics. This review focuses on the impact of intracellular localization of caveolin on signal transduction and cell regulation.—Fridolfsson, H. N., Roth, D. M., Insel, P. A., Patel, H. H. Regulation of intracellular signaling and function by caveolin. FASEB J. 28, 3823‐3831 (2014). www.fasebj.org
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