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

Teaching self-authorship and self-regulation: A story of resistance and transformation

Studies show that many learners feel resistant to or otherwise under-prepared for learning challenges due to underdeveloped ability to self-regulate or adapt thoughts, feelings, and actions to attain their own personal goals. This narrative account illustrates pathways and pitfalls in evoking such behavior and encouraging self-authorship—the internal defining of beliefs, identity and relationships. The author describes a project in which an initially resistant student generated creative, if short-lived, solutions to personal struggles. Helpful educational interventions included questioning behavioral patterns, establishing high expectations, and reinforcing belief in ability to change. Oversights and missed opportunities included unintentionally inviting mimicry and remaining ignorant of researched practices for fostering transformation

The Harvard Shaker Cemetery

The core of this paper is a systematic exploration of burying order in the Harvard Shaker cemetery. At issue is whether Shaker burial placement shows a pattern of social arrangements. Supplementing this analysis are the history of the cast metal marker as a practical solution to the general need for restoration in Shaker cemeteries, the story of one sister’s determination to clean up and keep order in the Harvard cemetery, and an account of the disappearing Shaker cemeteries of the twentieth century. Together these elements provide the context for understanding how the Harvard Shaker cemetery became the unique and extraordinary place it is today

Refreshed & Humbled: Altered Assumptions about Power and Payoffs

The author starts with a focus on a long-term, shifting relationship with work-study students serving as students consultants in his class, then takes an outward turn as he describes how he included graduate student voices from around the country as he wrote an external grant to support partnerships between research and teaching intensive institutions