Citations

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients.

Abstract Background Red blood cell (RBC) transfusion may be lifesaving, however transfusion-transmitted infections (TTI) and transfusion-associated graft-versus-host disease (TA-GVHD) still pose a threat despite current donor selection and testing requirements. Amustaline (S-303)/glutathione (GSH) pathogen reduction (PR) is designed to inactivate infectious microbes and leukocytes in RBCs. The RedeS study evaluates the safety and efficacy of amustaline/GSH PR-RBCs compared to conventional RBCs in a broad spectrum of patients requiring acute and/or repeated RBC transfusion support. Methods RedeS is a Phase 3, prospective, multi-center, randomized, double-blind, active-controlled, parallel-design study, with a 6-month extension option to evaluate patients requiring repeated transfusions including red cell exchange (RCE).Eligible subjects will be stratified according to site, baseline bleeding status and participation in the extension period. The study arms include a transfusion period of 28-days for anemia with any bleeding or non-bleeding patients or a 28-day+6-month extension for non-bleeding patients with chronic anemia requiring repeated simple transfusions, or for patients with sickle cell disease (SCD) expected to receive three RCE procedures. The study will seek to enroll 600-800 subjects in the overall safety analysis, including ~140 repeatedly-transfused subjects in the 6-month extension including up to 30 subjects receiving three RCE procedures. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days after the last study transfusion, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to PR-RBCs. The primary efficacy endpoint is the hemoglobin (Hb) increment in subjects who are non-bleeding at baseline, adjusted for the grams of Hb transfused and averaged over multiple transfusions. With 352 evaluable transfused non-bleeding subjects (176 per treatment group) from either arm, the study will have 80% power to demonstrate non-inferiority, defined as a Hb increment treatment difference of no more than 15% of the Control group mean, assuming a Control arm coefficient of variation of 50%. Discussion RedeS will characterize the safety of amustaline/GSH PR-RBCs and is designed to demonstrate the non-inferiority of PR-RBCs to conventional RBCs with respect to Hb increment, a common pragmatic clinical assessment of RBC transfusion effectiveness.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

Abstract Background Extensive evidence links cognition, tau, and neurodegeneration in Alzheimer's disease (AD). However, in U.S. POINTER imaging (a community‐recruited clinical trial cohort selected for high cardiovascular risk, ethnoracial diversity, and increased risk of cognitive decline and dementia) tau PET is more closely linked to cognition than in ADNI. Here, we further explore how ADNI and POINTER differ with respect to relationships between cross‐sectional AD biomarkers, cortical thickness, and different cognitive domains. Method U.S. POINTER imaging (Baseline; N = 775; 68.9±5.2 years, 62.8% female) and ADNI ( N = 405; 69.9±5.4 years, 58% female) were matched by age, sex, clinical status, and APOE4 genotype (Table 1). We examined associations between baseline AD biomarkers (Amyloid‐beta (Aβ) PET in centiloids, harmonized tau PET measures of MK6240 in POINTER and FTP in ADNI), regional cortical thickness, and verbal memory (Delayed Story Recall), executive function (Trail‐Making B), and global cognition (Preclinical Alzheimer's Cognitive Composite scores) across each cohort, controlling for age, sex, and education. Result Aβ burden in ADNI was associated with worse executive function ( p < .001) and global cognition ( p < .001) but not memory, whereas in POINTER Aβ burden was not associated with any cognitive domain (Figure 1A). Among Aβ+ individuals, tau burden was associated with poorer performance across domains in ADNI, but only with poorer verbal memory in POINTER (Figures 1B&1C). Additionally, there were stronger positive associations between cortical thickness and executive function and global cognition compared to verbal memory, particularly in ADNI Aβ+ individuals even after adjusting for entorhinal tau ( p < .01; Figure 2). Conclusion Cognitive performance was linked to all biomarkers (Aβ, tau, cortical thickness) but these associations were consistently stronger in ADNI compared to POINTER, particularly in Aβ+ individuals. The stronger thickness‐cognition relationships in ADNI were not driven by tau, indicating that there is a tau‐independent role of thickness in explaining cognition. In ADNI, there were subtle differences between cognitive domains such that executive function was more closely linked than verbal memory to Aβ and cortical thickness, whereas verbal memory was linked to tau in both cohorts. Our study highlights that frequently‐reported AD biomarker associations may be attenuated in heterogeneous, community‐recruited cohorts.

