Defining Clinical Meaningfulness in Huntington's Disease.

BACKGROUND: Minimal clinically important difference (MCID) represents the smallest within-person change on an outcome measure considered meaningful to the patient. Anchor-based MCID methods evaluate the relationship between changes in an outcome measure and the patient-reported clinical importance of that change. OBJECTIVE: This study aims to estimate longitudinal MCID for clinically relevant outcome measures for individuals who have Stages 2 or 3 disease as measured by the Huntington's Disease Integrated Staging System (HD-ISS). METHODS: Data were drawn from Enroll-HD, a large global longitudinal, observational study and clinical research platform for HD family members. We analyzed HD participants (N = 11,070) by staging group using time frames ranging from 12 to 36 months. The anchor was the physical component summary score of the 12-item short-form health survey. HD-relevant motor, cognitive, and functional outcome measures were independent, external criterion outcomes. Complex analysis was conducted using multiple, independent, linear mixed effect regression models with decomposition to calculate MCID for each external criterion by group. RESULTS: MCID estimates varied by progression stage. MCID estimates increased as stage progression increased and as the time frame increased. MCID values for key HD measures are provided. For example, starting in HD-ISS stage 2, meaningful group change over 24 months equals an average increase of 3.6 or more points on the Unified Huntington's Disease Rating Scale Total Motor Score. CONCLUSIONS: This is the first study to examine MCID estimation thresholds for HD. The results can be used to improve clinical interpretation of study outcomes and enable treatment recommendations to support clinical decision-making and clinical trial methodology. © 2023 International Parkinson and Movement Disorder Society.

Economic burden of Huntington disease in Europe and the USA: Results from the Huntington's Disease Burden of Illness study.

BACKGROUND AND PURPOSE: The prevalence of Huntington disease (HD) has increased over time; however, there is a lack of up-to-date evidence documenting the economic burden of HD by disease stage. This study provides an estimate of the annual direct medical, nonmedical, and indirect costs associated with HD from participants in the Huntington's Disease Burden of Illness (HDBOI) study in five European countries and the USA. METHODS: The HDBOI is a retrospective, cross-sectional study. Data collection was conducted between September 2020 and May 2021. Participants were recruited by their HD-treating physicians and categorized as early stage (ES), mid stage (MS), or advanced stage (AS) HD. Data were collected via three questionnaires: a case report form, completed by physicians who collected health care resource use associated with HD to compute direct medical cost, and optional patient and caregiver questionnaires, which included information used to compute nondirect medical and indirect costs. Country-specific unit cost sources were used. RESULTS: HDBOI cost estimates were €12,663 (n = 2094) for direct medical costs, €2984 (n = 359) for nondirect medical costs, and €47,576 (n = 436) for indirect costs. Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 (n = 846), €11,885 (n = 701), and €18,985 (n = 547) for ES, MS, and AS, respectively. Similar trends were observed for nondirect and indirect costs. Costs show large variations between patients and countries. CONCLUSIONS: Cost estimates from the HDBOI study show that people with HD and their caregivers bear a large economic burden that increases as disease progresses.

Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis.

Integrin activation contributes to key blood cell functions including adhesion, proliferation and migration. An essential step in the cell signaling pathway that activates integrin requires the binding of talin to the ß-integrin cytoplasmic tail. Whereas this pathway is understood in platelets in detail, considerably less is known regarding how integrin-mediated adhesion in endothelium contributes to postnatal angiogenesis. We utilized an inducible EC-specific talin1 knock-out mouse (Tln1 EC-KO) and talin1 L325R knock-in mutant (Tln1 L325R) mouse, in which talin selectively lacks the capacity to activate integrins, to assess the role of integrin activation during angiogenesis. Deletion of talin1 during postnatal days 1-3 (P1-P3) caused lethality by P8 with extensive defects in retinal angiogenesis and widespread hemorrhaging. Tln1 EC-KO mice displayed reduced retinal vascular area, impaired EC sprouting and proliferation relative to Tln1 CTRLs. In contrast, induction of talin1 L325R in neonatal mice resulted in modest defects in retinal angiogenesis and mice survived to adulthood. Interestingly, deletion of talin1 or expression of talin1 L325R in ECs increased MAPK/ERK signaling. Strikingly, B16-F0 tumors grown in Tln1 L325R adult mice were 55% smaller and significantly less vascularized than tumors grown in littermate controls. EC talin1 is indispensable for postnatal development angiogenesis. The role of EC integrin activation appears context-dependent as its inhibition is compatible with postnatal development with mild defects in retinal angiogenesis but results in marked defects in tumor growth and angiogenesis. Inhibiting EC pan-integrin activation may be an effective approach to selectively target tumor blood vessel growth.

