myHealthHub for older adult inpatients to reduce loneliness, and improve patient engagement and mental health: protocol of a pilot randomized controlled trial.

OBJECTIVES: Older Canadian adults make up 85% of hospital stays which are associated with increased loneliness, stress, anxiety, and/or depression. There is a need for novel approaches to reduce loneliness and mental health outcomes in older adult hospital inpatients to prevent further strain on an already overwhelmed healthcare system. METHODS: This is a pilot randomized controlled trial (RCT) exploring the efficacy of a bedside multimodal interaction system, myHealthHub, on loneliness, quality of life (QOL), patient engagement, and other mental health outcomes compared to an active control group in older adult inpatients (n = 60) from baseline to 5-days. Qualitative analyses will be conducted through semi-structured interviews with older adults (n = 8-10) and hospital staff, nurses, and clinicians (n = 4-5) facilitating the service to evaluate patient engagement and experience with myHealthHub. RESULTS: Not applicable. CONCLUSION: This novel pilot clinical trial will obtain preliminary data on the efficacy of myHealthHub in reducing loneliness, QOL, patient engagement, and mental health outcomes in older adult inpatients. If successful, this could provide a potential means to improve patient experience in hospitals and reduce the burden and additional expense on the healthcare system.

SOX4-SMARCA4 complex promotes glycolysis-dependent TNBC cell growth through transcriptional regulation of Hexokinase 2.

Tumor cells rely on increased glycolytic capacity to promote cell growth and progression. While glycolysis is known to be upregulated in the majority of triple negative (TNBC) or basal-like subtype breast cancers, the mechanism remains unclear. Here, we used integrative genomic analyses to identify a subset of basal-like tumors characterized by increased expression of the oncogenic transcription factor SOX4 and its co-factor the SWI/SNF ATPase SMARCA4. These tumors are defined by unique gene expression programs that correspond with increased tumor proliferation and activation of key metabolic pathways, including glycolysis. Mechanistically, we demonstrate that the SOX4-SMARCA4 complex mediates glycolysis through direct transcriptional regulation of Hexokinase 2 (HK2) and that aberrant HK2 expression and altered glycolytic capacity are required to mediate SOX4-SMARCA4-dependent cell growth. Collectively, we have defined the SOX4-SMARCA4-HK2 signaling axis in basal-like breast tumors and established that this axis promotes metabolic reprogramming which is required to maintain tumor cell growth.

Clinical Profile of Adult Hemophilia Patients with Special Reference to FISH and WFHPE Score: An Observational Cross-sectional Study.

BACKGROUND AND OBJECTIVES: Hemophilia is an X-linked recessive inherited disease affecting the coagulation pathway due to congenital deficiencies in either factor VIII (hemophilia A) or factor IX (hemophilia B). The clinical assessment of a patient's functional ability and the state of joint conditions is carried out by the clinicians by administering questionnaires namely the Gilbert or the World Federation of Hemophilia Physical Examination (WFH-PE) score for joint condition and Functional Independence Score in Hemophilia (FISH) for joint function. Here, we have studied the clinical profile of adult hemophilia patients with the short- and long-term complications of the disease. Additionally, the FISH score and the Gilbert score are calculated to assess functional independence and joint condition, respectively. The scores were also compared according to the severity of the disease. MATERIALS AND METHODS: An observational cross-sectional study of 40 adult hemophilia patients was carried out in Sir Sayajirao General Hospital and Medical College, Baroda, Gujarat, India, over a period of 1 year. Data regarding age, sex, and complications associated with the disease were collected in the form of a questionnaire. The overall mean and standard deviation (SD) of FISH and Gilbert scores were calculated and correlated with the severity of the disease. RESULTS: The majority of cases (19) were between 20 and 40 years, and most (24) were diagnosed in childhood. All the subjects were male and all except one had hemophilia A. Family history was seen in only half of the cases. Nine had mild, 20 had moderate, and 11 had severe disease. Around 46% of the subjects had joint arthropathy with the knee joint most affected (60%) followed by the ankle (22.5%). The mean FISH score was 27.132 ± 4.0691 with a minimum score of 15 in severe disease suggesting more functional deficit. The average Gilbert score was 7.4 ± 2.985 with a maximum score of 14 in severe disease suggesting more joint damage Interpretations and conclusion: All subjects were male and except one all had hemophilia A. Majority were between 20 and 40 years but most were diagnosed before 10 years of age and only 50% had positive family history. Arthropathy is the most common complication with the knee joint being most affected. Majority of mild hemophiliacs achieved a maximum FISH score denoting maximum functional capacity. Compared to existing studies, our study showed better FISH scores in moderate hemophiliacs suggesting more functional independence. While comparing Gilbert's score to other studies, moderate and severe hemophiliacs in our study showed less joint damage.

