Peripheral T-cell lymphoma: From biology to practice to the future.

Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research.

The who and the where: Attention to identities and locations in groups.

While it is widely accepted that the single gaze of another person elicits shifts of attention, there is limited work on the effects of multiple gazes on attention, despite real-world social cues often occurring in groups. Further, less is known regarding the role of unequal reliability of varying social and nonsocial information on attention. We addressed these gaps by employing a variant of the gaze cueing paradigm, simultaneously presenting participants with three faces. Block-wise, we manipulated whether one face (Identity condition) or one location (Location condition) contained a gaze cue entirely predictive of target location; all other cues were uninformative. Across trials, we manipulated the number of valid cues (number of faces gazing at target). We examined whether these two types of information (Identity vs. Location) were learned at a similar rate by statistically modelling cueing effects by trial count. Preregistered analyses returned no evidence for an interaction between condition, number of valid faces, and presence of the predictive element, indicating type of information did not affect participants' ability to employ the predictive element to alter behaviour. Exploratory analyses demonstrated (i) response times (RT) decreased faster across trials for the Identity compared with Location condition, with greater decreases when the predictive element was present versus absent, (ii) RTs decreased across trials for the Location condition only when it was completed first, and (iii) social competence altered RTs across conditions and trial number. Our work demonstrates a nuanced relationship between cue utility, condition type, and social competence on group cueing.

Treatment Patterns and Outcomes in U.S. Military Veterans Diagnosed With Chronic Lymphocytic Leukemia (CLL).

INTRODUCTION: U.S. veterans in the Veterans Affairs (VA) Healthcare System are managed in a national single-payer system with access to FDA-approved therapies. Prescribing patterns and outcomes of patients with CLL manage in the VA system are described. PATIENTS AND METHODS: This is a retrospective analysis of adult patients diagnosed with CLL managed in the VA from January 1999 through December 2020. First line treatment patterns are trended over 20 years. Factors associated with survival were analyzed in both untreated and treated patients. RESULTS: In the final analysis, 16,331 patients with CLL were included. The median overall survival (OS) for the whole cohort was 8.7 years (95% confidence interval [CI], 8.6-8.9). The median OS from diagnosis was 8.9 years (95% CI, 8.6-9.2 in untreated patients with CLL. In treated patients, the median time to first line treatment was 1.9 years (range, 0-21 years), and the median OS from initiation of treatment was 5.0 years (95% CI, 4.8-5.2). First line treatments varied over time, consistent with FDA approval of targeted therapies. Exposure to targeted therapies as either first line or in subsequent lines of therapy was associated longer survival: median OS of 8.5 years (95% CI, 8.0-9.1) compared to 3.5 years (95% CI, 3.5-3.9) in patients who never received targeted therapy (P < .0001). CONCLUSION: Patients treated in the VA have received therapies in line with current evidence-based treatment practices over the past 20 years. Treatment with targeted therapies is associated with longer median OS both in the first line and relapsed/refractory setting.

Mature T-cell and NK-cell lymphoma involvement of the central nervous system: a single center experience.

Mature T-cell and NK-cell lymphomas (MTNKL) are rare and heterogeneous lymphoproliferative disorders with poor clinical outcomes despite novel therapeutic advances. Although infrequent, central nervous system (CNS) involvement by MTNKL is associated with poor outcomes with a median overall survival (OS) of <12 months based on retrospective studies. We performed a retrospective analysis of patients who developed CNS involvement of MTNKL diagnosed at a single center from 1999 through 2020. Twenty-five patients were identified. Characteristics such as a diagnosis of adult T-cell leukemia/lymphoma, extranodal involvement, and poor performance status were associated with a higher risk of CNS involvement (p < 0.01). The median OS after diagnosis with CNS involvement was approximately 1 month (0.03-103.97 months). Patients exposed to novel therapeutics and/or clinical trial enrollment tolerated treatment without safety concerns and appeared to derive reasonable therapeutic benefit. Despite advances in the field, new therapeutic approaches are needed for patients with MTNKL with CNS involvement.

You read my mind: Generating and minimizing intention uncertainty under different social contexts in a two-player online game.

We investigate an ecologically pertinent form of social uncertainty regarding the ability to read another's intentions. We use classic measures (response time, accuracy) and dynamic measures (mouse trajectories) to investigate how people generate or minimize uncertainty regarding their own intentions under different social contexts, and how uncertainty regarding other's intentions affects decision making. Ninety-six participants (N = 48 dyads) completed a two-player online card game, where the goal was to collect cards with a certain feature (e.g., triangles), with participant cursor movements projected to both players. Participants played six games, three cooperatively and three competitively (Social Decision Context). Points were awarded for two decisions: collecting a card matching one's goal (ability to achieve personal goal) and correctly guessing the other player's goal (ability to guess intention). Data revealed: (a) Card scores did not vary with Social Decision Context, (b) Guess scores did vary with Social Decision Context, with more correct guesses when cooperating compared to competing, and (c) Mouse trajectories (durations and mouse distance traveled) decreased when cooperating compared to competing. These results indicate that better guessing during cooperative play is not due to explicit communication (i.e., circling desired cards), but may be due to increased speed and confidence when making decisions in a cooperative context. Additionally, participants could be actively hiding their intention in a competitive context. Thus, social uncertainty when reading another's intentions is both adaptive-affected by the prescribed social context, and automatic-indirectly inferred from the way another moves their mouse when acting with intention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Embodying cognitive ethology.

Cognitive psychology considers the environment as providing information, not affecting fundamental information processes. Thus, cognitive psychology's traditional paradigms study responses to precisely timed stimuli in controlled environments. However, new research demonstrates the environment does influence cognitive processes and offers cognitive psychology new methods. The authors examine one such proposal: cognitive ethology. Cognitive ethology improves cognitive psychology's ecological validity through first drawing inspiration from robust phenomena in the real world, then moving into the lab to test those phenomena. To support such methods, cognitive ethologists appeal to embodied cognition, or 4E cognition, for its rich relationships between agents and environments. However, the authors note while cognitive ethology focuses on new methods (epistemology) inspired by embodied cognition, it preserves most traditional assumptions about cognitive processes (ontology). But embodied cognition-particularly its radical variants-also provides strong ontological challenges to cognitive psychology, which work against cognitive ethology. The authors argue cognitive ethology should align with the ontology of less radical embodied cognition, which produces epistemological implications, offering alternative methodologies. For example, cognitive ethology can explore differences between real-world and lab studies to fully understand how cognition depends on environments.

How Do Artificial Neural Networks Classify Musical Triads? A Case Study in Eluding Bonini's Paradox.

How might artificial neural networks (ANNs) inform cognitive science? Often cognitive scientists use ANNs but do not examine their internal structures. In this paper, we use ANNs to explore how cognition might represent musical properties. We train ANNs to classify musical chords, and we interpret network structure to determine what representations ANNs discover and use. We find connection weights between input units and hidden units can be described using Fourier phase spaces, a representation studied in musical set theory. We find the total signal coming through these weighted connection weights is a measure of the similarity between two Fourier structures: the structure of the hidden unit's weights and the structure of the stimulus. This is surprising because neither of these Fourier structures is computed by the hidden unit. We then show how output units use such similarity measures to classify chords. However, we also find different types of units-units that use different activation functions-use this similarity measure very differently. This result, combined with other findings, indicates that while our networks are related to the Fourier analysis of musical sets, they do not perform Fourier analyses of the kind usually described in musical set theory. Our results show Fourier representations of music are not limited to musical set theory. Our results also suggest how cognitive psychologists might explore Fourier representations in musical cognition. Critically, such theoretical and empirical implications require researchers to understand how network structure converts stimuli into responses.

How we approach the perioperative management of patients with chronic lymphocytic leukaemia receiving continuous cancer-directed therapies.

Historically, invasive procedures and surgeries were deferred in patients with haematological malignancies including advanced stage chronic lymphocytic leukaemia (CLL) because of limited life expectancy. However, novel, and often continuous, treatments have markedly improved outcomes in CLL. Some patients may expect years of treatment response and disease control, overcoming the short life expectancy that deters interventionalists. Such patients now often undergo various invasive procedures including major surgery. To inform peri-operative management, we summarize the relevant side effects and drug interactions of continuous CLL therapies, highlight potential surgical risks, and provide recommendations on withholding specific CLL drugs around invasive procedures.

Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia.

BACKGROUND: A recent breakthrough therapy combining the BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long-term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL-2 or DNA methyltransferase modulates AML T-cell immunity. METHODS: By using flow cytometry and time-of-flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL-2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a clinical trial. The authors investigated the response of programmed cell death protein 1 (PD-1) inhibition in the DAC/VEN-treated samples in vitro and investigated the triple combination of PD-1 inhibition with HMA/venetoclax in the trial patients who had AML. RESULTS: DAC/VEN therapy effectively targeted leukemia cells and upregulated the expression of the immune checkpoint-inhibitory receptor PD-1 in T cells while preserving CD4-positive and CD8-positive memory T cells in a subset of patients with AML who were tested. In vitro PD-1 inhibition potentiated the antileukemia response in DAC/VEN-treated AML samples. The combined use of azacitidine, venetoclax, and nivolumab eliminated circulating blasts and leukemia stem cells/progenitor cells and expanded the percentage of CD8-positive memory T cells in an illustrative patient with relapsed AML who responded to the regimen in an ongoing clinical trial. CONCLUSIONS: Immunomodulation by targeting PD-1 enhances the therapeutic effect of combining an HMA and venetoclax in patients with AML.

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.

Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.

Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.

Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival, and they continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of expression of mitochondrial DNA and generation of mitochondrial reactive oxygen species indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, inhibition of OxPhos induced transfer of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via tunneling nanotubes under direct-contact coculture conditions. Inhibition of OxPhos also induced mitochondrial fission and increased functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, so we used electron microscopy to observe mitochondrial transport to the leading edge of protrusions of AML cells migrating toward MSCs. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased mitochondrial transfer of MSCs to AML cells triggered by OxPhos inhibition. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

Management of Angioimmunoblastic T-Cell Lymphoma (AITL) and other T Follicular Helper Cell lymphomas (TFH PTCL).

Despite the remarkable improvements in the treatment and outcome of patients with aggressive B-cell lymphoma, the peripheral T-cell lymphomas (PTCL) continue to carry a poor prognosis with the presently available treatment options. The PTCL are very rare diseases that account for only 10,000 to 15,000 new cases per year in the United States. The World Health Organization's 2016 classification describes 29 distinct subtypes of PTCL, thus making these both rate and incredibly heterogenous. The 2 most common forms of PTCL, for example, peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma , have an incidence of only 2500 and 1800 cases per year respectively, in the United States.