Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates

Non-Musical Choreographic Inspirations: Choreographic Curriculum Challenges with High School Students

For this study a curriculum was designed which encouraged high school students to explore non-musical inspirations for their choreography. The questions of concern in this study were: 1) What are the effects of non-musical inspirations on high school student choreography? 2) What curriculum will be most effective for encouraging student creativity? 3) How will this new curriculum align with national and state curriculum standards? 4) Will students and audiences be emotionally connected to compositions created this way? Students were led through a series of choreographic and improvisational lessons, and at the conclusion of the lessons students rehearsed selected pieces of choreography and performed in a concert. Audience members were asked their thoughts about the performance to gauge if there was a connection to the dance pieces performed, and if they preferred this concert to previous concerts. This study informed the creation of a comprehensive research-based choreography curriculum for a public high school dance program

Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review

Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D

Inhibiting the phosphatidylinositide 3-kinase pathway blocks radiation-induced metastasis associated with Rho-GTPase and Hypoxia-inducible factor-1 activity

AbstractBackground and purposeUndifferentiated follicular and anaplastic thyroid tumours often respond poorly to radiotherapy and show increased metastatic potential. We evaluated radiation-induced effects on metastasis in thyroid carcinoma cells and tumours, mechanistically focusing on phosphatidylinositide 3-kinase (PI3K) and associated pathways.Material and methodsMigration was analysed in follicular (FTC133) and anaplastic (8505c) cells following radiotherapy (0–6 Gray) with concomitant pharmacological (GDC-0941) or genetic inhibition of PI3K. Hypoxia-inducible factor-1 (HIF-1)-activity was measured using luciferase reporter assays and was inhibited using a dominant-negative variant. Activation and subcellular localisation of target proteins were assessed via Western blot and immunofluorescence. In vivo studies used FTC133 xenografts with metastatic lung dissemination assessed ex vivo.ResultsRadiation induced migration in a HIF-dependent manner in FTC133 cells but decreased migration in 8505c’s. Post-radiation HIF-activity correlated with migratory phenotype. PI3K-targeting inhibited migration under basal and irradiated conditions through inhibition of HIF-1α, Rho-GTPase expression/activity and localisation whilst having little effect on src/FAK. In vivo, radiation induced PI3K, HIF, Rho-GTPases and src but only PI3K, HIF and Rho-GTPases were inhibited by GDC-0941. Co-treatment with GDC-0941 and radiation significantly reduced metastatic dissemination versus radiotherapy alone.ConclusionsRadiation modifies metastatic characteristics of thyroid carcinoma cells, which can be successfully inhibited by targeting PI3K using GDC-0941 in vitro and in vivo

Sexual Interactions: Why We Should Talk About Sex in HCI

Within the CHI community there is growing interest in moving beyond cognition and expanding into the social, emotional, and bodily aspects of the human-computer experience. Sex lies at the intersection of these concerns, and indeed outside of HCI, has become a central topic for anthropology, behavioral sciences, and other areas of intellectual inquiry. Examining sex and themes related to it has benefited these disciplines and we intend to understand how it can contribute to HCI. There is a tendency to desexualize technology, despite the presence of sex and sexuality in a variety of interactions, including the use of the internet for viewing pornography, building online communities, and facilitating intimacy. By rendering these interactions sexless, we risk gaining only a marginal understanding of technology\u27s role in day-to-day life

Breast Health Teaching in Predominantly African American Rural Mississippi Delta

This study\u27s primary focus was breast health education to rural African American women in Mississippi and training of community members. Through practice in this area, women were found to lack knowledge of breast health which is the third leading cause of death in Mississippi Black women. They were open to education: N = 130, t = -16.6, df = 126, p \u3c .001; 1 year, N = 35; 2-3 year N = 16 and 3 trained. Data suggest knowledge increased, a small percentage continued practices and community members would become trainers. One participant was diagnosed with breast cancer, received treatment and remained cancer-free after two years

Hypoxia-inducible factor in thyroid carcinoma.

Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden

Interaction between cardiac sympathetic drive and heart rate in heart failure Modulation by adrenergic receptor genotype

ObjectivesIn the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine.BackgroundHeightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the α2-, β1-, and β2-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (α2and β2) and post-synaptically (β1and β2), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals.MethodsWe determined the β1-, β2-, and α2C-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method.ResultsWe showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 β2-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the β1-adrenoceptor. The genotype of the α2C- and β2-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves.ConclusionsFor the first time, we show that β2-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals

Radiation-induced neuroinflammation:a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity