Proving the Geriatrician's worth Reuben, David B.
Journal of the American Geriatrics Society (JAGS),
January 2024, 2024-01-00, 20240101, Letnik:
72, Številka:
1
Journal Article
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This Editorial comments on the article by Vandergrift et al in this issue.
The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, ...making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
► Phenformin is a mitochondrial inhibitor that selectively kills LKB1−/− NSCLC cells ► LKB1−/− NSCLC cells exhibit defective mitochondria and ROS following phenformin ► Phenformin improves tumors and survival in KrasG12DLkb1−/−, not KrasG12Dp53−/− mice ► eIF2α signaling markers are AMPK-independent biomarkers of biguanide treatment
Background
Despite possible major adverse cognitive, physical, social, and behavioral consequences, little is known about how persons living with dementia perceive satisfaction with life, a key ...component of well‐being. We sought to examine (i) whether persons living with dementia perceive a lower level of satisfaction compared to their peers without dementia and (ii) whether the associations between individual characteristics and life satisfaction are different between persons living with and without dementia.
Methods
Using a nationally representative sample of community‐dwelling older adults aged ≥70 years in the U.S. from the Health and Retirement Study, we compared scores on the Satisfaction with Life Scale (SWLS), a self‐reported 5‐item scale ranging from 1 to 7 (more satisfaction), between persons with probable dementia (n = 341) and those without (n = 5530), adjusting for individual characteristics. We also tested whether the associations between the individual characteristics and SWLS differ by dementia status.
Results
Scores on SWLS did not differ between persons with probable dementia and those without when adjusting for individual characteristics including limitations in activities of daily living (ADL) (adjusted difference, −0.09; 95% CI, −0.33 to +0.15; p‐value, 0.45). However, dementia status was associated with lower life satisfaction through the mediation of limitations in ADL (total effect, −0.29; bootstrapped 95% CI, −0.47 to −0.12). Most individual characteristics associated with lower life satisfaction were similar in the two groups, including younger age, more limitations in ADL, and depression. Less wealth was associated with lower satisfaction among persons without dementia but not among those with probable dementia.
Conclusions
Dementia status was only modestly associated with lower life satisfaction through the mediation of limitations in ADL among participants who were able to provide response. Future research is warranted to determine whether life satisfaction can be used as a meaningful outcome when evaluating well‐being among persons living with dementia.
In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a ...serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
This National Institutes of Health (NIH) Pathways to Prevention Workshop was cosponsored by the NIH Office of Disease Prevention (ODP), the NIH Pain Consortium, the National Institute on Drug Abuse, ...and the National Institute of Neurological Disorders and Stroke. A multidisciplinary working group developed the workshop agenda, and an evidence-based practice center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the workshop discussion. During the 1.5-day workshop, invited experts discussed the body of evidence, and attendees had opportunities to provide comments during open discussion periods. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the ODP Web site for 2 weeks for public comment. This article is an abridged version of the panel's full report, which is available at https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/opioids-chronic-pain/workshop-resources#final report.
By 2030 more people in the United States will be older than age sixty-five than younger than age five. Our health care system is unprepared for the complexity of caring for a heterogenous population ...of older adults-a problem that has been magnified by the coronavirus disease 2019 (COVID-19) pandemic. Here, as part of the National Academy of Medicine's Vital Directions for Health and Health Care: Priorities for 2021 initiative, we identify six vital directions to improve the care and quality of life for all older Americans. The next administration must create an adequately prepared workforce; strengthen the role of public health; remediate disparities and inequities; develop, evaluate, and implement new approaches to care delivery; allocate resources to achieve patient-centered care and outcomes, including palliative and end-of-life care; and redesign the structure and financing of long-term services and supports. If these priorities are addressed proactively, an infrastructure can be created that promotes better health and equitable, goal-directed care that recognizes the preferences and needs of older adults.
The case of an 83-year-old man who has had a fall-related injury and continues to be the sole caregiver for his wife who has dementia exemplifies a common situation that clinicians face--planning for ...the final years of an elderly individual's life. To appropriately focus on the patient's most pressing issues, the approach should begin with an assessment of life expectancy and incorporation of evidence-based care whenever possible. Short-term issues are focused on efforts to restore the patient to his previous state of health. Mid-range issues address providing preventive care, identifying geriatric syndromes, and helping him cope with the psychosocial needs of being a caregiver. Long-term issues relate to planning for his eventual decline and meeting his goals for the end of life. Unfortunately, the workload and inefficiencies of primary care practice present barriers to providing optimal care for older patients. Systematic approaches, including team care, are needed to adequately manage chronic diseases and coordinate care.
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