Bortezomib enhances cytotoxicity of ex vivo-expanded gamma delta T cells against acute myeloid leukemia and T-cell acute lymphoblastic leukemia.

Engagement between the natural killer group 2, member D (NKG2D) receptor and its ligands is one of the main mechanisms used by immune cells to target stressed cells for cell death. NKG2D ligands are known markers of cellular stress and are often upregulated on tumor cells. Certain drugs can further increase NKG2D ligand levels, thereby making tumor cells more susceptible to immune cell detection and destruction. However, the effectiveness of this approach appears to be limited with drug treatment alone, possibly due to immune dysregulation in the setting of malignancies. We hypothesized that a more effective approach would be a combination of NKG2D ligand-inducing drugs, such as the proteasome inhibitor bortezomib, and ex vivo-expanded peripheral blood γδ T cells (i.e., Vγ9Vδ2 T cells). Acute myeloid leukemia (AML) is a high-risk hematologic malignancy, and treatment has shown limited benefit with the addition of bortezomib to standard chemotherapy regimens. Two AML cells lines, Nomo-1 and Kasumi-1, were treated with increasing concentrations of bortezomib, and changes in NKG2D ligand expression were measured. Bortezomib treatment significantly increased expression of the NKG2D ligand UL16 binding protein (ULBP) 2/5/6 in both cell lines. Vγ9Vδ2 T cells were expanded and isolated from peripheral blood of healthy donors to generate a final cellular product with a mean of 96% CD3+/γδ T-cell receptor-positive cells. Combination treatment of the AML cell lines with γδ T cells and bortezomib resulted in significantly greater cytotoxicity than γδ T cells alone, even at lower effector-to-target ratios. Based on the positive results against AML and the generalizable mechanism of this combination approach, it was also tested against T-cell acute lymphoblastic leukemia (T-ALL), another high-risk leukemia. Similarly, bortezomib increased ULBP 2/5/6 expression in T-ALL cell lines, Jurkat and MOLT-4 and improved the cytotoxicity of γδ T cells against each line. Collectively, these results show that bortezomib enhances γδ T-cell-mediated killing of both AML and T-ALL cells in part through increased NKG2D ligand-receptor interaction. Furthermore, proof-of-concept for the combination of ex vivo-expanded γδ T cells with stress ligand-inducing drugs as a therapeutic platform for high-risk leukemias is demonstrated.

Detecting Sensitive Mobility Features for Parkinson's Disease Stages Via Machine Learning.

BACKGROUND: It is not clear how specific gait measures reflect disease severity across the disease spectrum in Parkinson's disease (PD). OBJECTIVE: To identify the gait and mobility measures that are most sensitive and reflective of PD motor stages and determine the optimal sensor location in each disease stage. METHODS: Cross-sectional wearable-sensor records were collected in 332 patients with PD (Hoehn and Yahr scale I-III) and 100 age-matched healthy controls. Sensors were adhered to the participant's lower back, bilateral ankles, and wrists. Study participants walked in a ~15-meter corridor for 1 minute under two walking conditions: (1) preferred, usual walking speed and (2) walking while engaging in a cognitive task (dual-task). A subgroup (n = 303, 67% PD) also performed the Timed Up and Go test. Multiple machine-learning feature selection and classification algorithms were applied to discriminate between controls and PD and between the different PD severity stages. RESULTS: High discriminatory values were found between motor disease stages with mean sensitivity in the range 72%-83%, specificity 69%-80%, and area under the curve (AUC) 0.76-0.90. Measures from upper-limb sensors best discriminated controls from early PD, turning measures obtained from the trunk sensor were prominent in mid-stage PD, and stride timing and regularity were discriminative in more advanced stages. CONCLUSIONS: Applying machine-learning to multiple, wearable-derived features reveals that different measures of gait and mobility are associated with and discriminate distinct stages of PD. These disparate feature sets can augment the objective monitoring of disease progression and may be useful for cohort selection and power analyses in clinical trials of PD. © 2021 International Parkinson and Movement Disorder Society.

Role of data measurement characteristics in the accurate detection of Parkinson's disease symptoms using wearable sensors.

BACKGROUND: Parkinson's disease (PD) is a progressive neurological disease, with characteristic motor symptoms such as tremor and bradykinesia. There is a growing interest to continuously monitor these and other symptoms through body-worn sensor technology. However, limited battery life and memory capacity hinder the potential for continuous, long-term monitoring with these devices. There is little information available on the relative value of adding sensors, increasing sampling rate, or computing complex signal features, all of which may improve accuracy of symptom detection at the expense of computational resources. Here we build on a previous study to investigate the relationship between data measurement characteristics and accuracy when using wearable sensor data to classify tremor and bradykinesia in patients with PD. METHODS: Thirteen individuals with PD wore a flexible, skin-mounted sensor (collecting tri-axial accelerometer and gyroscope data) and a commercial smart watch (collecting tri-axial accelerometer data) on their predominantly affected hand. The participants performed a series of standardized motor tasks, during which a clinician scored the severity of tremor and bradykinesia in that limb. Machine learning models were trained on scored data to classify tremor and bradykinesia. Model performance was compared when using different types of sensors (accelerometer and/or gyroscope), different data sampling rates (up to 62.5 Hz), and different categories of pre-engineered features (up to 148 features). Performance was also compared between the flexible sensor and smart watch for each analysis. RESULTS: First, there was no effect of device type for classifying tremor symptoms (p > 0.34), but bradykinesia models incorporating gyroscope data performed slightly better (up to 0.05 AUROC) than other models (p = 0.01). Second, model performance decreased with sampling frequency (p < 0.001) for tremor, but not bradykinesia (p > 0.47). Finally, model performance for both symptoms was maintained after substantially reducing the feature set. CONCLUSIONS: Our findings demonstrate the ability to simplify measurement characteristics from body-worn sensors while maintaining performance in PD symptom detection. Understanding the trade-off between model performance and data resolution is crucial to design efficient, accurate wearable sensing systems. This approach may improve the feasibility of long-term, continuous, and real-time monitoring of PD symptoms by reducing computational burden on wearable devices.

Comparing Variability, Severity, and Persistence of Depressive Symptoms as Predictors of Future Stroke Risk.

OBJECTIVE: Numerous studies show that depressive symptoms measured at a single assessment predict greater future stroke risk. Longer-term symptom patterns, such as variability across repeated measures or worst symptom level, might better reflect adverse aspects of depression than a single measurement. This prospective study compared five approaches to operationalizing depressive symptoms at annual assessments as predictors of stroke incidence. DESIGN: Cohort followed for incident stroke over an average of 6.4 years. SETTING: The Adult Changes in Thought cohort follows initially cognitively intact, community- dwelling older adults from a population base defined by membership in Group Health, a Seattle-based nonprofit healthcare organization. PARTICIPANTS: 3,524 individuals aged 65 years and older. MEASUREMENTS: We identified 665 incident strokes using ICD codes. We considered both baseline Center for Epidemiologic Studies-Depression scale (CES-D) score and, using a moving window of three most recent annual CES-D measurements, we compared most recent, maximum, average, and intra-individual variability of CES-D scores as predictors of subsequent stroke using Cox proportional hazards models. RESULTS: Greater maximum (hazard ratio [HR]: 1.18; 95% CI: 1.07-1.30), average (HR: 1.20; 95% CI: 1.05-1.36) and intra-individual variability (HR: 1.15; 95% CI: 1.06-1.24) in CES-D were each associated with elevated stroke risk, independent of sociodemographics, cardiovascular risks, cognition, and daily functioning. Neither baseline nor most recent CES-D was associated with stroke. In a combined model, intra-individual variability in CES-D predicted stroke, but average CES-D did not. CONCLUSIONS: Capturing the dynamic nature of depression is relevant in assessing stroke risk. Fluctuating depressive symptoms may reflect a prodrome of reduced cerebrovascular integrity.

