Genome-wide CRISPR/Cas9 library screening identified ATM signaling network genes as critical drivers for resistance to ATR inhibition in soft-tissue sarcomas: synthetic lethality and therapeutic implications.

Soft-tissue sarcoma (STS) are a heterogeneous group of rare tumors with different biological behavior that are fatal in more than 40% of cases, due to their metastatic evolution and inadequate treatment options. ATR inhibition already showed an activity, even if modest, in broad pre-clinical models of STS. By using genome-wide CRISPR/Cas9 library screening, we identified ATM signaling network genes as critical drivers for resistance to the specific ATR inhibitor AZD6738. The role of such genes in resistance to AZD6738 was confirmed by using CRISPR/Cas9 knockout models. More strikingly, the ATM inhibitor AZD0156 works synergistically with AZD6738 in vitro and abolishes STS growth in vivo in our models of most frequent histotypes (such as dedifferentiated liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma among others). Moreover, the combination of AZD6738 and AZD0156 induced significantly higher levels of DNA damage than either drug used as single agent alone. In summary, our results demonstrate that targeting ATM is an effective approach to overcome resistance to ATR inhibition in different STS subtypes, including the most frequent histologies.

Changes in dietary intake, plasma carotenoids and erythrocyte membrane fatty acids in breast cancer survivors after a lifestyle intervention: results from a single-arm trial.

BACKGROUND: The influence of nutrition on breast cancer prognosis is still inconclusive and therefore dietary interventions incorporating dietary biomarkers are needed to confirm compliance with dietary goals and clarify biological mechanisms. The present study assessed whether a lifestyle intervention in breast cancer survivors could affect dietary biomarkers of fruit and vegetables and fatty acids. METHODS: In this phase II single-arm trial, 37 overweight/obese early stage breast cancer patients completed a 12-week diet and exercise intervention. The intervention involved 1-h weekly diet sessions delivered by a dietician and 75-min bi-weekly physical activity sessions of moderate-to-high intensity led by trained monitors. Before and after the intervention, three 24-h dietary recalls were carried out to calculate nutrient intakes and, in addition, blood samples were taken to measure plasma carotenoids, vitamin E and retinol concentrations and erythrocyte membrane fatty acid (EFA) composition. Wilcoxon signed rank tests were used to assess changes in dietary and biomarkers measurements over the intervention period. RESULTS: After the intervention, there was a significant increase in the intake of dietary carotenoids (+15.1% compared to baseline) but not plasma carotenoids levels (+6.3%). Regarding the EFA levels, we observed a significant decrease in percentage of saturated fatty acids (-1.4%) and n-6 polyunsaturated fatty acids (-2.9%) and an increase in monounsaturated fatty acids (1.7%) and total and long-chain n-3 polyunsaturated fatty acids (by 13.1% and 13.7%, respectively). A favourable decrease in the ratio of long-chain n-6 to n-3 polyunsaturated fatty acids (-9.1%) was also observed. CONCLUSIONS: After a short-term diet and exercise intervention in overweight/obese breast cancer survivors, we observed significant changes in dietary nutrients and fatty acid biomarkers, suggesting positive dietary changes that could be relevant for breast cancer prognosis.

The role of posttraumatic stress and posttraumatic growth on online information use in breast cancer survivors.

OBJECTIVE: Changes perceived as both positive (eg, posttraumatic growth [PTG]) and negative (eg, posttraumatic stress symptoms [PTSS]) have been associated with intensive Internet use among breast cancer survivors. In this multicenter study, we analyzed the role of PTG and PTSS on the amount of time spent looking for online cancer information, its content, and its psychological impact. METHODS: Posttraumatic stress symptoms and PTG were assessed in 182 breast cancer survivors by using the Post-traumatic Stress Disorder Checklist and Post-traumatic Growth Inventory questionnaires. Subjects also completed a questionnaire about their behavior when looking for online illness-related information (ie, time spent, type of contents, and psychological impact). RESULTS: Posttraumatic stress symptoms positively correlated with the amount of time spent looking for cancer-related information, including both medical and psychosocial content. By contrast, PTG showed no relationships with the amount of time, but with a predominant search for cancer-related psychosocial information. The psychological impact of online information was associated with participants' levels of PTG and/or PTSS. Whereas PTG was related to a decrease of women's hope, PTSS was linked to the perception of being less conscious or inadequately informed about the illness, thereby increasing feelings of distress. CONCLUSIONS: Posttraumatic stress symptoms and PTG show relationships with the amount of time spent online, the type of information accessed online, and the psychological impact of Internet use. Health professionals should prescribe online information according to the psychological response to cancer. There is a need for professional-led online resources to provide patients with timely information as well as support sites to facilitate psychological adjustment.

Chemical and biological characterization of an active substance of the human placenta.

Acetic acid extracts of human term placenta have been fractionated by pH and salt precipitations and by exclusion chromatography on a Sephadex G-75 column. A partially purified fraction (F-II) possessing uterotropic activity in immature and young mice was obtained. This active fraction was submitted to the action of protein denaturating agents (heat, 8 M urea) and of specific proteolytic enzymes (trypsin, alpha-chymotrypsin and pronase). These treatments completely destroy the uterotropic activity showing that the active substance is of protein nature. The administration of F-II to spayed mice did not produce any increase in their uterine weight suggesting that the uterotropic activity would be due to stimulation of the female gonad.

Biological and immunological studies of a placental gonadotropic protein.

Precocious sexual maturity, ovarian weight increase and stimulation of the sex accessory organs in impuber female mice, was induced by a partially purified protein fraction obtained from human placenta. The relationship between this biologically active protein and HCG was studied by a comparative immuno-double diffusion technique (Ouchterlony) and two agglutination inhibition tests. Results showed that this protein with gonadotropic activity is neither immunologically related to HCG nor contaminated with this hormone.