Abstract Background More than 85% of Alzheimer's disease (AD) donor brains exhibit some degree of cerebral amyloid angiopathy (CAA), which is characterized predominantly by Aβ40 deposits in the brain vasculature and can cause blood brain barrier (BBB) leakage. CAA is associated with risk of infarcts, cerebral hemorrhages, and cognitive decline. Brain cell type‐specific mechanisms that influence CAA pathology, as well as related measures such as Aβ40 biochemical measures and tight junction proteins, an indicator of BBB integrity, are still elusive. Method We performed single‐nucleus RNA sequencing (snRNAseq) of temporal cortex tissue from 79 AD donors, with varying levels of CAA co‐pathology. Measurements of soluble, insoluble and membrane‐associated fractions of brain Aβ40 and tight junction protein (claudin‐5, occludin) levels were available for these donors. We correlated these measures with cell proportions. We also conducted differential gene expression and analyses for intercellular communications and regulatory networks. Result We identified 25 clusters and annotated them with major brain cell types. There were 3 oligodendrocyte, 7 excitatory and 7 inhibitory neuronal, 2 microglial, 2 astrocytic, and 1 each for endothelial, pericytic, fibroblast, and oligodendrocyte precursor cell clusters. We found that higher CAA and Aβ40 levels correlate with reduced neuronal and increased microglial, astrocytic and vascular cell proportions. Increased tight junction proteins correlate with increased inhibitory neuronal and reduced microglial, astrocytic and vascular cell proportions. Among all clusters, one microglial, both astrocytic and the pericytic clusters have greater number of genes significantly associated with CAA, Aβ40 and tight junction protein levels. Most significant genes have negative associations with CAA and membrane‐bound Aβ40 and positive with tight junction protein measures. Using these genes as input for intercellular communications analysis, we prioritized ligand‐target interactions from microglia or astrocytes to pericytes. Some of the prioritized targets are transcription factors in pericytes. Using regulon analysis, we identified genes downstream of these transcription factors that are also significantly associated with lower CAA and membrane‐bound Aβ40 and higher tight junction protein levels. Conclusion We revealed glia‐to‐pericytes intercellular interactions and pericytic gene regulatory networks that are potentially perturbed by CAA and BBB breakdown. Future directions include analyzing external snRNAseq datasets and performing functional validations.

Background: Ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) with once-daily oral capsule, tablet, and oral suspension formulations approved in the United States across indications of chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, and previously treated chronic graft-versus-host disease, and for mantle cell lymphoma in Europe. Patients with difficulty swallowing capsules or tablets may require alternative formulations or administration options to optimize treatment. Objectives: To evaluate the relative bioavailability of ibrutinib oral suspension relative to capsule or tablet formulations and to examine compatibility for optimal administration methods. Methods: Relative bioavailability of ibrutinib oral suspension was evaluated in healthy volunteers or patients in comparison to capsule or tablet formulations. Dose recovery and delivery, presence of impurities, particle size, and hold time were evaluated after in vitro mock oral suspension administration via syringe and nasogastric and percutaneous endoscopic gastrostomy (PEG) tubes. Results: Clinical bioavailability was comparable for ibrutinib oral suspension and capsules (420 mg/day) under the fasted state in healthy volunteers. Dose-normalized pharmacokinetic values were similar across ibrutinib formulations in patient studies. All evaluated enteral tubes achieved 90%–110% ibrutinib dose recovery regardless of tube type or syringe after 2 × 3 mL water rinses. Oral suspension preservative may be adsorbed into enteral tubes after a 60-minute hold time. Conclusion: Ibrutinib oral suspension bioavailability was comparable with ibrutinib tablet and capsule formulations. When dosed via standard enteral tube administration methods, ibrutinib oral suspension is stable and compatible with polyurethane, silicone, or polyvinyl nasogastric or PEG tubes. To ensure full dose recovery and prevent drug preservative adsorption into tubes, ibrutinib oral suspension should be administered immediately and followed by two rinses of 3 mL of water each. Ibrutinib oral suspension is a viable BTKi treatment option for patients requiring or preferring alternatives to oral capsules and tablets.