Examining the association between late-life depressive symptoms, cognitive function, and brain volumes in the context of cognitive reserve.

OBJECTIVE: The present study aimed to investigate whether cognitive reserve moderated the association between depressive symptoms and cognition, as well as brain volumes in a sample of older adults. METHODS: Non-demented participants (n = 3484) were selected from the Washington Heights/Hamilton Heights Inwood Columbia Aging Project (Northern Manhattan). A subsample of these participants without dementia (n = 703), who had brain imaging data, was also selected for a separate analysis. Depressive symptomatology was assessed with the 10-item Center for Epidemiologic Studies Depression Scale. Reading level and years of education were used as measures of cognitive reserve. Four distinct cognitive composite scores were calculated: executive function, memory, visual-spatial, and language. RESULTS: Multiple regression analysis revealed interaction effects between both measures of cognitive reserve and depressive symptoms on all the cognitive outcome measures except for visual-spatial ability. Those with greater reserve showed greater cognitive decrements than those with lower levels of reserve as depressive symptoms increased. A borderline interaction effect was revealed between reading level and depressive symptoms on total brain volumes. Those with lower reading scores showed greater volume loss as depressive symptoms increased than those with higher reading scores. CONCLUSIONS: Our findings indicate that the association between late-life depressive symptoms and core aspects of cognition varies depending on one's level of cognitive reserve. Those that had greater levels of education and/or reading ability showed a greater decrease in memory, executive, and language performances as depressive symptoms increased than those with lower years of education and reading ability.

Demographic characteristics do not decrease the utility of depressive symptoms assessments: examining the practical impact of item bias in four heterogeneous samples of older adults.

OBJECTIVE: Previous studies have identified differential item function (DIF) in depressive symptoms measures, but the impact of DIF has been rarely reported. Given the critical importance of depressive symptoms assessment among older adults, we examined whether DIF due to demographic characteristics resulted in salient score changes in commonly used measures. METHODS: Four longitudinal studies of cognitive aging provided a sample size of 3754 older adults and included individuals both with and without a clinical diagnosis of major depression. Each study administered at least one of the following measures: the Center for Epidemiologic Studies Depression scale (20-item ordinal response or 10-item dichotomous response versions), the Geriatric Depression Scale, and the Montgomery-Åsberg Depression Rating Scale. Hybrid logistic regression-item response theory methods were used to examine the presence and impact of DIF due to age, sex, race/ethnicity, and years of education on the depressive symptoms items. RESULTS: Although statistically significant DIF due to demographic factors was present on several items, its cumulative impact on depressive symptoms scores was practically negligible. CONCLUSIONS: The findings support substantive meaningfulness of previously reported demographic differences in depressive symptoms among older adults, showing that these individual differences were unlikely to have resulted from item bias attributable to demographic characteristics we examined.

The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment.

INTRODUCTION: It is unclear whether white matter hyperintensities (WMHs), magnetic resonance imaging markers of small-vessel cerebrovascular disease, promote neurodegeneration and associated clinical decline in Alzheimer's disease (AD), or simply co-occur with recognized pathogenic processes. METHODS: In 169 patients with mild cognitive impairment, followed for 3 years, we examined the association of (1) baseline regional WMH and cerebral spinal fluid-derived t-tau (total tau) with entorhinal cortex atrophy rates, as a marker of AD-related neurodegeneration, and conversion to AD; and (2) baseline regional WMH with change in t-tau level. RESULTS: In participants with low baseline t-tau, higher regional WMH volumes were associated with faster entorhinal cortex atrophy. Higher parietal WMH volume predicted conversion to AD in those with high t-tau. Higher parietal and occipital WMH volumes predicted increasing t-tau. DISCUSSION: WMHs affect AD clinical and pathologic processes both directly and interacting with tau.

