Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20–50 % ...lower risk of developing Parkinson’s and Alzheimer’s disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.
Advancing Survivorship in Older Adults With Cancer DuMontier, Clark; Driver, Jane A
The journals of gerontology. Series A, Biological sciences and medical sciences,
08/2021, Letnik:
76, Številka:
8
Journal Article
OBJECTIVE:To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.
METHODS:This was a retrospective cohort study of US veterans ≥65 years of age with type 2 ...diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.
RESULTS:We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio HR for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval CI 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79–0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87–1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63–0.91), had good renal function (HR 0.86; 95% CI 0.76–0.97), and were white (HR 0.87; 95% CI 0.77–0.99).
CONCLUSIONS:After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.
The terms undertreatment and overtreatment are often used to describe inappropriate management of older adults with cancer. We conducted a comprehensive scoping review of the literature to clarify ...the meanings behind the use of the terms.
We searched PubMed (National Center for Biotechnology Information), Embase (Elsevier), and CINAHL (EBSCO) for titles and abstracts that included the terms undertreatment or overtreatment with regard to older adults with cancer. We included all types of articles, cancer types, and treatments. Definitions of undertreatment and overtreatment were extracted, and categories underlying these definitions were derived through qualitative analysis. Within a random subset of articles, C.D. and K.P.L. independently performed this analysis to determine final categories and then independently assigned these categories to assess inter-rater reliability.
Articles using the terms undertreatment (n = 236), overtreatment (n = 71), or both (n = 51) met criteria for inclusion in our review (n = 256). Only 14 articles (5.5%) explicitly provided formal definitions; for the remaining, we inferred the implicit definitions from the terms' surrounding context. There was substantial agreement (κ = 0.81) between C.D. and K.P.L. in independently assigning categories of definitions within a random subset of 50 articles. Undertreatment most commonly implied less than recommended therapy (148; 62.7%) or less than recommended therapy associated with worse outcomes (88; 37.3%). Overtreatment most commonly implied intensive treatment of an older adult in whom the harms of treatment outweigh the benefits (38; 53.5%) or intensive treatment of a cancer not expected to affect an older adult in his/her remaining lifetime (33; 46.5%).
Undertreatment and overtreatment of older adults with cancer are imprecisely defined concepts. We propose new, more rigorous definitions that account for both oncologic factors and geriatric domains.
Abstract Objectives To determine if readily obtainable markers of frailty predict disease-free survival (DFS) in elderly women with endometrial cancer treated with curative intent. Methods 88 ...consecutive women ≥ age 60 treated with surgery, chemotherapy and radiation for stage I–IV endometrial cancer were included. We considered the following health deficits as markers of “frailty”: albumin < 3.5 mg/dL, hemoglobin < 10 mg/dL, BMI < 20 kg/m,2 unintentional weight loss, ECOG performance status ≥ 2, history of osteopenia or osteoporosis and Charlson comorbidity score. Kaplan–Meier estimates and Cox proportional hazards models of DFS were calculated. Results The median age was 68.5 (range 60–88 years). The majority of women (65/88) had at least one frailty factor at baseline and 23/88 had two or more. All women received radiation and chemotherapy. Treatment was delayed, modified or truncated in 46% (40/88) of women due to treatment-related toxicity. Age (< 70 vs. ≥ 70 y) did not independently predict toxicity or recurrence risk. Women with at least one baseline frailty factor had twice the risk of disease recurrence (HR = 2.21;95% CI:1.02–4.80) when adjusted for age, stage, grade and Charlson score. The 3-year DFS was 77% in those with no frailty markers and 48% in those with at least one ( p = 0.02). The presence of a frailty marker also predicted shortened overall survival (HR = 2.34;95% CI:1.08–5.03) irrespective of treatment administered and stage of disease. Conclusions A combined frailty measure was a more robust predictor of DFS and OS than patient age, tumor characteristics and comorbidities in this cohort of older women with very good functional status.
A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer’s disease (AD), especially glucose-related dysfunction; one hypothesis for ...this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (
P
= 6.78 × 10
− 22
), LDL (
P
= 1.74 × 10
− 253
) and HDL (
P
= 7.94 × 10
− 18
). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (
P
meta
< 1.6 × 10
− 8
, single trait
P
< 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.
Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the ...defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Pin1 is an intracellular signaling molecule which plays a critical but opposite role in the pathogenesis of Alzheimer's disease (AD) and many human cancers.
We review the structure and function of ...the Pin1 enzyme, the diverse roles it plays in cycling cells and neurons, the epidemiologic evidence for the inverse association between cancer and AD, and the potential therapeutic implications of Pin1-based therapies.
Pin1 is a unique enzyme that has effects on the function of target proteins by “twisting” them into different shapes. Cycling cells use Pin1 to help coordinate cell division. It is over-expressed and/or activated by multiple mechanisms in many common human cancers, and acts on multiple signal pathways to promote tumorigenesis. Inhibition of Pin1 in animal models has profound anti-tumor effects. In contrast, Pin1 is down-regulated or inactivated by multiple mechanisms in AD brains. The absence of Pin1 impairs tau function and amyloid precursor protein processing, leading to tangle- and amyloid-related pathologies and neurodegeneration in an age-dependent manner, resembling human AD. We have developed cis and trans conformation-specific antibodies to provide the first direct evidence that tau exists in distinct cis and trans conformations and that Pin1 accelerates its cis to trans conversion, thereby protecting against tangle formation in AD.
Available studies on Pin1 suggest that cancer and AD may share biological pathways that are deregulated in different directions. Pin1 biology opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
•Pin1 regulates the function of a subset of phosphoproteins by catalyzing cis–trans isomerization.•Pin1 is activated and thereby promotes tumorigenesis by turning on multiple cancer pathways.•Pin1 inhibition leads to the buildup of the abnormal cis-conformation of tau and APP, thereby promoting Alzheimer's disease.•Pin1 opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration.
IMPORTANCE: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are childhood-onset disorders that may persist into adulthood. Several studies have suggested that they ...may be associated with an increased risk of mortality; however, the results are inconsistent. OBJECTIVE: To assess the risk of mortality among persons with ASD or ADHD and their first-degree relatives. DATA SOURCES: A search of MEDLINE, Embase, Scopus, Web of Science, and PsycINFO (published from inception to April 1, 2021) was supplemented by searching reference lists of the retrieved articles. STUDY SELECTION: Cohort and case-control studies that reported mortality rate ratios (RRs) in persons with ASD or ADHD and/or their first-degree relatives compared with the general population or those without ASD/ADHD were included. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction, and quality assessment were performed by at least 2 researchers independently. A random-effects model was used to meta-analyze individual studies and assessed heterogeneity (I2). MAIN OUTCOMES AND MEASURES: All-cause mortality in association with ASD or ADHD. Secondary outcome was cause-specific mortality. RESULTS: Twenty-seven studies were included, with a total of 642 260 individuals. All-cause mortality was found to be higher for persons with ASD (154 238 participants; 12 studies; RR, 2.37; 95% CI, 1.97-2.85; I2, 89%; moderate confidence) and persons with ADHD (396 488 participants; 8 studies; RR, 2.13; 95% CI, 1.13-4.02; I2, 98%; low confidence) than for the general population. Among persons with ASD, deaths from natural causes (4 studies; RR, 3.80; 95% CI, 2.06-7.01; I2, 96%; low confidence) and deaths from unnatural causes were increased (6 studies; RR, 2.50; 95% CI, 1.49-4.18; I2, 95%; low confidence). Among persons with ADHD, deaths from natural causes were not significantly increased (4 studies; RR, 1.62; 95% CI, 0.89-2.96; I2, 88%; low confidence), but deaths from unnatural causes were higher than expected (10 studies; RR, 2.81; 95% CI, 1.73-4.55; I2, 92%; low confidence). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that ASD and ADHD are associated with a significantly increased risk of mortality. Understanding the mechanisms of these associations may lead to targeted strategies to prevent avoidable deaths in high-risk groups. The substantial heterogeneity between studies should be explored further.
CONTEXT The lifetime risk of heart failure at age 40 years is approximately 1 in 5 in the general population; however, little is known about the association between modifiable lifestyle factors and ...the remaining lifetime risk of heart failure. OBJECTIVE To examine the association between modifiable lifestyle factors and the lifetime risk of heart failure in a large cohort of men. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study using data from 20 900 men (mean age at baseline, 53.6 years) from the Physicians' Health Study I (1982-2008) who were apparently healthy at baseline. Six modifiable lifestyle factors were assessed: body weight, smoking, exercise, alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables. MAIN OUTCOME MEASURE Lifetime risk of heart failure. RESULTS During a mean follow-up of 22.4 years, 1200 men developed heart failure. Overall, the lifetime risk of heart failure was 13.8% (95% confidence interval CI, 12.9%-14.7%) at age 40 years. Lifetime risk remained constant in men who survived free of heart failure through age 70 years and reached 10.6% (95% CI, 9.4%-11.7%) at age 80 years. Lifetime risk of heart failure was higher in men with hypertension than in those without hypertension. Healthy lifestyle habits (normal body weight, not smoking, regular exercise, moderate alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables) were individually and jointly associated with a lower lifetime risk of heart failure, with the highest risk in men adhering to none of the 6 lifestyle factors (21.2%; 95% CI, 16.8%-25.6%) and the lowest risk in men adhering to 4 or more desirable factors (10.1%; 95% CI, 7.9%-12.3%). CONCLUSION In this cohort of apparently healthy men, adherence to healthy lifestyle factors is associated with a lower lifetime risk of heart failure.
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