Background-Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment. Sunitinib, a recently-approved, multi-targeted TKI, prolongs survival for patients with metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), but concerns about cardiac safety have arisen with this agent.

Purpose: In prostate cancer cells, there is CD24-dependent inactivation of mutant p53, but the mechanism and its significance remain largely unknown. Here, we validated this observation and explored the therapeutic potential of targeting CD24 in TP53 mutant prostate cancer cells.Experimental Design: Overall, 553 prostate cancers (522 formalin-fixed paraffin-embedded and 31 frozen tissues) were assessed for protein or mRNA expression of CD24 and TP53. The effects of CD24 on p53-dependent transcriptional regulation, cancer cell growth, the cell cycle, apoptosis, and mutant p53 restoration were also determined.Results: As determined with three sample cohorts, CD24 and p53 were not expressed in prostate epithelial cells but in prostate cancer cells in 48% of cases for CD24 and 16% of cases for p53 (mutant form). Expressions of CD24 and mutant p53 were more frequently observed in late-stage and metastatic prostate tumors. Mutant p53 accompanied with CD24 was expressed in most cases (91.6%, 76/83). Silencing of CD24 increased the transcriptional activity of p53 target genes, such as CDKNA1, VDR, and TP53INP1, leading to suppression of p53-dependent cell growth, cell-cycle arrest, and apoptosis in most TP53-mutant prostate cancer cells. Silencing of CD24 enhanced restoration of PRIMA-1-induced mutant p53 in endogenous TP53 P223L/V274F DU145 cells and in PC3 cells transfected with TP53 R273H . Conclusions: In human prostate cancers, there is CD24-dependent inactivation of mutant p53. The coexpression of CD24 and p53 may help identify aggressive cancers. Targeting CD24 provides a strategy to enhance mutant p53-restoring therapies, especially in patients with TP53 R273H prostate cancer.

The cinobufagin (CB) has a broad spectrum of cytotoxicity to inhibit cell proliferation of various human cancer cell lines, but the molecular mechanisms still remain elusive. Here we observed that CB inhibited the cell proliferation and tumor growth, but induced cell cycle arrest and apoptosis in a dose-dependent manner in non-small cell lung cancer (NSCLC) cells. Treatment with CB significantly increased the reactive oxygen species but decreased the mitochondrial membrane potential in NSCLC cells. These effects were markedly blocked when the cells were pretreated with N-acetylcysteine, a specific reactive oxygen species inhibitor. Furthermore, treatment with CB induced the expression of BAX but reduced that of BCL-2, BCL-XL and MCL-1, leading to an activation of caspase-3, chromatin condensation and DNA degradation in order to induce programmed cell death in NSCLC cells. In addition, treatment with CB reduced the expressions of p-AKTT308 and p-AKTS473 and inhibited the AKT/mTOR signaling pathway in NSCLC cells in a time-dependent manner. Our results suggest that CB inhibits tumor growth by inducing intrinsic apoptosis through the AKT signaling pathway in NSCLC cells.

BackgroundThe Mobile Insulin Titration Intervention (MITI) program helps patients with type 2 diabetes find their correct basal insulin dose without in-person care. Requiring only basic cell phone technology (text messages and phone calls), MITI is highly accessible to patients receiving care in safety-net settings. MITI was shown in a randomized controlled trial (RCT) to be efficacious at a New York City (NYC) safety-net clinic where patients often have challenges coming for in-person care. In 2016, MITI was implemented as usual care at Bellevue Hospital (the site of the original RCT) and at Gouverneur Health (a second NYC safety-net clinic) under 2 different staffing models.ObjectiveThis implementation study examined MITI’s transition into real-world settings. To understand MITI’s flexibility, generalizability, and acceptability among patients and providers, we evaluated whether MITI continued to produce positive outcomes in expanded underserved populations, outside of an RCT setting.MethodsPatients enrolled in MITI received weekday text messages asking for their fasting blood glucose (FBG) values and a weekly titration call. The goal was for patients to reach their optimal insulin dose (OID), defined either as the dose of once-daily basal insulin required to achieve either an FBG of 80-130 mg/dL (4.4-7.2 mmol/L) or as the reaching of the maximum dose of 50 units. After 12 weeks, if OID was not reached, the patients were asked to return to the clinic for in-person care and titration. MITI program outcomes, clinical outcomes, process outcomes, and patient satisfaction were assessed.ResultsMITI was successful at both sites, each with a different staffing model. Providers referred 170 patients to the program—129 of whom (75.9%, 129/170) were eligible. Of these, 113 (87.6%, 113/129) enrolled. Moreover, 84.1% (95/113) of patients reached their OID, and they did so in an average of 24 days. Clinical outcomes show that mean FBG levels fell from 209 mg/dL (11.6 mmol/L) to 141 mg/dL (7.8 mmol/L), P<.001. HbA1c levels fell from 11.4% (101 mmol/mol) to 10.0% (86 mmol/mol), P<.001. Process outcomes show that 90.1% of MITI’s text message prompts received a response, nurses connected with patients 81.9% of weeks to provide titration instructions, and 85% of attending physicians made at least one referral to the MITI program. Satisfaction surveys showed that most patients felt comfortable sharing information over text and felt the texts reminded them to take their insulin, check their sugar, and make healthy food choices.ConclusionsThis implementation study showed MITI to have continued success after transitioning from an RCT program into real-world settings. MITI showed itself to be flexible and generalizable as it easily fits into a second site staffed by general medical clinic–registered nurses and remained acceptable to patients and staff who had high levels of engagement with the program.