Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Racial and Ethnic Differences in Social Determinants of Health and Health-Related Social Needs Among Adults - Behavioral Risk Factor Surveillance System, United States, 2022.

Social determinants of health (SDOH) are a broad array of social and contextual conditions where persons are born, live, learn, work, play, worship, and age that influence their physical and mental wellbeing and quality of life. Using 2022 Behavioral Risk Factor Surveillance System data, this study assessed measures of adverse SDOH and health-related social needs (HRSN) among U.S. adult populations. Measures included life satisfaction, social and emotional support, social isolation or loneliness, employment stability, food stability/security, housing stability/security, utility stability/security, transportation access, mental well-being, and health care access. Prevalence ratios were adjusted for age, sex, education, marital status, income, and self-rated health. Social isolation or loneliness (31.9%) and lack of social and emotional support (24.8%) were the most commonly reported measures, both of which were more prevalent among non-Hispanic (NH) American Indian or Alaska Native, NH Black or African American, NH Native Hawaiian or other Pacific Islander, NH multiracial, and Hispanic or Latino adults than among NH White adults. The majority of prevalence estimates for other adverse SDOH and HRSN were also higher across all other racial and ethnic groups (except for NH Asian) compared with NH White adults. SDOH and HRSN data can be used to monitor needed social and health resources in the U.S. population and help evaluate population-scale interventions.

The Development of Social Determinants of Health Outcome Measures: The Role of Multisector Partnerships and Community Validation.

PURPOSE: To develop a set of social determinants of health (SDOH) measurements. PROBLEM: Despite burgeoning interest in addressing both SDOH and health-related social needs, the evidence on what works is limited due in part to the lack of standardized measures for evaluation. METHODS: In 2020, the Centers for Disease Control and Prevention (CDC) National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) identified 5 SDOH domains related to chronic disease for future programmatic work. These included built environment, community connections to clinical care, tobacco-free policies, social connectedness, and food and nutrition security. Subsequently, NCCDPHP launched an effort to develop a set of SDOH measures for evaluating funded programs in these domains. The approach involved a literature scan and a rating process based on 5 criteria relevant to NCCDPHP's SDOH priorities. A complementary community review by 13 multisector community partnerships (MCPs) applied a real-world public health practice lens to measure development. MCPs' ratings were analyzed to create summary scores for each measure, and open-ended feedback was synthesized using rapid qualitative analysis. RESULTS: The internal workgroup identified 59 measures from the initial 200 measures. Feedback from the MCPs identified issues of relevancy and burden of measures. Their high scores narrowed the 59 measures to 22 covering all 5 domains. In response, CDC is honing the original measures review criteria to include community perspectives. CONCLUSION: Public health measures development is often an academic pursuit. Engaging MCPs lends real-world credibility to the development of common SDOH measures.

Sleep architecture of elite soccer players surrounding match days as measured by WHOOP straps.

This study aimed to quantify and compare sleep architecture before and after home and away matches in elite soccer players from the English Premier League. Across two seasons, 6 male players (age 28 ± 5 y; body mass 85.1 ± 9.5 kg; height 1.86 ± 0.09 m) wore WHOOP straps to monitor sleep across 13 matches that kicked off before 17:00 h. For each, sleep was recorded the night before (MD-1), after (MD) and following the match (MD +1). Across these 3 days total sleep time (TST), sleep efficiency (SE), sleep disturbances, wake time, light sleep, deep sleep, REM sleep, sleep and wake onsets, alongside external load, were compared. TST was reduced after MD versus MD +1 (392.9 ± 76.4 vs 459.1 ± 66.7 min, p = 0.003) but no differences existed in any other sleep variables between days (p > 0.05). TST did not differ after home (386.9 ± 75.7 min) vs. away matches (401.0 ± 78.3 min) (p = 0.475), nor did other sleep variables (p > 0.05). GPS-derived external load peaked on MD (p < 0.05). In conclusion, despite reduced TST on MD, sleep architecture was unaffected after matches played before 17:00 h, suggesting sleep quality was not significantly compromised.

Effects of negative dietary cation-anion difference and calcidiol supplementation in transition diets fed to sows on piglet survival, piglet weight, and sow metabolism.

Diets that provide a negative dietary anion cation difference (DCAD) and supplement with a vitamin D metabolite 25-OH-D3 (calcidiol) may increase calcium availability at parturition, and enhance piglet survival and performance. This factorial study assessed the effects of DCAD, calcidiol (50 µg/kg), and parity (parity 1 or >1) and their interactions. Large White and Landrace sows (n = 328), parity 1 to 8 were randomly allocated in blocks to treatment diets from day 103 of gestation until day 3 postfarrow: 1) negative DCAD without calcidiol (negative DCAD + no CA), n = 84, 2) negative DCAD with calcidiol (negative DCAD + CA) n = 84, 3) positive DCAD without calcidiol (negative DCAD + no CA), n = 81, and 4) positive DCAD with calcidiol (positive DCAD + CA), n = 79. Negative DCAD diets were acidified with an anionic feed (2 kg/t) and magnesium sulfate (2 kg/t). All treatment diets contained cholecalciferol at 1,000 IU/kg. Dry sow diets contained 14.8% crude protein (CP), 5.4% crude fiber (CF), 0.8% Ca, and 83 mEq/kg DCAD. Treatment diets 1 and 2 contained 17.5% CP, 7.3% CF, 0.8% Ca, and -2 mEq/kg DCAD. Treatment diets 3 and 4 contained 17.4% CP, 7.4% CF, 0.8% Ca, and 68 mEq/kg DCAD. Before farrowing, all negative DCAD sows had lower urine pH than all sows fed a positive DCAD (5.66 ± 0.05 and 6.29 ± 0.05, respectively; P < 0.01); urinary pH was acidified for both DCAD treatments indicating metabolic acidification. The percentage of sows with stillborn piglets was not affected by DCAD, calcidiol, or parity alone but sows fed the negative DCAD + CA diet had a 28% reduction in odds of stillbirth compared to the negative DCAD + no CA diet and even lesser odds to the positive DCAD + CA diet. At day 1 after farrowing, blood gas, and mineral and metabolite concentrations were consistent with feeding a negative DCAD diet and that negative DCAD diets influence energy metabolism, as indicated by increased glucose, cholesterol, and osteocalcin concentrations and reduced nonesterified free fatty acids and 3-hydroxybutyrate concentrations. In the subsequent litter, total piglets born and born alive (14.7 ± 0.3 and 13.8 ± 0.3 piglets, respectively; P = 0.029) was greater for positive DCAD diets compared to negative DCAD diets; and there was an interaction between DCAD, calcidiol, and parity (P = 0.002). Feeding a negative DCAD diet influenced stillbirth, subsequent litter size, and metabolic responses at farrowing. More studies are needed to define optimal diets prefarrowing for sows.