Abstract Background Tau‐PET tracers are essential for visualizing pathology in Alzheimer’s (AD). High detectability to tau is crucial for early detection and monitoring of tau deposition. This study compares the noise to dynamic range ratio (NRR) of [ 18 F]FTP, [ 18 F]MK6240, [ 18 F]PI2620, and [ 18 F]RO948, cross‐sectionally and longitudinally. Methods 460 individuals from the HEAD study (23 cognitively unimpaired (CU) young, 249 CU old and 188 cognitively impaired) underwent [ 18 F]FTP and [ 18 F]MK6240 tau‐PET scans; 94 additionally received [ 18 F]PI2620 and [ 18 F]RO948. A subset of 28 individuals (15 CU and 13 CI) underwent [ 18 F]FTP and [ 18 F]MK6240 follow‐up scans (1.5 ± 0.1 years later). Annual change was measured as [(followup‐baseline)/time between scans]. Noise was calculated as the standard deviation (SD) of CU Aβ‐ participants aged ≤65 (SD CUAβ‐≤65 ). The dynamic range was calculated as the SD across all subjects (SD range ). A lower the NRR (=SD CUAβ‐≤65 /SD range ) indicates more detectability. Analyses were performed at both region‐of‐interest and voxel‐wise levels. Results Across the whole cohort, [ 18 F]MK6240 exhibited lower NRR than [ 18 F]FTP in all regions. Voxel‐wise, differences were most pronounced in the frontal medial temporal regions (Figure 1). Within the four‐tracers subset, [ 18 F]PI2620 and [ 18 F]FTP showed the highest NRR in Braak II, followed by [ 18 F]RO948 and [ 18 F]MK6240. In Braak IV‐VI, [ 18 F]MK6240 consistently demonstrated the lowest values, followed by [ 18 F]PI2620, [ 18 F]FTP and [ 18 F]RO948. Similarly, in metatemporal‐ROI and Braak III, [ 18 F]MK6240 remained the lowest, however followed by [ 18 F]FTP, [ 18 F]PI2620 and [ 18 F]RO948 (Figure 2). Lower [ 18 F]MK6240 NRR was due to larger SD range , while [ 18 F]FTP's lower values stemmed from smaller SD CUAβ‐≤65 . Conversely, high [ 18 F]PI2620 and [ 18 F]RO948 values are driven by larger SD CUAβ‐≤65 . Longitudinal analyses further confirmed that [ 18 F]MK6240 exhibited the lowest NRR across the entire brain, including AD‐related regions, with voxel‐wise differences mainly in the temporal and parietal lobes. Conclusion Tau‐PET tracers exhibit significant variability in detectability. [ 18 F]MK6240 consistently demonstrated lower NRR, implying better detectability across all regions, cross‐sectionally and longitudinally. Despite differences in NRR, [ 18 F]FTP, [ 18 F]RO948 and [ 18 F]PI2620 followed similar pattern. These results provide insights into the differential tracer detectability, helping guide their optimal use in detecting and tracking tau pathology. Ongoing follow‐up scans will further clarify longitudinal tracer detectability and its implications for tau progression in AD.

Background/Objectives: Surveillance for anal squamous cell carcinoma (ASCC) recurrence relies on clinical examination and imaging. Post-treatment edema, fibrosis, and inflammation can result in clinically indeterminate findings (CIFs) that delay diagnosis and increase patient and system burden. Circulating tumor tissue-modified viral (TTMV)-HPV DNA offers a biologically specific, noninvasive biomarker that may clarify equivocal assessments. Methods: In this multi-center retrospective study, 233 patients with HPV-associated ASCC were evaluated, including 185 with ≥1 post-treatment TTMV-HPV DNA test. CIFs were defined as exams or imaging results not definitively positive or negative for disease, and were paired with subsequent TTMV-HPV DNA tests. Concordance was defined by prespecified follow-up windows comparing TTMV-HPV DNA results with subsequent clinical outcomes. Results: Ninety patients (39%) experienced 214 CIFs, arising from exams (46%, 98) or imaging (54%, 116). Indeterminate rates by assessment were 7% for exams, 17% for imaging, and 1.3% for TTMV-HPV DNA testing. Overall, 52 CIF/TTMV-HPV DNA pairs were eligible for analysis, and TTMV-HPV DNA resolved disease status accurately for 48/52 (92%, 95% CI: 81.5–97.9). Negative tests predicted cancer-free status for 37/41 CIFs (90%), while 100% of positive tests (11/11) were concordant with clinically confirmed recurrence. In 73% of positive cases (8/11), TTMV-HPV DNA was the first indication of recurrence (median lead-time 29 days; IQR 25–147). Conclusions: TTMV-HPV DNA testing reliably clarifies clinically indeterminate findings during ASCC surveillance, demonstrating high accuracy (92%) and earlier detection of recurrence. These data support integration into post-treatment management to reduce diagnostic uncertainty and guide timely care.

