BackgroundAdolescents with intellectual disabilities (ID) who live a sedentary lifestyle may lead to an increased risk of chronic cardiovascular disease in adulthood. The aim of this study is to investigate the effects of 8‐week progressive rope skipping training on physical, cardiovascular fitness and exercise tolerance of high school students with moderate ID.MethodsThirty‐four senior high school with ID (aged 15–18 years old) were randomised into experimental group received progressive skipping rope exercise (RS, n = 17) and control group no rope skipping exercise intervention group (CON, n = 17). The RS group were received progressive rope skipping exercise for 50 min each time, three times a week, for 8 weeks. The control group was not allowed to participate in intervention activities during the study period. The physical fitness, body composition, arterial stiffness index (ASI) and blood pressure were measured before and after the 8‐week intervention.ResultsAfter the 8‐week progressive skipping rope exercise intervention, the participants from the RS group increased in the 3‐min step test, sit‐up test, grip strength and sit and reach test, when compared to the baseline (P < 0.05). The RS group exhibited lower the area under curve of heart rate (HR) during post‐exercise recovery (P < 0.05). The participants in the RS group showed significant decreases in systolic (SBP) and diastolic (DBP) blood pressure, mean arterial pressure (MAP) and HR when compared to the baseline (P < 0.05). Change SBP has moderate positive correlation with change ASI.ConclusionsThe results of this experiment suggest that progressive rope skipping exercise might improve physical fitness and promote cardiovascular health, as well as enhance exercise tolerance for adolescent students with moderate ID.

"Basal-like" breast cancer (BLBC) is a very aggressive subtype of breast cancer. BLBC has very poor prognosis — median time to distant recurrence is just 2.6 years vs. 5 years overall, and survival time from diagnosis of distant metastatic disease is 9 months vs. 22 months. BLBC tumors usually do not express ER, Her2, or progesterone receptor. As such, they cannot be treated by the current targeted therapies, which target these molecules. What drive the formation and progression of BLBCs is largely unclear. Ras GTPases are best known for mediating growth factor signaling. Oncogenic mutations in the RAS genes, K-RAS in particular, are found in more than 30% of human tumors. Surprisingly, oncogenic RAS mutations are rare in breast cancer. However, we found that wild-type N-RAS is overexpressed in BLBCs, possibly partly via promoter demethylation, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpressing it enhances these processes even in preinvasive BLBC cells. In contrast, in breast cancer cells of other subtypes, repressing N-RAS expression does not affect growth and transforming activities. We identified N-Ras-responsive genes, most of which encode chemokines and cytokines, e.g., IL8. High expression levels of these N-Ras-responsive genes as well as of N-RAS itself in tumors correlate with poor patient outcome. N-Ras, but not K-Ras, induces IL8 by binding and activating the cytoplasmic pool of JAK2; IL8 then acts on both the cancer cells and stromal fibroblasts. In conclusion, N-Ras drives BLBC by promoting transformation in epithelial cells, which may in turn remodel the tumor microenvironment to create a proinvasive state. Although oncogenic mutations affecting RAS are common in many other human cancers, tumorigenesis in an important subset of breast cancers is driven instead by increasing activity of wild-type N-Ras. Thus, to fully assess the impact of Ras on tumorigenesis, the role of wild-type as well as mutant Ras proteins must be carefully examined. Citation Format: Zheng Z-Y, Bu W, Tian L, Fan C, Gao X, Zhang X, Yu C, Wang H, Liao Y-H, Li Y, Lewis MT, Edwards D, Zwaka TP, Hilsenbeck SG, Medina D, Perou CM, Creighton CJ, Zhang XH, Chang EC. Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-11.

Background:Basal-like breast cancer (BLBC) is an aggressive form of breast cancer that are usually triple negative for ER, PR, and HER2. There is no effective targeted therapy for BLBC due to the lack of a druggable driver. Ras GTPases are powerful drivers for tumorigenesis. We have shown that wild type N-Ras, but not K- or H-Ras, is overexpressed in BLBC and driving itsgrowth and transforming activities. However, there is currently no treatment that directly target Ras. This study thus screened existing pharmacologically active and approved compounds for the new ability to induce N-Ras degradation in BLBC. Methods:Compounds in the LOPAC library were screened by an automated microscopy system for the ability to reduce GFP-N-Ras signals in the cells. Isolated compounds were then examined to identify those that can degrade endogenous N-Ras in BLBC cells without impacting levels of other Ras proteins. Final candidate compounds were further examined to determine by which proteolytic pathway N-Ras is induced to be degraded. The potentials of the identified compound to treat BLBC were assessed by examining cell growth and soft agar colony formation in vitroand tumor growth in vivo. Results:We identified flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RASsilencingin vitroby selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivoFLN inhibited tumor growth of a BLBC xenograft model. Conclusion:This proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics against BLBC. Citation Format: Zheng Z-Y, Li J, Li F, Zhu Y, Cui K, Wong ST, Chang EC, Liao Y-h. Target N-Ras for degradation by flunarizine to treat basal-like breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-06.