Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.

Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.

How I treat unique and difficult-to-manage cases of CAR T-cell therapy-associated neurotoxicity.

With growing indications for chimeric antigen receptor (CAR) T-cell therapy, toxicity profiles are evolving. There is an urgent and unmet need of approaches to optimally manage emerging adverse events that extend beyond the standard paradigm of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). Although management guidelines exist for ICANS, there is little guidance on how to approach patients with neurologic comorbidities, and how to manage rare neurotoxicity presentations, such as CAR T-cell therapy-related cerebral edema, severe motor complications or late-onset neurotoxicity. In this study, we present 3 scenarios of patients treated with CAR T cells who develop unique types of neurotoxicity, and we describe an approach for the evaluation and management based on experience because objective data are limited. The goal of this study is to develop an awareness of emerging and unusual complications, discuss treatment approaches, and help institutions and health care providers establish frameworks to navigate how to best address unusual neurotoxicities to ultimately improve patient outcomes.

mRNA-based therapeutic strategies for cancer treatment.

In the rapidly evolving landscape of medical research, the emergence of RNA-based therapeutics is paradigm shifting. It is mainly driven by the molecular adaptability and capacity to provide precision in targeting. The coronavirus disease 2019 pandemic crisis underscored the effectiveness of the mRNA therapeutic development platform and brought it to the forefront of RNA-based interventions. These RNA-based therapeutic approaches can reshape gene expression, manipulate cellular functions, and correct the aberrant molecular processes underlying various diseases. The new technologies hold the potential to engineer and deliver tailored therapeutic agents to tackle genetic disorders, cancers, and infectious diseases in a highly personalized and precisely tuned manner. The review discusses the most recent advancements in the field of mRNA therapeutics for cancer treatment, with a focus on the features of the most utilized RNA-based therapeutic interventions, current pre-clinical and clinical developments, and the remaining challenges in delivery strategies, effectiveness, and safety considerations.

Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma.

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades Narginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib by increasing: 1) killing of human MM cells by stimulating both bortezomib mediated apoptosis and necroptosis, a process regulated by p62; and 2) preservation of bone mass by stimulating osteoblasts differentiation and inhibiting osteoclastic bone destruction. Co-administration of bortezomib and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, coadministration of bortezomib and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti-MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.

The Effect of Varied Microperimetric Biofeedback Training in Central Vision Loss: A Randomized Trial.

SIGNIFICANCE: This investigation reports for the first time the effects of different microperimetric biofeedback strategies in visually impaired subjects with central field loss. PURPOSE: This study aimed to evaluate the effects of two MP-3 microperimeter biofeedback strategies on the visual performance of subjects with central vision loss. Moreover, changes between the groups were compared to provide indications of practice with biofeedback stimulation in subjects with central vision loss. METHODS: Using simple randomization, 19 participants were trained according to two different biofeedback stimulation approaches using the MP-3 microperimeter. Patients were assigned to two different groups: subjects trained for 2 days a week (group A) and 3 days a week (group B). The patients in each group were randomized to perform a total of 10 or 15 sessions. RESULTS: Fixation stability increased from 4.5 ± 2.8 to 2.3 ± 2.2° 2 and from 8.2 ± 6.9 to 1.4 ± 1° 2 after 2 and 3 weekly biofeedback training sessions, respectively ( P < .05). Biofeedback training induced a significant improvement of 40.7 and 29.4% in reading speed for groups A and B, respectively ( P < .05). A comparison of two weekly biofeedback training sessions with three weekly biofeedback sessions demonstrated greater fixation stability in group B ( P < .05). CONCLUSIONS: This study concludes that a biofeedback intervention is effective in enhancing oculomotor control in patients with central vision loss. In our study, a more intensive biofeedback strategy seemed to produce significantly better results in terms of functional vision parameters.

Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.

Efficacy and Patients' Satisfaction with the ORCAM MyEye Device Among Visually Impaired People: A Multicenter Study.

To evaluate usability of and satisfaction with OrCam MyEye, a finger-size wearable assistive technology device for visually impaired during real-world tasks. This prospective multicenter study was conducted on visually impaired people recruited from 5 vision rehabilitation centers. Patients performed real-world tasks such as near and distance reading, money handling, colour identification and face recognition in 2 different scenarios: without using any low vision aid and with OrCam. System Usability Scale (SUS), Patient's Global Impression of Change (PGIC), the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0) and the Psychosocial Impact of Assistive Devices Scale (PIADS) were administered after the use of the OrCam device. Among the 100 participants, use of OrCam MyEye device improved many daily-living tasks (F = 1.67, P < .05), and in particular reading and face recognition. Multivariate logistic regression showed that age and visual field defect explained 89% of the variation in efficacy of the device. Nearly half (45%) of the participants indicated a positive rating with the SUS. The PGIC rates showed a minimal improvement with a mean score of 4.2 (SD:1.8). The most highlighted parameter with the QUEST 2.0 test was "ease of use" in 58% (48 subjects). The PIADS indicator showed that the device positively impacted on the daily-living tasks of users (r2 = 0.72, P < .05). Regression modelling demonstrated a good relation between the questionnaires scores and demographic, disease and visual factors (P < .05). OrCam MyEye allowed visually impaired people to read, handle money and face recognition independently. This device may offer to these subjects to be independent.

Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML.

Biofeedback stimulation in the visually impaired: a systematic review of literature.

BACKGROUND: It is estimated that approximately 1.3 billion people live with some form of distance or near visual impairment. Numerous studies have been carried out to evaluate the effects of biofeedback (BF) and establish if it could be a useful tool in vision rehabilitation for various eye diseases. OBJECTIVE: This systematic review aimed: 1) to examine the current evidence of BF efficacy for the rehabilitation of the visually impaired and 2) to describe methodological variations used in previous BF studies to provide recommendations for vision rehabilitation interventions. METHODS: A systematic review was conducted in the Medline, PubMed, Cochrane Library and Web of Science databases to collect documents published between January 2000 and May 2020. Of the 1,960 studies identified, 43 met the criteria for inclusion. The following information was collected from each study: sample size, control group, any eye disease, apparatus used, frequency and number of sessions of BF, main outcomes of training and whether a follow-up was conducted. The first group included studies published as scientific articles in peer-reviewed journals. The second group included abstracts of studies presented at peer-reviewed conferences. Publications were also grouped according to the eye disease treated. RESULTS: 25 articles and 18 peer-reviewed conference abstracts (PRCAs) were included in this review. BF stimulation is a commonly used technique for the treatment of visual impairment caused by macular disease. Most BF studies evaluate the effect of training on the preferred retinal locus (PRL), particularly with regard to fixation location and stability. Across these studies, participants who received BF intervention improved fixation stability and reading speed. High variability in the number of sessions and the duration of BF training was found. Most studies did not use a control group. CONCLUSIONS: The findings of this review present evidence for biofeedback treatment in vision rehabilitation, with improved oculomotor abilities. Currently, it is not possible to formulate evidence-based recommendations for a standard training procedure due to the poor quality of existing randomised controlled trials. High-quality studies are needed to develop standard protocols for a range of eye diseases.

Epidemiological Surveillance of Eye Disease and People Awareness in the Abruzzo Region, Italy.

Background and Objectives: Vision impairments and related blindness are major public health problems. The prevalence of eye disease and barriers to optimal care markedly vary among different geographic areas. In the Abruzzo region (central Italy), an epidemiological surveillance on the state of ocular health in the population aged over 50 years was performed in 2019. Materials and Methods: Participants were sampled to be representative of the region's inhabitants. Data were collected through a telephone interview and an eye examination. Prevalence of cataract, glaucoma, retinopathy, and maculopathy was assessed. The Cohen's kappa (k) was used to measure the agreement between the presence of eye disease and awareness of the disease by the participants. Results: Overall, 983 people with a mean age of 66.0 ± 9.5 years were included in the study. The prevalence of cataracts, glaucoma, maculopathy, and retinopathy was 52.6%, 5.3%, 5.6%, and 29.1%, respectively. Among the total of the affected people, those aware of their condition were 21.8% (k = 0.12, slight agreement) for cataract, 65.4% (k = 0.78, substantial agreement) for glaucoma, 7.1% (k = 0.10, slight agreement) for maculopathy, and 0% for retinopathy (k = -0.004, agreement lower than that expected by chance). Refractive defects were corrected in the vast majority of participants. Conclusion: In the Abruzzo region, about two thirds of citizens aged 50 years or over suffer from cataract, glaucoma, retinopathy, or maculopathy, which are recognized as leading causes of blindness. Many people with eye disease do not know they have it. These data can be used by clinicians and policymakers to undertake clinical, political, and social actions.

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results.

Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/µL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 µg/kg and 240 µg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated ß2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. Clinicaltrials.gov identifier: NCT02193191.

Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma.

BACKGROUND: Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established. METHODS: In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation. RESULTS: Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb- patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine. DISCUSSION: This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation.

CAR T cell Toxicities: Bedside to Bench - How Novel Toxicities Inform Laboratory Investigations.

Multiple chimeric antigen receptor (CAR) T cell therapies are FDA approved, and several are under development. While effective for some cancers, toxicities remain a limitation. The most common toxicities, i.e. cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), are well described. With increasing utilization, providers worldwide are reporting on other emergent, and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalogue these emerging and emergent CAR T toxicities and describe management approaches, the American Society of Hematology Subcommittee on Emerging Gene and Cell Therapies organized the first Scientific Workshop on CAR T cell toxicities during the annual society meeting. The workshop functioned to 1) aggregate reports of CAR T emergent toxicities, including movement disorders after BCMA CAR T, coagulation abnormalities, and prolonged cytopenias; 2) disseminate bedside to bench efforts elucidating pathophysiological mechanisms of CAR-T toxicities, including the intestinal microbiota and systemic immune dysregulation; and 3) highlight gaps in the availability of clinical tests such as cytokine measurements, which could be utilized to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, while clinical manifestations may develop before the pathophysiologic mechanisms are understood, these must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears central to these emergent toxicities and research is needed to elucidate links between tumor, CAR T, and microbiota. Finally, there was consensus around an urgency to create a repository to capture emergent CAR-T toxicities and the real-world management.

Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.

Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition.