ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis.

PURPOSE: Limited effective treatments are currently available for central nervous system (CNS) metastasis (CM). This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated inhibitor, as a radiosensitizer for breast cancer CM treatment. EXPERIMENTAL DESIGN: Three patient-derived xenograft (PDX) tumors including 2 HER2+ and 1 triple-negative breast cancer harboring DNA damage response (DDR) gene mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. RESULTS: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival of 222 days compared with 123 days in controls. Administration of AZD1390 posttreatment for 21 days had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in some mice 50 to 100 days posttreatment in all models. Gene expression comparing these tumors with complete responders demonstrated changes in upregulation of oncogenic proteins, which are potential drivers of tumor growth after treatment. CONCLUSIONS: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CM to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CM.

Supported Palladium-Catalyzed Carbonylative Synthesis of Diaryl Ketones from Aryl Bromides and Arylboronic Acids.

A palladium supported on graphitic carbon nitride (Pd/g-C3 N4 ) catalyzed carbonylative reaction of aryl bromides and arylboronic acids by has been developed for the construction of diaryl ketones. Using benzene-1,3,5-triyl triformate (TFBen) as the CO source, the reaction proceeded well to give various diaryl ketones in moderate to good yields.

Protein supplementation enhances cerebral oxygenation during exercise in elite basketball players.

OBJECTIVE: The aim of the present study was to examine cerebral oxygenation during high-intensity exercise in elite basketball players who consumed supplements with different whey protein contents after a short postexercise recovery to determine whether changing whey protein content in carbohydrate-based supplementation influences cerebral hemodynamic response when the supplement was consumed during a 2-h recovery after a 1-h exercise challenge. METHODS: This was a randomized, counterbalanced crossover study. Fifteen Division 1 collegiate basketball players (18-20 y) consumed 6.25 kcal/kg of either high-protein (36% protein in total calorie) or an isocaloric low-protein (12% protein in total calorie) control supplement in a carbohydrate-based drink immediately after a 1-h cycling (70% of maximal oxygen consumption [VO2max]). After a 2-h rest, the athletes were challenged on a cycloergometer at 80% VO2max. Blood perfusion (total hemoglobin) and oxygen saturation of frontal brain were continuously measured by near-infrared spectroscopy during the cycling. RESULTS: Before the cycloergometer test, high-protein supplementation increased peak insulin response and lowered glucose increases during the recovery compared with the low-protein trial. High-protein supplementation enhanced increases in cerebral oxygen saturation (P < 0.01) and attenuated increases in cerebral blood perfusion (total hemoglobin; P < 0.01) during the cycloergometer exercise; and resulted in a 16% longer cycling time (from 474 ± 49 s to 553 ± 78 s, P < 0.05), compared with the low-protein trial. CONCLUSION: Enhanced fatigue recovery after consumption of a high-protein supplement is associated with enhanced cerebral oxygenation against exercise challenge, which spares brain blood demand for periphery.

Aged cells in human skeletal muscle after resistance exercise.

It remains unclear how exercise, as an entropic event, brings benefit against human aging. Here we examined longitudinal changes of p16Ink4a+ senescent cells in skeletal muscle of young men (aged 22.5±1.7 y) before and after resistance exercise (0 h and 48 h) with multiple biopsies at two different protein availabilities: low protein (14%) and isocaloric high protein (44%) supplemented conditions. Immunohistochemistry analysis of muscle cross-sections using p16Ink4a and CD34 antibodies confirmed that the detected senescent cells were endothelial progenitor cells. Leukocyte infiltration into skeletal muscle increased during resistance exercise. The senescent cells in muscle decreased (-48%, P < 0.01) after exercise for 48 h. Low protein supplementation resulted in greater infiltrations of both CD68+ phagocytic macrophage and leukocyte, further decreased p16Ink4a+ senescent cells (-73%, P < 0.001), and delayed increases in regenerative CD163+ macrophage in skeletal muscle, compared with high protein supplemented condition. Significant gain in muscle mass after 12 weeks of training occurred only under high protein supplemented condition. CONCLUSION: Rapid senescent cell clearance of human skeletal muscle during resistance exercise seems to associate with enhanced in situ phagocytosis. High protein availability accelerates resolution of muscle inflammation and promotes muscle increment after training.

[Research about the effect of exercise on the vascular endothelial cells AMPK activated in atherosclerotic rat].

OBJECTIVE: To study the molecular mechanism of exercise to improve cardiovascular health, and exploring the effect of different intensity exercise on AMP activated protein kinase (AMPK) protein expression and phosphorylation of vascular endothelial cells in rat. METHODS: Forty-eight Wistar rats were divided into control group (group C), model group (group AS), low intensity exercise model group (ASL) and high intensity exercise model group (ASH). The serum inflammatory factor concentrations such as IL-6, TNF-alpha, CRP were studied, and the endothelial cell total AMPK and p-AMPK protein were checked by means of Western blot. RESULTS: (1) The level of IL-6 between AS group and control group had no significant difference, the value of ASH group was markedly increased and had significant difference compared with that of the control group or AS group. The serum TNF-alpha levels of AS group and ASL group were significantly higher than those in control group, but the value of ASH and ASL was significantly lower than that in AS group. The serum concentration of CRP after the AS molding was significantly higher than that of the control group, there was no statistical difference between that of ASL and ASH groups. (2) The total AMPK protein content of ASL and ASH groups was significantly higher than that in control group. When compared between the two groups, there was statistical significance. (3) The value of p-AMPK protein of ASL and ASH groups was significantly higher than that of AS group, the value of p-AMPK protein of ASH group was significantly higher than that of the control group at the same time. CONCLUSION: Exercise can reduce the serum levels of inflammatory factors in atherosclerosis rat, and increase AMPK protein expression and phosphorylation level in endothelial cell.

[The effects of exercise and glucose and/or acanthopanacis senticosi after workout on AMPK in muscle cell of rat].

OBJECTIVE: To explore the effect of glucose and/or acanthopanacis senticosi administration supplement on AMP-activated protein kinase (AMPK) activation and its change in different phase after exercise in muscle cell of rat. METHODS: 128 rats were divided into exercise control groups (C groups), exercise and glucose administration groups (G groups), exercise and acanthopanacis senticosi administration groups (A groups), exercise and glucose and acanthopanacis senticosi administration groups (GA groups). The glucose and acanthopanacis senticosi supplement were completed by intragastric administration in half hour after exercise. All rats were killed in different designed time points before or after glycogen depletion exercise (0 h, 4 h and 12 h respectively) and finally divided into 16 groups (n = 8). The values of AMPK in soleus muscle were analyzed by Western blot. RESULTS: (1) After exercise, the protein content of AMPK quickly increased and reached the peak (209.23 +/- 21.32) then gradually decreased. (2) Acanthopanacis senticosi administration markedly increased the protein content of AMPK in the 0 h and 4 h points after glycogen consumption training (225.11 +/- 20.58 and 186.31 +/- 15.26 vs 195.19 +/- 13.31 and 157.11 +/- 16.43) without any difference after 12 h. (3) Glucose administration had no significant effect on AMPK activation. (4) Both glycogen and acanthopanacis senticosi were supplied simultaneously that had enhanced the AMPK content in 4 h and 12 h point (217.96 +/- 19.25 and 191.86 +/- 14.69). However, the AMPK content in GA group was lower than that in the C groups at 12 h point (121.89 +/- 15.23 vs 137.92 +/- 16.01). CONCLUSION: Exercise could markedly activate the AMPK protein in muscle cell and acanthopanacis senticosi administration augmented such activation. Glucose administration had no significant effect on AMPK activation.