PURPOSE The feasibility of Oncotype DX Breast Recurrence Score testing on diagnostic core needle biopsy (CNB) samples has been demonstrated through analysis of a large central laboratory experience. However, concordance with paired samples from the same primary breast tumor has not been comprehensively evaluated. The primary objective of this study was to determine the degree of concordance of Recurrence Score (RS) results between paired CNB and surgical excision (SE) specimens from the same untreated primary breast tumor of patients with early-stage, hormone receptor–positive, human epidermal growth factor receptor 2–negative invasive breast cancer. MATERIALS AND METHODS Patients with a clinical RS result on either a CNB or SE specimen were included. Lin concordance correlation coefficient (CCC) with 95% CIs was estimated to assess agreement of continuous RS results between paired samples. Cohen Kappa with 95% CIs was used to evaluate categorical RS result concordance. RESULTS A total of 134 patients were identified with paired CNB and SE specimens. The median age was 62 years (range, 33-99; 23 patients [17%] were age ≤50 years v 111 [83%] age >50 years). The mean RS results were 15.6 (range, 0-56) for CNB and 16.6 (range, 0-59) for SE ( P = .003), with no statistically significant differences in RS categories. Agreement between continuous RS results from paired samples was strong, with a Lin CCC of 0.86 (95% CI, 0.80 to 0.90). The overall percent agreement in RS categories was 91.8% (95% CI, 87.1 to 96.4). Categorical agreement was further supported by a Cohen Kappa statistic of 0.64 (95% CI, 0.44 to 0.83), indicating substantial agreement between CNB and SE specimens. CONCLUSION The results of this study demonstrate high concordance of RS results between paired samples, which supports the use of CNB for Oncotype DX testing.

Background and Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multisystem involvement, including renal cysts, hepatic cysts, intracranial aneurysms, and aortic root dilatation and dissection. Though exceedingly rare, cervical artery dissections (CeAD) have been reported in association with ADPKD. The aim of this retrospective observational study is to investigate clinical features in patients with ADPKD that increase the probability of an associated CeAD diagnosis. Materials and Methods: The National Inpatient Sample from 2016 to 2020 was utilized to compare clinical features for patients with an ICD-10 code diagnosis of ADPKD, CeAD, and both ADPKD and CeAD. The Cochran–Armitage test and Chi-square test were utilized to assess clinical features or trends in ADPKD patients associated with a concurrent CeAD diagnosis. Results: Between 2016 and 2020, there were 224,065 people with ADPKD, 86,135 with CeAD and 155 with both (0.05%). The total cohort had a mean age of 56.74 years, with 47.26% female participants (p = 0.70), and was predominantly white (66.15%, p < 0.001). In patients with ADPKD, comorbid acute ischemic stroke (p < 0.001), transient ischemic attack (p < 0.001), aortic dissection (p < 0.001), coronary artery dissection (p < 0.001), subarachnoid hemorrhage (p < 0.001), coagulation defects (p = 0.002), and hypertension (p < 0.001) are risk factors associated with an increased probability of concomitant CeAD. Conclusions: CeAD in ADPKD patients is rare. In ADPKD patients, acute ischemic stroke, transient ischemic attack, aortic dissection, coronary artery dissection, subarachnoid hemorrhage, coagulation defects, and hypertension are risk factors of concomitant CeAD. Recognizing these factors can aid in the decision to screen for concomitant CeAD in patients with ADPKD.