Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Plant chemicals and the sexual behavior of male tephritid fruit flies

Plant compounds affect insects in many different ways. In addition to being a food source, plants also contain secondary metabolites that may have positive and negative impacts on insects. The influence of these compounds on sexual behavior, in particular, has been the focus of many recent studies. Here, we review the existing literature on the effects of plant compounds on the sexual behavior of tephritid fruit fly males. We put special focus on polyphagous species whose males congregate in leks, where females exert strong mate selection. We first summarize the main findings related to plant compounds that increase male signaling behavior and attraction of females and consequently increase mating frequency, a phenomenon that has been recorded mainly for species of Anastrepha and Ceratitis. In other tephritid species, males are attracted to phenylpropanoids produced by plants (such as methyl eugenol or raspberry ketone) that, upon encounter, are consumed and sequestered by males. These compounds, or metabolic derivatives, which normally have negligible nutritional value, are included in the pheromone and also confer advantages in a sexual context: enhanced female attraction and improved male mating success. These phenomena have been reported for several Bactrocera species as well as for Zeugodacus cucurbitae. Because many tephritid species are serious pests, the effect of plant compounds on male behavior has been explored for potential incorporation into control strategies such as the sterile insect technique (SIT). We conclude noting several factors, such as age and nutrition during larval and adult stage, that modulate the effect of plant compounds on male mating behavior as well as some prominent gaps that preclude a thorough understanding of the plant-mediated enhancement of male sexual performance and hence limit our ability to effectively utilize phytochemicals in pest control strategies.Instituto de GenéticaFil: Segura, Diego Fernando. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética. Laboratorio de Genética de Insectos de Importancia Económica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Belliard, Silvina A. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética. Laboratorio de Genética de Insectos de Importancia Económica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vera, María Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Tucumán. Facultad de Agronomía y Zootecnia; ArgentinaFil: Bachmann, Guillermo Enrique. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética. Laboratorio de Genética de Insectos de Importancia Económica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ruiz, María Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Tucumán. Facultad de Agronomía y Zootecnia; ArgentinaFil: Jofre-Barud, Flavia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Juan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Patricia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Delta del Paraná; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lopez, M. Liza. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Juan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Shelly, Todd E. United States Department of Agriculture. Animal and Plant Health Inspection Service; Estados Unido

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. Methods: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated, amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs