Citations

Abstract Cognitive impairment is among the most common non-motor symptoms in parkinsonism and Parkinson’s disease, ranging from subjective complaints to dementia. Although several predictive factors have been described, their prognostic relevance remains uncertain. This study aims to examine the predictive association between clinical features and the risk of dementia and determine the incidence of dementia in a population-based cohort of incident parkinsonism cases. Patients with parkinsonism onset between 1991 and 2020 were identified using the Rochester Epidemiology Project records-linkage system. Subjects with cognitive impairment preceding motor symptoms onset or concomitant Alzheimer’s disease were excluded. Diagnoses of dementia and mild cognitive impairment were established using neuropsychological testing or brief cognitive screening. Development of dementia was assessed using a Cox proportional hazards regression model. Associations between dementia and each risk factor were individually estimated in adjusted Cox models. All risk factors were also included in a least absolute shrinkage and selection operator (LASSO) penalized multivariable Cox model. A total of 1,104 patients were included: 153 (13.9%) developed mild cognitive impairment and 543 (49.2%) developed dementia during follow-up. The cumulative incidence of dementia was 30.3% at 5 years, 48.6% at 10 years, 61.4% at 15 years, and 69.3% at 20 years, indicating that a considerable portion of patients remained free of dementia after a prolonged follow-up. The majority of patients with dementia were males (61.5%), and older age at disease onset was associated with risk of dementia (hazard ratio [HR] = 1.32, P < 0.001 per 5-year increment). In the penalized model, dementia risk was significantly higher among individuals presenting with impaired postural reflexes (HR = 1.26, P = 0.014), consistent with a poorer prognosis in akinetic-rigid-predominant parkinsonism. Eye movement abnormalities including reduced ocular range of motion (HR = 1.86, P < 0.001), and smooth pursuit alterations (HR = 1.34, P = 0.024) were also associated with dementia. Non-motor symptoms, including REM sleep behavior disorder (HR = 1.51, P < 0.001), orthostatic hypotension (HR = 1.30, P = 0.009), and constipation (HR = 1.24, P = 0.022), were linked to dementia risk, supporting a potential involvement of non-dopaminergic and central autonomic pathways in cognitive decline. These findings were largely confirmed in the Parkinson’s disease/Parkinson’s disease with dementia group, in which 77 (13.5%) developed mild cognitive impairment and 249 (43.5%) developed dementia. Among these patients, smooth pursuit alterations, reduced ocular range of motion, orthostatic hypotension, and constipation were associated with dementia.

Abstract T-cell immune tolerance is established in part through the activity of the autoimmune regulator (AIRE) transcription factor in medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue–specific self-antigens for presentation to naïve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of “selfness” at the RNA and protein levels which, when presented on major histocompatibility complexes (MHC), shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by resetting the immunologic selfness of cancer cells, this AIRE-mediated immunotherapy (i) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; (ii) conferred upon nonimmunogenic tumors de novo sensitivity to immune checkpoint blockade; (iii) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and (iv) lead to potent T cell–mediated rejection of aggressive, immunologically cold, nonimmunogenic tumors. Patient RNA sequencing data showed that the expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting that our studies have therapeutic translational value.

Purpose: Hereditary transthyretin amyloidosis (ATTRv) is a progressive multisystem disease in which median mononeuropathy at the wrist (MNW) is common and often precedes systemic involvement. Nerve conduction studies (NCS) have historically been the gold standard for MNW, but neuromuscular ultrasound (NMUS) is complementary. The aim of this study was to compare NMUS with electrodiagnostic (EDX) testing for the diagnosis of MNW in patients with symptomatic ATTRv. Methods: A retrospective review was performed of patients 18 years and older with ATTRv confirmed by genetic testing who underwent both EDX testing and NMUS of the median nerve between 2019 and 2025. Demographic, NMUS, and EDX data were collected. Results: Data from 15 upper limbs in 10 patients were analyzed. Median nerve cross‐sectional area at the wrist was significantly greater than reference values ( P = 0.041). MNW was identified in 80% of wrists by NMUS and 100% by NCS, with no significant difference between modalities. Median nerve cross‐sectional area at the wrist did not significantly correlate with MNW severity determined by NCS ( r = −0.018; P = 0.941) or with any NCS parameters (all P > 0.080). Concurrent polyneuropathy was diagnosed in 60% of patients, but there was no association between polyneuropathy and MNW detection by either modality ( P > 0.197). Conclusions: NMUS and NCS demonstrate comparable diagnostic accuracy for MNW in ATTRv. Given its noninvasive nature and efficiency, NMUS may serve as an adjunct to classic EDX testing in this population.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

ABSTRACT Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND‐AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND‐AML treated with frontline Ven‐HMA who subsequently underwent ASCT. A total of 111 ND‐AML patients (58% male, 60% secondary/therapy‐related, median age 70 years [range, 37–80]) received a median of 3 cycles of Ven‐HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS , TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven‐HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA‐matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow‐up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1‐, 2‐, 3‐year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation ( STAG2 MUT ) , and DNMT3A MUT were associated with superior posttransplant survival. Patients were stratified into low‐ (0–1 point), intermediate‐ (2 points), and high‐risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3‐year survival rates of 89%, 59%, and 19%, respectively ( p < 0.01). Taken together, age, STAG2 MUT and DNMT3A MUT stratified posttransplant survival in Ven‐HMA treated patients with ND‐AML.