Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor.

Hormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.

Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer.

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.

Implantable brain-computer interface for neuroprosthetic-enabled volitional hand grasp restoration in spinal cord injury.

Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in one 21-year-old male subject with complete cervical quadriplegia (C5 American Spinal Injury Association Impairment Scale A) using a portable fully implanted brain-computer interface within the home environment. The brain-computer interface consists of subdural surface electrodes placed over the dominant-hand motor cortex and connects to a transmitter implanted subcutaneously below the clavicle, which allows continuous reading of the electrocorticographic activity. Movement-intent was used to trigger functional electrical stimulation of the dominant hand during an initial 29-weeks laboratory study and subsequently via a mechanical hand orthosis during in-home use. Movement-intent information could be decoded consistently throughout the 29-weeks in-laboratory study with a mean accuracy of 89.0% (range 78-93.3%). Improvements were observed in both the speed and accuracy of various upper extremity tasks, including lifting small objects and transferring objects to specific targets. At-home decoding accuracy during open-loop trials reached an accuracy of 91.3% (range 80-98.95%) and an accuracy of 88.3% (range 77.6-95.5%) during closed-loop trials. Importantly, the temporal stability of both the functional outcomes and decoder metrics were not explored in this study. A fully implanted brain-computer interface can be safely used to reliably decode movement-intent from motor cortex, allowing for accurate volitional control of hand grasp.

Spatial heterogeneity in resources alters selective dynamics in Drosophila melanogaster.

Environmental features can alter the behaviors and phenotypes of organisms, influencing the dynamics of natural and sexual selection. Experimental environmental manipulation, particularly when conducted in experiments where the dynamics of the purging of deleterious alleles are compared, has demonstrated both direct and indirect effects on the strength and direction of selection. However, many of these studies are conducted with fairly simplistic environments, where it is not always clear how or why particular forms of spatial heterogeneity influence behavior or selection. Using Drosophila melanogaster, we tested three different spatial environments designed to determine if spatial constraint of critical resources influences the efficiency of natural and sexual selection. We conducted two allele purging experiments to (1) assess effects of these spatial treatments on selective dynamics of six recessive mutations, and (2) determine how these dynamics changed when sexual selection was relaxed and spatial area reduced for two of the mutants. Allele purging dynamics depended on spatial environment, however the patterns of purging rates between the environments differed across distinct deleterious mutations. We also tested two of the mutant alleles, and demonstrate sexual selection increased the purging rate.

Safety Resources and Processes in MR Imaging Departments.

PURPOSE: To identify current standards of safety practices, common safety resources in use, and gaps in workflow practices in magnetic resonance (MR) imaging departments. METHODS: Qualitative observational research and visual assessments of safety resources available at clinical rotation sites were conducted with subsequent open coding analysis. RESULTS: The sample varied in terms of the strength of MR systems, types of facilities, patient populations, and safety resources available. Qualitative themes included carelessness of personnel, facility design flaws, and inconsistencies in safety practices and staffing. DISCUSSION: Proper screening of patients and other individuals, appropriate use of barriers, and ferromagnetic detection systems can be effective tools for ensuring patient and personnel safety. Although various safety resources were available at most MR imaging facilities, the resources proved to be only as effective as the safety practices of the MR technologists. CONCLUSION: Safety practices in MR imaging departments can be improved upon continually. This study provides a foundation for future research on MR safety practices.