Citations

Abstract Family caregivers are major providers of long-term care and support for family members with age-related decline and disability. Caregiving is a demanding and complex undertaking that has demonstrated extensive physical, emotional, relational, and financial burden on families. These factors underscore the urgency of addressing the needs of family caregivers at the policy level. This presentation focuses on the origins, goals, and mandates of federal policy efforts that support family caregivers. This includes an analysis on how federal support for caregivers has evolved over time, most notably through the National Family Caregiver Support Program, part of the Older Americans Act. It will also discuss the passage of more recent legislation (e.g., RAISE Family caregiver Act and the Grandparents Raising Grandchildren Act) that will contribute to a national strategy to support family caregivers. Moreover, through the discussion of these policies, we will articulate specific areas where gerontology research and public policy can and should intersect in order to optimize the effectiveness of policy efforts to support family caregivers.

Abstract To date, nearly 40 U.S. states have passed the Caregiver Advise Record and Enable (CARE) Act to support family caregivers during transitions from hospital to home. These laws require hospitals to: 1) record designated family caregivers’ name in a patient medical records during a hospital stay; 2) inform the caregiver when the patient will be discharged; 3) provide education and instructions on care tasks needed for post-hospital discharge. Transitions from hospital to home are often fraught with adverse event risk and poor continuity of care, especially for rural patients with progressive life-limiting conditions. The CARE ACT has potential to address healthcare system factors that are sometimes attributable to poor transitions in care. Our presentation focuses on preliminary findings from an intervention that provides teaching, guidance, and counseling to caregivers caring for an individual receiving palliative care in the hospital and transitioning home to a rural setting. Findings suggest that the CARE ACT may be vital, but not fully sufficient, for successful transitions. Additional targets for caregiver interventions to improve transitions for this subset of very ill patients include: 1) attend to caregivers’ medical and non-medical needs which may impact their capacity to provide care; 2) advise clinical teams to communicate truthfully about prognosis and likely outcomes when creating post-hospital plans of care; 3) encourage caregivers to identify and engage services early in the transition; 4) urge caregivers to draw on multiple sources for social support. Findings can help optimize the CARE Act implementation, particularly in states with large rural populations.

Advances in HIV-1 therapy have transformed the once fatal infection into a manageable, chronic condition, yet the search for a widely applicable approach to cure remains elusive. The ineffectiveness of antiretroviral therapy (ART) in reducing the size of the HIV-1 latent reservoir has prompted investigation into the mechanisms of HIV-1 latency and immune escape.

We previously reported that testis‐specific Y‐encoded‐like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN‐AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1246 Poster Board I-268 B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a variable clinical course. Genomic aberrations as detected by FISH analysis and the mutational status of the IgVH genes have been found to have prognostic clinical significance with unmutated IgVH genes associated with clinically more aggressive disease. Previous studies have suggested that unmutated IgVH B-CLL is associated with increased chromosomal instability and increased chromosomal aberrations leading to accelerated disease progression. We recently performed a high-throughput, high-resolution array-based comparative genomic hybridization (aCGH) in a cohort of B-CLL patients. Fifty-eight patients have been analyzed by using the Sureprint G3 microarray (one million probes, Agilent). Our working hypothesis was that we would see increased genomic aberrations and instability in the unmutated IgVH group. The total number of copy number aberrations and total megabases (Mb) deleted or gained per genome were used as a surrogate marker for genomic instability. Variations in chromosomal aberrations in various VH families were also evaluated. B-CLL with unmutated IgVH genes utilized members of the VH1, VH3, VH4 and VH5 families with VH1-69 the most prevalent. B-CLL with mutated IgVH genes utilized VH families VH1, VH2, VH3, VH4, and VH6. Considerable variation was seen in the number of genomic abnormalities between cases. Overall, 315 abnormalities have been identified (236 deletions and 79 gains), with a median of 4 copy-number abnormalities per patient (range 0-32). In patients with IgVH mutational status available the median number of chromosomal aberrations in the mutated group was 5 (range 1-17) and unmutated group was 4 (range 0-20). Copy number deletions were significantly more common than chromosomal gains for the total group and in both the unmutated and mutated IgVH gene groups. Mean number of megabases (Mb) of DNA deleted in the unmutated IgVH group was 17.80Mb (standard deviation 24.17 Mb, median 6.63 Mb, range 0 - 90.55Mb) and 40.65 Mb in the mutated IgVH group (standard deviation 86.04 Mb, median 15.35Mb, range 0 – 307.57Mb). Mean number of Mb gained in the unmutated group was 37.74Mb (standard deviation 57.58Mb, median 0.44Mb, range 0 – 132.47Mb) and 32.99Mb (standard deviation 59.76Mb, median 0.14Mb, range 0 – 172.50Mb) in the mutated group. Nine patients had B-CLL with VH1-69 genes and 8 of them were unmutated. Median number of chromosomal deletions was 2 and gains also 2 (ranges 0 – 8 deletions and 0 – 4 gains) for this group. Similar findings were seen for the other VH families. These results initially suggest that total copy number variations do not account for the observed clinical differences between mutated and unmutated IgVH B-CLL. The catalogue of potentially clinically relevant chromosomal abnormalities found in this aCGH study is being currently evaluated. Disclosures Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Genentech: Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphenon E International: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding; Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees. Fonseca:BMS: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Medtronic: Consultancy; Genzyme: Consultancy.