The Effect of Altitude and Travel on Rugby Union Performance: Analysis of the 2012 Super Rugby Competition.

The aim of this study was to investigate whether playing rugby at altitude or after travel (domestic and international) disadvantaged teams. In a retrospective longitudinal study, all matches (N = 125) played in the 2012 Super Rugby Competition were analyzed for key performance indicators (KPI) from coded game data provided by OPTA sports data company. Matches were played in a home-away format in New Zealand, South Africa, and Australia. Teams based at sea level but playing at altitude (1,271-1,753 m) were more likely to miss tackles (mean ± 90% confidence interval, 1.4 ± 1.7) and score fewer points in the first half compared with games at sea level. In the second half of games, sea level teams at altitude were very likely to make fewer gain lines (-4.0 ± 2.7) compared with the second half of games at sea level. The decreased ability to break the defensive line, which may be the result of altitude-induced fatigue, could reduce the likelihood of scoring points and winning a game. Travel also had an effect on KPI, where international travel resulted in more missed tackles (1.7 ± 1.3) and less frequent gain lines (-3.0 ± 1.9) in the first half relative to matches at home; overall, away teams (domestic and international) scored 4 less points in the second half compared with home teams. In conclusion, playing away from home in another country, particularly at altitude, can have a detrimental effect on KPI, which may affect the overall performance and the chances of winning matches.

Relationship between depressive symptoms and cognition in older, non-demented African Americans.

Knowledge of the relationship between depressive symptoms and cognition in older adults has primarily come from studies of clinically depressed, functionally impaired or cognitively impaired individuals, and in predominately White samples. Limited minority representation in depression research exposes the need to examine these associations in more ethnic/racially diverse populations. We sought to examine the relationship between depressive symptoms and cognition in a sample of non-demented older African Americans recruited from surrounding U.S. cities of New York, Greensboro, Miami, and Nashville (N=944). Depressive symptoms were evaluated with the Geriatric Depression Scale (GDS). Cognition was evaluated with a comprehensive neuropsychological battery. Test scores were summarized into attention, executive function, memory, language, and processing speed composites. Controlling for age, education, reading level, and sex, African American older adults who endorsed more symptoms obtained significantly lower scores on measures of memory, language, processing speed, and executive functioning. Further investigation of the causal pathway underlying this association, as well as potential mediators of the relationship between depressive symptoms and cognitive test performance among older African Americans, such as cardiovascular and cerebrovascular disease, may offer potential avenues for intervention.

The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces.

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.

Interplay of demographics, geography and COVID-19 pandemic responses in the Puget Sound region: The Vashon, Washington Medical Reserve Corps experience.

