Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling. Cancer Res; 75(18); 3842–52. ©2015 AACR.
PURPOSE:Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs.PATIENTS AND METHODS:Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers.RESULTS:Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1α (P = .037 and .025, respectively).CONCLUSION:Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.
Filter bank multicarrier/offset quadrature amplitude modulation (FBMC/OQAM) is a multicarrier modulation technique projected to replace orthogonal frequency division multiplexing (OFDM) in upcoming sixth-generation (6G) networks. However, because its orthogonality is confined to real-valued symbols, FBMC/OQAM suffers from intrinsic imaginary interference, which complicates channel estimation (CE) tasks. CE plays a crucial role in wireless communication systems; therefore, accurate CE is essential for next-generation networks, especially those supporting low-latency and vehicular applications. While evaluating channel characteristics accurately is critical, conventional CE methods are often inefficient. Recently, feedforward deep neural networks (DNNs) have garnered attention for their impressive performance in enhancing CE techniques. In this study, we propose and investigate a CE scheme based on neural networks, specifically the M-IAM-LS-DNN (Modified Interference Approximation Method Least Squares) approach, for FBMC/OQAM systems. This method uses neural networks to correct noise errors in LS channel estimation. According to simulation data, the suggested M-IAM-LS-DNN surpasses the conventional M-IAM-LS in terms of accuracy, by reducing the NMSE of the proposed M-IAM-LS-DNN for the 64 subcarriers scenario by 10
Objective To estimate the prevalence of US adults' exposure to point-of-sale corrective statements about the health effects, addictiveness, and deceptive marketing of cigarettes, as well as reactions to these messages.Methods We analysed data from the 2024 Health Information National Trends Survey, a cross-sectional, nationally representative sample of the US civilian non-institutionalised population aged 18+ (March-September 2024, N=7278). Weighted multivariable logistic regression models estimated associations of tobacco use, sociodemographic characteristics and perceptions of conflicting health recommendations with self-reported exposure and reactions.Results In 2024, 36.5% of US adults reported seeing point-of-sale corrective statements. Individuals who currently smoked (52.9%) were more likely to report exposure compared with those who never (34.7%) or formerly smoked (34.3%). Among those exposed, 53.6% trusted the information, 49.3% supported the court's mandate, 26.5% thought about friends/family who smoke and 7.9% wanted to look for more information about smoking risks. 41.1% of individuals who currently smoked and saw the statements reported thinking about quitting. Multivariable analyses indicated that those who smoked or used non-cigarette tobacco products were more likely to report exposure and less likely to support the mandate, while individuals who believed that health recommendations often conflict were less likely to trust the information.Conclusions About one in three US adults-and about half of people who smoke-reported noticing point-of-sale corrective statements in 2024. Although exposure rates were relatively consistent across sociodemographic groups, variations in individual reactions point to a need for strategies that enhance the impact of corrective statements, particularly among those who smoke.
Hyperpolarized (HP) carbon-13 [13C] enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, [1-13C]pyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use. Signal Amplification by Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) achieves rapid hyperpolarization by using parahydrogen (p-H2) as the source of nuclear spin order. Currently, SABRE is clinically limited due to the toxicity of the iridium catalyst, which is crucial to the SABRE process. To mitigate Ir contamination, we introduce a novel iteration of the SABRE catalyst, incorporating bis(polyfluoroalkylated) imidazolium salts. This novel perfluorinated SABRE catalyst retained polarization properties while exhibiting an enhanced hydrophobicity. This modification allows the easy removal of the perfluorinated SABRE catalyst from HP [1-13C]-pyruvate after polarization in an aqueous solution, using the ReD-SABRE protocol. The residual Ir content after removal was measured via ICP-MS at 177 ppb, which is the lowest reported to date for pyruvate and is sufficiently safe for use in clinical investigations. Further improvement is anticipated once automated processes for delivery and recovery are initiated. SABRE-SHEATH using the perfluorinated SABRE catalyst can become an attractive low-cost alternative to d-DNP to prepare biocompatible HP [1-13C]-pyruvate formulations for in vivo applications in next-generation molecular imaging modalities.
