Multiple Sclerosis (MS) is characterized by focal CNS inflammation leading to the death of oligodendrocytes (OLs) with subsequent demyelination, neuronal degeneration, and severe functional deficits. Inhibitory chondroitin sulfate proteoglycans (CSPGs) are increased in the extracellular matrix in the vicinity of MS lesions and are thought to play a critical role in myelin regeneration failure. We here show that CSPGs curtail remyelination through binding with their cognate receptor, protein tyrosine phosphatase σ (PTPσ) on oligodendrocyte progenitor cells (OPCs). We report that inhibition of CSPG/PTPσ signaling by systemically deliverable Intracellular Sigma Peptide (ISP), promotes OPC migration, maturation, remyelination, and functional recovery in animal models of MS. Furthermore, we report a downstream molecular target of PTPσ modulation in OPCs involving upregulation of the protease MMP-2 that allows OPCs to enzymatically digest their way through CSPGs. In total, we demonstrate a critical role of PTPσ/CSPG interactions in OPC remyelination in MS.
Background: Maintaining functional status is important to older adults with cancer, but data are limited on how systemic treatments affect functional status. We systematically reviewed changes in functional status during systemic cancer treatments and identified characteristics associated with functional decline and improvement. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Register of Controlled Trials for articles examining characteristics associated with functional changes in older adults during systemic cancer treatment published in English between database inception and January 11, 2019 (PROSPERO CRD42019123125). Findings were summarized with descriptive statistics. Study characteristics between older adult–specific and non–older adult–specific studies were compared using the Fisher exact test. Results: We screened 15,244 titles/abstracts and 519 full texts. The final analysis included 44 studies, which enrolled >8,400 patients; 39% of studies focused on older adults (1 study enrolled adults aged ≥60 years, 10 enrolled adults aged ≥65 years, and 6 enrolled adults aged ≥70 years). Almost all studies (98%) used patient-reported outcomes to measure functional status; only 20% used physical performance tests. Reporting of functional change was heterogeneous, with 48% reporting change scores. Older adult–specific studies were more likely to analyze functional change dichotomously (29% vs 4%; P=.008). Functional decline ranged widely, from 6% to 90%. The most common patient characteristics associated with functional decline were older age (n=7 studies), worse performance status (n=4), progressive disease status (n=4), pain (n=4), anemia (n=4), and worse nutritional status (n=4). Twelve studies examined functional improvement and identified 11 unique associated characteristics. Conclusions: Functional decline is increasingly recognized as an important outcome in older adults with cancer, but definitions and analyses are heterogeneous, leading to a wide range of prevalence. To identify patients at highest risk of functional decline during systemic cancer treatments, trials need to routinely analyze functional outcomes and measure characteristics associated with decline (eg, nutrition).
Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) experience intense inpatient healthcare at the end-of-life (EOL) . Early advance care planning (ACP) may improve care at EOL for patients with AML and MDS. The Serious Illness Care Program (SICP) is a multicomponent, communication intervention developed to improve conversations about values for patients with serious illnesses. The SICP has been shown to improve the quality and frequency of ACP discussions. We adapted the SICP for delivery via telehealth to older patients with AML and MDS. We conducted a single-center qualitative study of 45 participants (25 clinicians, 15 older patients with AML and MDS, and 5 caregivers). Participants, whether clinicians, patients, or caregivers, agreed that the SICP would help older patients with AML and MDS to share their personal values with their care team. Four qualitative themes emerged from our data: 1) Serious illness conversations can be conducted via telehealth, 2) Older patients have limited experience using technology but are willing and able to learn, 3) Patients feel that serious illness conversations will help them understand their AML or MDS diagnosis and prognosis better, and 4) Serious illness conversations should be common and routine, not extra-ordinary. The adapted SICP may provide older patients with AML and MDS an opportunity to share what matters most to them with their care team and may assist oncologists in aligning patient care with patient values. The adapted SICP is the subject of an ongoing single-arm pilot study at the Wilmot Cancer Institute.
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