BACKGROUND: Rural U.S. communities are at risk from COVID-19 due to advanced age and limited access to acute care. Recognizing this, the Vashon Medical Reserve Corps (VMRC) in King County, Washington, implemented an all-volunteer, community-based COVID-19 response program. This program integrated public engagement, SARS-CoV-2 testing, contact tracing, vaccination, and material community support, and was associated with the lowest cumulative COVID-19 case rate in King County. This study aimed to investigate the contributions of demographics, geography and public health interventions to Vashon's low COVID-19 rates. METHODS: This observational cross-sectional study compares cumulative COVID-19 rates and success of public health interventions from February 2020 through November 2021 for Vashon Island with King County (including metropolitan Seattle) and Whidbey Island, located ~50 km north of Vashon. To evaluate the role of demography, we developed multiple linear regression models of COVID-19 rates using metrics of age, race/ethnicity, wealth and educational attainment across 77 King County zip codes. To investigate the role of remote geography we expanded the regression models to include North, Central and South Whidbey, similarly remote island communities with varying demographic features. To evaluate the effectiveness of VMRC's community-based public health measures, we directly compared Vashon's success of vaccination and contact tracing with that of King County and South Whidbey, the Whidbey community most similar to Vashon. RESULTS: Vashon's cumulative COVID-19 case rate was 29% that of King County overall (22.2 vs 76.8 cases/K). A multiple linear regression model based on King County demographics found educational attainment to be a major correlate of COVID-19 rates, and Vashon's cumulative case rate was just 38% of predicted (p < .05), so demographics alone do not explain Vashon's low COVID-19 case rate. Inclusion of Whidbey communities in the model identified a major effect of remote geography (-49 cases/K, p < .001), such that observed COVID-19 rates for all remote communities fell within the model's 95% prediction interval. VMRC's vaccination effort was highly effective, reaching a vaccination rate of 1500 doses/K four months before South Whidbey and King County and maintaining a cumulative vaccination rate 200 doses/K higher throughout the latter half of 2021 (p < .001). Including vaccination rates in the model reduced the effect of remote geography to -41 cases/K (p < .001). VMRC case investigation was also highly effective, interviewing 96% of referred cases in an average of 1.7 days compared with 69% in 3.7 days for Washington Department of Health investigating South Whidbey cases and 80% in 3.4 days for Public Health-Seattle & King County (both p<0.001). VMRC's public health interventions were associated with a 30% lower case rate (p<0.001) and 55% lower hospitalization rate (p = 0.056) than South Whidbey. CONCLUSIONS: While the overall magnitude of the pre-Omicron COVID-19 pandemic in rural and urban U.S. communities was similar, we show that island communities in the Puget Sound region were substantially protected from COVID-19 by their geography. We further show that a volunteer community-based COVID-19 response program was highly effective in the Vashon community, augmenting the protective effect of geography. We suggest that Medical Reserve Corps should be an important element of future pandemic planning.

Adipocyte-mediated epigenomic instability in human T-ALL cells is cytotoxic and phenocopied by epigenetic-modifying drugs.

The world's population with obesity is reaching pandemic levels. If current trends continue, it is predicted that there will be 1.5 billion people with obesity by 2030. This projection is alarming due to the association of obesity with numerous diseases including cancer, with recent studies demonstrating a positive association with acute myeloid leukemia (AML) and B cell acute lymphoblastic leukemia (B-ALL). Interestingly, several epidemiological studies suggest the converse relationship may exist in patients with T cell acute lymphoblastic leukemia (T-ALL). To determine the relationship between obesity and T-ALL development, we employed the diet-induced obesity (DIO) murine model and cultured human T-ALL cells in adipocyte-conditioned media (ACM), bone marrow stromal cell-conditioned media, stromal conditioned media (SCM), and unconditioned media to determine the functional impact of increased adiposity on leukemia progression. Whereas only 20% of lean mice transplanted with T-ALL cells survived longer than 3 months post-inoculation, 50%-80% of obese mice with leukemia survived over this same period. Furthermore, culturing human T-ALL cells in ACM resulted in increased histone H3 acetylation (K9/K14/K18/K23/K27) and methylation (K4me3 and K27me3) posttranslational modifications (PTMs), which preceded accelerated cell cycle progression, DNA damage, and cell death. Adipocyte-mediated epigenetic changes in human T-ALL cells were recapitulated with the H3K27 demethylase inhibitor GSK-J4 and the pan-HDAC inhibitor vorinostat. These drugs were also highly cytotoxic to human T-ALL cells at low micromolar concentrations. In summary, our data support epidemiological studies demonstrating that adiposity suppresses T-ALL pathogenesis. We present data demonstrating that T-ALL cell death in adipose-rich microenvironments is induced by epigenetic modifications, which are not tolerated by leukemia cells. Similarly, GSK-J4 and vorinostat treatment induced epigenomic instability and cytotoxicity profiles that phenocopied the responses of human T-ALL cells to ACM, which provides additional support for the use of epigenetic modifying drugs as a treatment option for T-ALL.

Humanistic Burden of Huntington Disease: Evidence From the Huntington Disease Burden of Illness Study.