Family caregiver engagement in clinical encounters can promote relationship-centered care and optimize outcomes for people with Alzheimer’s disease and related dementias (ADRD). Little is known, however, about effective ways for health care providers to engage family caregivers in clinical appointments to provide the highest quality care. We describe what caregivers of people with ADRD and people with mild cognitive impairment (MCI) consider potential best practices for engaging caregivers as partners in clinical appointments. Seven online focus groups were convened. Three groups included spousal caregivers ( n = 42), three included non-spousal caregivers ( n = 36), and one included people with MCI ( n = 15). Seven potential best practices were identified, including the following: “acknowledge caregivers’ role and assess unmet needs and capacity to care” and “communicate directly with person with ADRD yet provide opportunities for caregivers to have separate interactions with providers.” Participants outlined concrete steps for providers and health care systems to improve care delivery quality for people with ADRD.

Abstract Integrins play fundamental roles in many biological processes such as development, immunity, cancer, wound healing, hemostasis, and thrombosis. Integrin activation is essential for cell adhesion, spreading, survival, proliferation, and migration. Integrins are heterodimeric transmembrane glycoproteins composed of a and b subunits. The function of integrins is modulated by bi-directional transmembrane signaling: inside-out and outside-in signaling, which are mediated through the interactions between integrin a or b subunit cytoplasmic tails and intracellular proteins and can be regulated by many different biochemical signaling pathways. αIIbβ3 is a major integrin expressed in megakaryocytes and platelets. Antagonists of αIIbβ3 are potent anti-thrombotic drugs and new inhibitors targeting αIIbβ3 are under preclinical testing or large patient trials to treat acute coronary syndromes. Integrin αIIbβ3 activation involves binding of proteins, including talin, kindlins, Src kinase, and Gα13 to the cytoplasmic domain of its β subunit. To gain insight into αIIbβ3signaling and to identify new proteins that regulate αIIbβ3 activation, agarose beads conjugated with glutathione S-transferase (GST)-β3 integrin cytoplasmic domain fusion protein (GST-β3CD) or GST-αIIb integrin cytoplasmic domain fusion protein (GST-αIIbCD) were incubated with human platelet lysates. Proteins pulled down by the GST-β3CD or GST-αIIbCD beads were subjected to mass spectrometric analysis. We found that the GST-β3CD but not the GST-αIIbCD beads specifically pulled down a previously unreported protein, the vacuolar protein sorting-associated protein 33B (VPS33B), encoded by the VPS33B gene. To verify that VPS33B is in a complex with αIIbβ3, we infected Chinese hamster ovary (CHO) cells stably expressing αIIbβ3 (A5 cells) with an adenovirus containing FLAG epitope-tagged human VPS33B cDNA. Cells were allowed to adhere and spread on fibrinogen. FLAG-VPS33B exhibited a significant intracellular colocalization with aIIbb3. Immunoblotting analysis revealed a specific association of b3 with precipitated FLAG-VPS33B. The specific interaction was also confirmed by reciprocal immunoprecipitation using a specific β3antibody. Furthermore, in an in vitro binding assay, we were able to pull down VPS33B from the lysates of CHO cells overexpressing VPS33B by the GST-β3CD beads. The interaction appears to be direct, since we were also able to pull down purified FLAG-VPS33B with GST-β3CD and GST-β1CD proteins. The pulldown assay showed that the β3 fragment spanning residues 716~730 bound efficiently to FLAG-VPS33B. In contrast, the fragments containing either residues 729~762 or residues 744~762 fragments failed to do the same. More importantly, using the rabbit polyclonal antibody against VPS33B, we were able to coimmunoprecipitate endogenous b3 subunit with VPS33B from human platelet lysate. Thus, we identified a novel binding protein of integrin β3. Next, we investigated the role of VPS33B in integrin activation using a recombinant integrin activation model of CHO cells. Overexpression of VPS33B in CHO cells expressing αIIbβ3 (A5 cells) markedly potentiated cell spreading on fibrinogen and F-actin formation. To establish a role of VPS33B in integrin activation in platelets, we created a mouse