Memorability of Novel Words Correlates With Anterior Fusiform Activity During Reading

Our memory for the words we already know is best predicted by their associated meanings. However, the factors that influence whether we will remember a new word after we see it for the first time are unclear. We record memory performance for 2100 novel pseudowords across 1804 participants during a continuous recognition task. Participants show significant agreement across individuals for which novel words were memorable or forgettable, suggesting an intrinsic memorability for individual pseudowords. Pseudowords that are similar to low-frequency known words, with sparse orthographic neighbourhoods and rarely occurring letter pairs, are more memorable. Further, using intracranial recordings in 36 epilepsy patients we show a region in the anterior fusiform cortex that shows sensitivity to the memorability of these pseudowords. These results suggest that known words in our lexicon act as a scaffold for remembering novel word forms, with rare and unique known words providing the best support for novel word learning

Cat: A Conditional Association Test for Microbiome Data Using a Permutation Approach

In microbiome analysis, researchers often seek to identify taxonomic features associated with an outcome of interest. However, microbiome features are intercorrelated and linked by phylogenetic relationships, making it challenging to assess the association between an individual feature and an outcome. This paper proposes a novel conditional association test, CAT, that can account for other features and phylogenetic relatedness when testing the association between a feature and an outcome. CAT adopts a permutation approach, measuring the importance of a feature in predicting the outcome by permuting operational taxonomic unit/amplicon sequence variant counts belonging to that feature from the data and quantifying how much the association with the outcome is weakened through the change in the coefficient of determination $R^{2}$. Compared with marginal association tests, it focuses on the added value of a feature in explaining outcome variation that is not captured by other features. By leveraging global tests including PERMANOVA and MiRKAT-based methods, CAT allows association testing for continuous, binary, categorical, count, survival, and correlated outcomes. We demonstrate through simulation studies that CAT can provide a direct quantification of feature importance that is distinct from that of marginal association tests, and illustrate CAT with applications to two real-world studies on the microbiome in melanoma patients: one examining the role of the microbiome in shaping immunotherapy response, and one investigating the association between the microbiome and survival outcomes. Our results illustrate the potential of CAT to inform the design of microbiome interventions aimed at improving clinical outcomes

Anti-Viral CD8 Central Memory Veto Cells as a New Platform for Car T Cell Therapy

Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that these cells could offer an attractive platform for CAR cell therapy, we evaluated methodologies for their effective transduction with 2 retroviral vectors. Initially, a vector directed against Her2 was tested and optimal transduction was attained at day 5 of culture. The transduced cells were expanded for an additional 7 days and exhibited marked anti-tumor reactivity ex-vivo while retaining their veto activity. Transduction with a vector directed at CD19 was effectively attained at days 4-5 allowing for substantial harvest of transduced cells at day 12 of culture. These Veto-CD19CAR central memory CD8 T cells exhibited marked anti-tumor reactivity in-vitro and in-vivo without GVHD, measured following transplantation into immune-deficient mice. These results strongly suggest that Veto-CAR T cells offer an attractive platform for CAR T cell therapy without gene editing for addressing the risk of GVHD or graft rejection

Spontaneous Tumor Regression and Immunotherapy Response Demonstrate Clonal T-Cell Expansion in Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that is responsive to immune checkpoint inhibitors (ICI). On rare occasion, MCC spontaneously regresses. It is speculated that this regression occurs when biopsy-induced antigen shedding precipitates an immune response. Here, we demonstrate the activation of an adaptive immune response in a patient whose tumor underwent spontaneous regression after biopsy. To evaluate the tumor immune microenvironment during regression, we performed quantitative immunohistochemical analysis and T-cell receptor (TCR) sequencing. Relative to baseline, the regressing tumor showed evidence of an activated cytotoxic T-cell response together with increased TCR clonality, greater representation of dominant T-cell clones, and the emergence of novel high-frequency T-cell clones. Similar changes in TCR profiles were observed in an MCC tumor undergoing ICI-induced regression. Taken together, our results provide evidence that the expansion of novel and pre-existing adaptive immune responses drives spontaneous MCC regression

Overcoming Nk-Mediated Rejection by Anti-3rd-Party Central Memory Veto CD8 T Cells Through Downregulation of Dnam-1 on Alloreactive Nk Cells