Background and Objectives: Huntington disease (HD) is a rare, inherited, and highly complex neurodegenerative disorder with no currently approved disease-modifying treatments. We investigated the effect of HD on health-related quality of life and other patient-reported outcomes in the Huntington's Disease Burden of Illness (HDBOI) study. Methods: The HDBOI study is a retrospective, cross-sectional study conducted between September 2020 and May 2021 in France, Germany, Italy, Spain, the United Kingdom, and the United States. People with symptomatic onset HD (PwHD) were recruited by their HD-treating physicians and categorized as early (ES), mid (MS), or advanced stage (AS) HD. Physicians provided sociodemographic and clinical information from the participant's medical records in electronic case report forms (eCRF); participants or their proxies completed online Patient Public Involvement Engagement questionnaires (PPIE-P). Patient-reported outcomes included the 5-level EQ-5D version (EQ-5D-5L), Short-Form-(SF)-36 v2 (and SF-6-Dimension [SF-6D] utility), Huntington Quality of Life Instrument (H-QoL-I), and the Work Productivity and Activity Impairment Specific Health Problem. All outcomes were summarized using descriptive statistics, and differences between disease stages were assessed by Kruskal-Wallis tests. Results: A total of 2,094 PwHD were enrolled with completed eCRFs (100%) and PPIE-P forms (n = 482, 23%). Participants' mean age was 47.3 years; they were generally evenly distributed across countries, with the majority being ES (40%) followed by MS (33%) and LS (26%). The mean EQ-5D-5L (n = 336) utility score was 0.59 (SD, 0.27), with the highest mean utility scores [SD] in ES (0.72 [0.22]) followed by MS (0.62 [0.18]) and AS (0.37 [0.30]), p < 0.001. The mean SF-6D score (n = 482) was 0.57 (SD, 0.10), with mean values decreasing with advanced disease (ES, 0.61; MS, 0.56; AS, 0.50, p < 0.001). H-QoL-I mean scores (n = 482) also worsened with more advanced disease, from 0.58 for ES to 0.49 for MS and 0.37 for AS, p < 0.001. Impairment in daily activities and in work productivity also increased with more advanced disease. Overall proxy respondents reported on average worse outcomes than PwHD (self-reported) across all outcomes and disease stages suggesting a possible unawareness of deficits by PwHD. Discussion: The HDBOI study provides new insights into the characteristics and humanistic burden of PwHD and offers a meaningful contribution to this underserved research area.

Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia.

The incidence of obesity is rising with greater than 40% of the world's population expected to be overweight or suffering from obesity by 2030. This is alarming because obesity increases mortality rates in patients with various cancer subtypes including leukemia. The survival differences between lean patients and patients with obesity are largely attributed to altered drug pharmacokinetics in patients receiving chemotherapy; whereas, the direct impact of an adipocyte-enriched microenvironment on cancer cells is rarely considered. Here we show that the adipocyte secretome upregulates the surface expression of Galectin-9 (GAL-9) on human B-acute lymphoblastic leukemia cells (B-ALL) which promotes chemoresistance. Antibody-mediated targeting of GAL-9 on B-ALL cells induces DNA damage, alters cell cycle progression, and promotes apoptosis in vitro and significantly extends the survival of obese but not lean mice with aggressive B-ALL. Our studies reveal that adipocyte-mediated upregulation of GAL-9 on B-ALL cells can be targeted with antibody-based therapies to overcome obesity-induced chemoresistance.

B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12.

Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.

Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds.

Aging-associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging-associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin-37 (IL-37) is a potent anti-inflammatory cytokine, and we present data demonstrating that IL-37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin-37 (IL-37) in aged mice reduces or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL-37 expression decreases the surface expression of programmed cell death protein 1 (PD-1) and augments cytokine production from aged T-cells. Improved T-cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T-cells and Lat in CD8+ T-cells when aged mice were treated with recombinant IL-37 (rIL-37) but not control immunoglobin (Control Ig). Importantly, IL-37-mediated rejuvenation of aged endogenous T-cells was also observed in aged chimeric antigen receptor (CAR) T-cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL-37 in boosting the function of aged T-cells and highlight its therapeutic potential to overcome aging-associated immunosenescence.