model with megakaryocyte- and platelet-specific deletion of VPS33B. Platelets lacking VPS33B were defective in spreading on fibrinogen. VPS33B-/- platelets failed to support clot retraction. On the other hand, thrombin-induced fibrinogen binding to platelets and platelet aggregation were not affected by the loss of VPS33B. Collectively, these results demonstrate an essential role of VPS33B in αIIbβ3 outside-in signaling but is not requried for integrin inside-out signaling. We further demonstrate that VPS33B promotes αIIbβ3 outside-in signaling through RhoA and Rac1 activation, leading to clot retraction and cell spreading, respectively. Therefore, our results for the first time establish vesicle trafficking proteins as an important novel class of modifiers of integrin function in platelets and cells. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: AL amyloidosis is a very heterogeneous disease. Prognosis is a function of organ tropism, extent of organ damage, and ability of tissues to heal, the last of which relates both to hematologic response and intrinsic toxicity of the light chain. Using mass spectroscopy (MS) technology, we are able to distinguish immunoglobulin light chain variable gene family (IGVL) usage on clinical samples. The goal of this study was to evaluate if IGVL usage impacts patient outcomes in patients with light chain amyloidosis (AL). Methods: IGVL usage was determined by mass spectroscopy (MS) of amyloid in clinical tissue specimens of Mayo Clinic patients. Specimens were from fat pad (n=257), bone marrow (n=172), myocardium (n=113), gastrointestinal (n=58), kidney (n=20), lung (n=15), and nerve (n=5). For those cases for which the IGVL could not be identified--not otherwise specified (NOS)—but constant region could be identified as lambda or kappa, we assume that the amyloid consisted primarily of immunoglobulin light chain gene constant regions or variable genes with somatic mutations making them uninterpretable to our matching algorithms. The medical records from these 700 patients were abstracted for relevant clinical and laboratory data. Results: The baseline characteristics of patients are shown in table 1. Three hundred and thirty-two patients have died with a median follow-up of surviving patients of 38 months. The estimated median survival for the entire population is 59 months. Out of 700 patients, 214 (31%) achieved a CR or a VGPR, 432 (62%) were not evaluable (NE) for hematologic or organ response, and 54 (8%) achieved a PR or did not respond (NR). The distribution of IGVL cases is shown in table 2. Overall survival (OS) for the whole group was not different across different IGVLs on univariate analysis, but when corrected for hematologic response, outcomes differed significantly based on IGVL. Patients could be further assembled into two groups, based on risk for death on univariate analyses: an IGVL high risk, which included KV1, LV1, LV2, LV3, and LV6; and low risk, which included all other cases (Figure). In a multivariate model that included level of hematologic response (CR/VGPR versus PR/NR/NE) and IGVL, IGVL family was independently associated with overall survival (RR=1.5 (95% CI 1.2-1.9, p=0.008). The risk ratio for CR/VGPR was 0.28 (95% CI 0.20-0.38, p<0.0001). This effect persisted when either the Mayo 2006 or the 2012 staging system was included in the multivariate. Conclusion: IGVL usage appears to have prognostic significance in patients who have not achieved VGPR or better to initial chemotherapy. Table 1. Baseline characteristics of patients N= 700 Age 63 (32-94) Male, (%) 447 (64%) Biopsy site Solid organ/Soft tissue 271 (39%) Fat pad 257 (37%) Bone Marrow 172 (25%) Organ involvement Cardiac 432 (62%) Renal 346 (49%) Gastrointestinal 168 (24%) Liver 56 (8%) Nerve 107 (15%) Lung 42 (6%) Soft Tissue 92 (13%) Organs involved 1 321 (46%) 2 228 (33%) ≥3 151 (22%) Laboratory characteristics NTBNP, pg/ml 2547 (11.3-70000) Troponin, ng/ml 0.03 (0.001-0.84) dFLC, mg/dl 26 (0.04-2330) Cardiac Stage 1 59 (18%) 2 125 (38%) 3 144 (44%) Table 2. Variable region family distribution. Light Chain N=700 N (%) KV1 107 (15%) KV2 3 (0.4%) KV3 17 (2%) KV4 25 (4%) KV6 1 (0.1%) LV1 85 (12%) LV2 64 (9%) LV3 118 (17%) LV4 3 (0.4%) LV6 97 (14%) LV8 1 (0.1%) LV9 1 (0.1%) Kappa NOS1 34 (4%) Lambda NOS1 140 (19%) Heavy chain amyloidosis 4 (0.6%) 1 No IGVL family could be identified Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.