Atypical Presentation of Primary Hyperparathyroidism as Recurrent Pancreatitis: A Case Report With a Review of the Literature.

The majority of the patients with primary hyperparathyroidism (PHPT) are asymptomatic. The most common organ systems involved in PHPT are the kidneys and the skeletal system. In rare instances, acute or chronic pancreatitis may be presenting feature in PHPT patients. The association between these both diseases is still the topic of debate. Here, we put forth a case of a 52-year-old female with three episodes of pancreatitis in the last six months who was diagnosed with PHPT during the fourth episode of pancreatitis based on raised serum amylase and serum lipase levels along with ultrasonography (USG) findings of the abdomen. Pancreatitis in the absence of additional risk factors such as gallstones and alcohol abuse along with raised parathyroid hormone (PTH), hypercalcemia and osteolytic bone lesions led us towards the diagnosis of PHPT. On radio imaging such as MRI and CT scans of the neck, parathyroid adenoma was found in the posterior aspect of the right lobe of the thyroid. She was treated with parathyroidectomy. Serum calcium and PTH levels normalised postoperatively. As can be seen from our case, recurrent pancreatitis with hypercalcaemia should be evaluated for PHPT.

Impact of Diabetes on Inpatient Length of Stay in Adult Mental Health Services in a Community Hospital Setting: A Retrospective Cohort Study.

OBJECTIVE: Our aim in this study was to characterise the relationship between comorbid mental health diagnosis and diabetes type on inpatient length of stay (LOS). METHODS: This retrospective, chart review study was conducted at a community hospital in Ontario, Canada. Individuals admitted to the inpatient mental health unit with a reported diagnosis of type 1 or type 2 diabetes were included in the analysis. Relevant data related to mental health conditions at admission and LOS were collected from the electronic health record. Analyses of variance and coviariance were used to determine the impact on LOS. RESULTS: A total of 249 encounters were included in the analyses. Overall, individuals with type 2 diabetes (mean, 14.70 days; standard deviation, 15.75 days) had a significantly longer LOS than individuals with type 1 diabetes (mean, 8.01 days; standard deviation, 7.27 days). Upon including sociodemographic factors, individuals older in age and with a most recent admission of <1 year also had a longer LOS. There was no significant relationship between the most responsible mental health diagnosis and LOS. CONCLUSIONS: Individuals with type 2 diabetes may be more likely to have a longer LOS in inpatient mental health settings than those with type 1 diabetes. More dedicated support would be beneficial for this population. Future work should focus on in-depth exploration of the challenges that lead to the observed LOS.

Analytical similarity assessment of MYL-1402O to reference Bevacizumab.

BACKGROUND: Bevacizumab (BEV) is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to vascular endothelial growth factor (VEGF)-A and acts as an antiangiogenic agent. It is approved for treatment of many cancer indications, including metastatic colorectal cancer and nonsquamous non-small cell lung cancer. RESEARCH DESIGN AND METHODS: The analytical similarity of the BEV biosimilar MYL-1402O to reference BEV sourced from the European Union and United States was assessed using physicochemical and functional tests to support the clinical development of MYL-1402O. Assessment of physicochemical and analytical similarity showed that MYL-1402O has the same amino acid sequence and similar posttranslational modification profile as the reference BEV products. RESULTS: The functional and biologic activity of MYL-1402O assessed using inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells, inhibition of VEGF-induced VEGF receptor 2 phosphorylation, and fragment antigen and fragment crystallizable receptor binding, was comparable to reference BEV products. CONCLUSIONS: The totality of the data assessment confirms the high degree of similarity of MYL-1402O to reference BEV with respect to physicochemical and in vitro functional properties. The product quality data presented here, along with data from phase 1 clinical studies, demonstrate the similarity of MYL-1402O to reference BEV products, supporting further clinical development of this BEV biosimilar.

CPT1A and fatty acid ß-oxidation are essential for tumor cell growth and survival in hormone receptor-positive breast cancer.

Chromosome 11q13-14 amplification is a defining feature of high-risk hormone receptor-positive (HR+) breast cancer; however, the mechanism(s) by which this amplicon contributes to breast tumorigenesis remains unclear. In the current study, proteogenomic analyses of >3000 breast tumors from the TCGA, METABRIC and CPTAC studies demonstrated that carnitine palmitoyltransferase 1A (CPT1A), which is localized to this amplicon, is overexpressed at the mRNA and protein level in aggressive luminal tumors, strongly associated with indicators of tumor proliferation and a predictor of poor prognosis. In vitro genetic studies demonstrated that CPT1A is required for and can promote luminal breast cancer proliferation, survival, as well as colony and mammosphere formation. Since CPT1A is the rate-limiting enzyme during fatty acid oxidation (FAO), our data indicate that FAO may be essential for these tumors. Pharmacologic inhibition of FAO prevented in vitro and in vivo tumor growth and cell proliferation as well as promoted apoptosis in luminal breast cancer cells and orthotopic xenograft tumor models. Collectively, our data establish an oncogenic role for CPT1A and FAO in HR+ luminal tumors and provide preclinical evidence and rationale supporting further investigation of FAO as a potential therapeutic opportunity for the treatment of HR+ breast cancer.