The transition period between late gestation and lactation is critical to farrowing and successful lactation; sows with higher blood calcium have less risk of dystocia. We evaluated transition diets that provided a negative dietary cation­anion difference (DCAD) and supplemented with calcidiol (CA), both of which influence calcium metabolism. Purebred Landrace or Large White sows (n = 328) were enrolled in the experiment and selected sows that were either primiparous (n = 99) or multiparous (n = 229; average parity = 2.59 ± 1.51; parity range = 1 to 8) were fed a dry sow ration until day 103 of gestation and were then fed transition diets until day 3 postfarrowing in a factorial study. The diets were formulated to include 1) negative DCAD + no CA, 2) negative DCAD + CA, 3) positive DCAD + no CA, or 4) positive DCAD + CA. All diets induced a metabolic acidosis as indicated by urinary pH. Sows fed the negative DCAD with added calcidiol had a >28% reduction in odds of stillbirth over negative DCAD + no CA and positive DCAD + CA diets. Following weaning and re-mating, there were 0.9 more piglets born in the subsequent litter for both positive DCAD diets compared to negative DCAD diets. Blood gas, and mineral and metabolite concentrations provided evidence that negative DCAD diets positively influenced energy metabolism.

IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.

Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

A Database Tool Integrating Genomic and Pharmacologic Data from Adrenocortical Carcinoma (ACC) Cell Lines, PDX, and Patient Samples.

Adrenocortical carcinoma (ACC) is a rare and highly heterogeneous disease with a notably poor prognosis due to significant challenges in diagnosis and treatment. Emphasising on the importance of precision medicine, there is an increasing need for comprehensive genomic resources alongside well-developed experimental models to devise personalized therapeutic strategies. We present ACC_CellMinerCDB, a substantive genomic and drug sensitivity database (available at https://discover.nci.nih.gov/acc_cellminercdb) comprising ACC cell lines, patient-derived xenografts, surgical samples, combined with responses to over 2,400 drugs examined by NCI and NCATS. This database exposes shared genomic pathways among ACC cell lines and surgical samples, thus authenticating the cell lines as research models. It also allows exploration of pertinent treatment markers such as MDR-1, SOAT1, MGMT, MMR and SLFN11, and introduces the potential to repurpose agents like temozolomide for ACC therapy. ACC_CellMinerCDB provides the foundation for exploring larger preclinical ACC models.

PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma.

The hippo signaling pathway is a central tumor suppressor cascade frequently inactivated in selected human cancers, leading to the aberrant activation of TEAD transcription factors. Whereas several TEAD auto-palmitoylation inhibitors are currently in development, a comprehensive assessment of this novel drug-modality is missing. Here, we report a comparative analysis among six TEADi(s) using cell-based and biochemical assays in Hippo pathway deficient mesothelioma. Our analysis revealed varying potency and selectivity across TEADi, also highlighting their limited efficacy. To overcome this limitation, we performed an unbiased, quantitative high-throughput drug screening by combining the TEADi VT-103 with a library of approximately 3000 oncology-focused drugs. By exploiting this library's mechanistic redundancy, we identified several drug-classes robustly synergized with TEADi. These included glucocorticoid-receptor (GR) agonists, Mek1/2 inhibitors, mTOR inhibitors, and PI3K inhibitors, among others. Altogether, we report a coherent single-agent dataset informing on potency and selectivity of TEAD-palmitoylation inhibitors as single-agents. We also describe a rational pipeline enabling the systematic identification of TEAD druggable co-dependencies. This data should support the pre-clinical development of drug combination strategies for the treatment of Hippo-deficient mesothelioma, and more broadly, for other cancers dependent on the oncogenic activity of YAP/TEAD.

Leveraging Clinical Informatics to Address the Quintuple Aim for End-of-Life Care.

As the population of older adults grows at an unprecedented rate, there is a large gap to provide culturally tailored end-of-life care. This study describes a payor-led, informatics-based approach to identify Medicare members who may benefit from a Compassionate CareSM Program (CCP), which was designed to provide specialized care management services and support to members who have end-stage and/or life-limiting illnesses by addressing the quintuple aim. Potential participants are identified through machine learning models whereby nurse care managers then provide tailored outreach via telephone. A retrospective, observational cohort analysis of propensity-weighted Medicare members was performed to compare decedents who did or did not participate in the CCP. This program enhanced the end-of-life care experience while providing equitable outcomes regardless of age, gender, and geography and decreased inpatient (-37%) admissions with concomitant reduced (-59%) medical spend when compared to decedents that did not utilize the end-of-life care management program.