Anti-3rd-party central memory veto CD8 T (veto Tcm) cells can overcome T cell-mediated graft rejection under mild conditioning without causing significant graft versus host disease (GVHD). We previously demonstrated that these veto Tcm cells can effectively delete anti-donor T cell clones through a Fas-FasL mechanism, whereas their ability to neutralize alloreactive natural killer (NK) cells and the mechanism of such potential activity remained unknown. Using “nude” mice as recipients of allogeneic T cell-depleted hematopoietic stem cell transplantation (HSCT), we demonstrate effective inhibition of NK-mediated rejection by Tcm cells. Ex vivo studies revealed that Tcm cells express high levels of CD155, the ligand of the activating receptor DNAX accessory molecule-1 (DNAM-1). Conjugate formation between alloreactive NK cells and the veto cells induces NK anergy through a unique mechanism mediated by DNAM-1 internalization and degradation. These insights on veto Tcm cells and their impact on alloreactive NK cells offer potential translational approaches for haploidentical bone marrow transplantation and off-the-shelf chimeric antigen receptor (CAR) cell therapies

Analyzing Pain Patterns in Stroke Survivors in Outpatient Clinics: A Retrospective, Cross-Sectional, Observational Study

Background: Pain is one of the most common sequelae after a stroke. Yet it is under-recognized, under-treated, and under-investigated, with no standard care guidelines for management during post-stroke recovery. Purpose: The primary objective of this study was to capture the prevalence of pain and different pain types in stroke survivors. Patients and methods: The study included stroke survivors who completed a pre-visit telehealth review of systems instrument between March 1, 2020, and February 28, 2022. 442 out-patient subjects were identified and matched to their respective electronic health record from the incident stroke. Subjects were divided into pain and no-pain groups based on self-report of post-stroke pain. Bivariate analyses were performed to test the association between the patient\u27s demographic and clinical characteristics and pain using t-tests or Wilcoxon rank sum tests for continuous variables and chi-square tests for categorical variables. Random forest imputation was used to address missing values. Multivariable analysis was performed using the logistic regression method. Results: Of the 442 subjects, 58% (N=258) reported pain, with 56% experiencing multiple pain types. Musculoskeletal pain (36%), Neuropathic pain (22%), and Headaches (17%) were the most common pain types. Only 20% of patients reporting pain used analgesics, with gabapentin (43%) and opioids (11%) being the most common prescriptions. Obstructive sleep apnea (OSA), history of recreational drug use, and gender showed a significant relationship with pain in univariate analysis. In the final logistic regression model, OSA (OR: 3.37, 95% CI: 1.34-9.80, p: 0.015) and history of recreational drug use (OR: 2.05, 95% CI: 1.16-3.83, p: 0.018) remained significant. The model achieved moderate discrimination with an AUC of 0.62. Conclusion: Over half of stroke survivors experienced pain, with 30% reporting multiple pain types. The low rate of analgesic use (20%) and significant proportion of patients experiencing pain highlight the critical need for evidence-based pain management guidelines in post-stroke care

AI/ML-Empowered Approaches for Predicting T Cell-Mediated Immunity and Beyond

T cells play a dual role in various physiopathological states, capable of eliminating tumors and infected cells, while also playing a pathogenic role when activated by autoantigens, causing self-tissue damage. The regulation of T cell-peptide/major histocompatibility complex (TCR-pMHC) recognition is crucial for maintaining disease balance and treating cancer, infections, and autoimmune diseases. Despite efforts, predictive models of TCR-pMHC specificity are still in the early stages. Inspired by advances in protein structure prediction via deep neural networks, we evaluated AlphaFold 3 (AF3)-based AI computation as a method to predict TCR epitope specificity. We demonstrate that AlphaFold can model TCR-pMHC interactions, distinguishing valid epitopes from invalid ones with increasing accuracy. Immunogenic epitopes can be identified for vaccine development through in silico high-throughput processes. Additionally, higher-affinity and specific T cells can be designed to enhance therapy efficacy and safety. An accurate TCR-pMHC prediction model is expected to greatly benefit T-cell-mediated immunotherapy and aid drug design. Overall, precise prediction of T-cell immunogenicity holds significant therapeutic potential, allowing the identification of peptide epitopes linked to tumors, infections, and autoimmune diseases. Although there is much work to be done before these predictions achieve widespread practical use, we are optimistic that deep learning-based structural modeling is a promising pathway for the generalizable prediction of TCR-pMHC interactions