Cochlear Implantation in Pierre Robin Syndrome.

Hereditary hearing loss accounts for nearly 60% of deafness in developed countries and about 30% of them are syndromic. Pierre Robin Syndrome is one such condition. The patient with this syndrome usually presnts with triad of micrognathia, glossoptosis and cleft palate. Hearing loss is mostly conductive but there can be sensorineural hearing loss also. Here we present a case of Pierre Robin Syndrome who presented with congenital hearing loss. He also had bilateral serous otitis media. He underwent cochlear implant surgery and was prescribed antihistaminics and steroid spray for middle ear effusion. Therefore, proper clinical evaluation is required.

Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia.

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

Physicochemical and functional characterization of trastuzumab-dkst, a trastuzumab biosimilar.

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.

FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036.

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.

SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2.

Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer.

The underlying molecular heterogeneity of cancer is responsible for the dynamic clinical landscape of this disease. The combination of genomic and proteomic alterations, including both inherited and acquired mutations, promotes tumor diversity and accounts for variable disease progression, therapeutic response, and clinical outcome. Recent advances in high-throughput proteogenomic profiling of tumor samples have resulted in the identification of novel oncogenic drivers, tumor suppressors, and signaling networks; biomarkers for the prediction of drug sensitivity and disease progression; and have contributed to the development of novel and more effective treatment strategies. In this review, we will focus on the impact of historical and recent advances in single platform and integrative proteogenomic studies in breast and ovarian cancer, which constitute two of the most lethal forms of cancer for women, and discuss the molecular similarities of these diseases, the impact of these findings on our understanding of tumor biology as well as the clinical applicability of these discoveries.

Evaluation of Diagnostic Accuracy of Magnetic Resonance Imaging in Posterior Ligamentum Complex Injury of Thoracolumbar Spine.

STUDY DESIGN: Prospective diagnostic imaging study. PURPOSE: The stability of the thoracic and lumbar spine depends significantly on the posterior ligamentum complex (PLC). Therefore, it is essential to diagnose PLC injuries accurately before deciding on a treatment plan for thoracolumbar injury patients. However, the efficacy of magnetic resonance imaging (MRI) in diagnosing PLC remains undetermined. OVERVIEW OF LITERATURE: MRI has become the ultimate tool in diagnosing spine injury cases, as previous literature suggests that it has very high sensitivity and specificity. But this is still controversial and as many surgeons rely on just MRI for selecting the patient for surgery, it becomes important to know the diagnostic accuracy of it. METHODS: Patients who sustained injuries from T1 to L3 and required posterior surgery were prospectively studied. The treating surgeon and musculoskeletal radiologist participating in the study reviewed preoperative MRI images to characterize the level(s) of injury and the integrity of the six components of the PLC. These were classified as intact, incompletely disrupted, or disrupted. During the surgical procedure, the surgeon also classified each component of the PLC, and the radiologist's and surgeon's findings were compared. RESULTS: Out of 66 patients, 46 were males (69.7%) and 20 were females (30.3%), and the average age was 34.12 years. According to the kappa score, there was a moderate level of agreement between the radiologist's interpretation and the intraoperative findings for all PLC components except for the thoracolumbar fascia and ligamentum flavum for which there was a slight agreement. The sensitivity for the intact PLC components ranged from 100% (supraspinous ligament) to 66.67% (ligamentum flavum). The specificity ranged from 100% (interspinous ligament) to 52% (thoracolumbar fascia). The Spearman's rank correlation ranged from 0.061 for the thoracolumbar fascia to 0.918 for the interspinous ligament, and the percentage agreement ranged from 81.82% (interspinous ligament to 36.36% (thoracolumbar fascia). CONCLUSIONS: The sensitivity and specificity of MRI for diagnosing injury of the PLC in this study were lower than those previously reported in the literature. The integrity of the PLC as determined by MRI should not be used in isolation to determine treatment.

C2 IgM Natural Antibody Enhances Inflammation and Its Use in the Recombinant Single Chain Antibody-Fused Complement Inhibitor C2-Crry to Target Therapeutics to Joints Attenuates Arthritis in Mice.

Natural IgM antibodies (NAbs) have been shown to recognize injury-associated neoepitopes and to initiate pathogenic complement activation. The NAb termed C2 binds to a subset of phospholipids displayed on injured cells, and its role(s) in arthritis, as well as the potential therapeutic benefit of a C2 NAb-derived ScFv-containing protein fused to a complement inhibitor, complement receptor-related y (Crry), on joint inflammation are unknown. Our first objective was to functionally test mAb C2 binding to apoptotic cells from the joint and also evaluate its inflammation enhancing capacity in collagen antibody-induced arthritis (CAIA). The second objective was to generate and test the complement inhibitory capacity of C2-Crry fusion protein in the collagen-induced arthritis (CIA) model. The third objective was to demonstrate in vivo targeting of C2-Crry to damaged joints in mice with arthritis. The effect of C2-NAb on CAIA in C57BL/6 mice was examined by inducing a suboptimal disease. The inhibitory effect of C2-Crry in DBA/1J mice with CIA was determined by injecting 2x per week with a single dose of 0.250 mg/mouse. Clinical disease activity (CDA) was examined, and knee joints were fixed for analysis of histopathology, C3 deposition, and macrophage infiltration. In mice with suboptimal CAIA, at day 10 there was a significant (p < 0.017) 74% increase in the CDA in mice treated with C2 NAb, compared to mice treated with F632 control NAb. In mice with CIA, at day 35 there was a significant 39% (p < 0.042) decrease in the CDA in mice treated with C2-Crry. Total scores for histopathology were also 50% decreased (p < 0.0005) in CIA mice treated with C2-Crry. C3 deposition was significantly decreased in the synovium (44%; p < 0.026) and on the surface of cartilage (42%; p < 0.008) in mice treated with C2-Crry compared with PBS treated CIA mice. Furthermore, C2-Crry specifically bound to apoptotic fibroblast-like synoviocytes in vitro, and also localized in the knee joints of arthritic mice as analyzed by in vivo imaging. In summary, NAb C2 enhanced arthritis-related injury, and targeted delivery of C2-Crry to inflamed joints demonstrated disease modifying activity in a mouse model of human inflammatory arthritis.

The Outcome of Structured Education in Adults With Type 2 Diabetes Mellitus and Substance Use Disorder: A Literature Review.

OBJECTIVE: Structured diabetes education for patients is a cornerstone of therapy; it empowers the patients by giving them appropriate tools for the self-management of the illness. The objective of this work was to determine how substance use disorder influences the outcome of structured diabetes education in patients with type 2 diabetes mellitus, and whether patients with substance use disorder are less likely to benefit because of their addiction issues. METHODS: Only clinical trials involving substance use, which were randomized, in the context of type 2 diabetes mellitus were included. RESULTS: Literature was only available for alcohol use disorder, and there were no studies available on any other recreational substance use disorders and its effects on structured diabetes education. Out of 3 relevant studies, in the context of alcohol use disorder, 2 studies identified alcohol use by the patients as a limiting factor in receiving structured diabetes education. One study did not show any impact of alcohol on structured diabetes education. CONCLUSIONS: More high-quality randomized controlled trials with better sample sizes are required to say with confidence if alcohol use affects the patient's ability to participate in structured educational programs for type 2 diabetes mellitus management.

Efficacy of Depression Management in an Integrated Psychiatric-Diabetes Education Clinic for Comorbid Depression and Diabetes Mellitus Types 1 and 2.

OBJECTIVES: Patients with type 1 and type 2 diabetes mellitus (DM) are 2 times as predisposed to developing mood disorders, such as major depressive disorder (MDD), compared with patients without diabetes. Management of comorbid MDD and DM remains a challenge because patients often suffer from poor medication compliance, lifestyle factors and refractory depression. Integration of psychiatric care into diabetes education clinics (DECs) has been suggested as an effective method of managing the comorbid conditions. As this strategy is being implemented into clinical care, its effectiveness in practice warrants further research. METHODS: A retrospective chart review of 24 patients (10 men and 14 women) followed by an integrated psychiatry-DEC in Newmarket, Ontario, Canada, between April 2016 and July 2019 was performed. Depressive symptom severity at each appointment was assessed with the Patient Health Questionnaire-9 (PHQ-9) depression rating scale. RESULTS: There was no significant change in PHQ-9 depression rating scale scoring between the first and most recent appointments (paired t test, p=0.356); however, patients who had improved PHQ-9 scoring were more likely to have more clinic visits (analysis of variance, p=0.0271). A significant negative correlation was found between both number of visits (Pearson coefficient, -0.56; p=0.005) and overall time the patients were followed by DEC (Pearson coefficient, -0.42; p=0.040) and PHQ-9 score changes between the first and most recent appointments. PHQ-9 change between individual appointments also displayed a positive correlation with time between appointments (Pearson coefficient, 0.26; p=0.027). CONCLUSIONS: Regular follow up in a psychiatry-DEC service might be beneficial in managing MDD symptom severity for comorbid MDD and DM.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.