Provider Attitudes and Perspectives on Rehabilitation for Pediatric Cancer Patients

PurposeTwenty percent of childhood cancer survivors experience physical function impairments, and ∼75% develop a chronic health condition. Physical and occupational therapists (PT/OTs) can mitigate these late effects, yet few children receive cancer rehabilitation (CR). This research aimed to identify provider attitudes and perspectives towards CR services for children across inpatient and outpatient settings at a cancer center.MethodsThree cardiac rehabilitation instruments were adapted to evaluate knowledge, attitudes, and perceptions regarding CR delivery. Descriptive statistics were used to summarize participant survey results.ResultsTwenty administrators, 20 physicians/advanced practice providers (APPs), and 20 PT/OTs completed surveys. All disciplines strongly agreed on the value of CR for patient outcomes and care quality. Barriers to CR access included insurance models that disincentivize healthcare systems from providing CR, lack of a standardized screening and referral process, and inconsistent patient participation. Physicians/APPs (81%) endorsed clinical practice guidelines (CPGs) to promote CR referrals, and 90% of PT/OTs agreed hybrid CR delivery, which includes both supervised and unsupervised exercise, would increase patient participation.ConclusionThis study identified opportunities to increase CR access for childhood cancer survivors, including CPGs, streamlining referral processes, hybrid CR delivery, and closing insurance gaps. Future research should address these factors to improve CR access and ultimately improve outcomes for pediatric survivors

Bayesian Inference of Fitness Landscapes via Tree-Structured Branching Processes

Motivation: The complex dynamics of cancer evolution, driven by mutation and selection, underlies the molecular heterogeneity observed in tumors. The evolutionary histories of tumors of different patients can be encoded as mutation trees and reconstructed in high resolution from single-cell sequencing data, offering crucial insights for studying fitness effects of and epistasis among mutations. Existing models, however, either fail to separate mutation and selection or neglect the evolutionary histories encoded by the tumor phylogenetic trees. Results: We introduce FiTree, a tree-structured multi-type branching process model with epistatic fitness parameterization and a Bayesian inference scheme to learn fitness landscapes from single-cell tumor mutation trees. Through simulations, we demonstrate that FiTree outperforms state-of-the-art methods in inferring the fitness landscape underlying tumor evolution. Applying FiTree to a single-cell acute myeloid leukemia dataset, we identify epistatic fitness effects consistent with known biological findings and quantify uncertainty in predicting future mutational events. The new model unifies probabilistic graphical models of cancer progression with population genetics, offering a principled framework for understanding tumor evolution and informing therapeutic strategies

Summary of Research: Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02

of the original article, \u27Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02\u27. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate, which is a chemotherapy with a linker (deruxtecan) joined to an antibody (trastuzumab). Trastuzumab binds to the human epidermal growth factor receptor 2 (HER2) protein on cancer cells, where it releases the chemotherapy to kill these cells. The DESTINY-PanTumor02 clinical study tested the effectiveness of T-DXd for people with various HER2-expressing cancers and the safety of treatment. Previous results from DESTINY-PanTumor02 showed that T-DXd had antitumor activity, and the greatest effects were seen in people with the highest tumor level of HER2 [defined as immunohistochemistry (IHC) 3+]. In this previous analysis, the HER2 expression was measured at a central laboratory. In clinical practice, HER2 expression will likely be measured at a local laboratory, so understanding whether T-DXd has similar effects regardless of how HER2 expression is measured is important. Here, we looked at the effects of T-DXd based on the HER2 test result used to determine a person\u27s eligibility for the study, which could be measured using a local or central laboratory. In people with IHC 3+ tumors (where HER2 was measured at a local or central laboratory), 51% had a decrease in the size or number of tumors, according to established criteria (referred to as an objective response), while, in people with IHC 2+ tumors, 26% had an objective response. Side effects with T-DXd were consistent with previous studies. These results confirm T-DXd has antitumor effects in HER2-expressing cancers where the HER2 expression is measured by a local or central laboratory