Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

FoxM1-dependent RAD51 and BRCA2 signaling protects idiopathic pulmonary fibrosis fibroblasts from radiation-induced cell death

Radiation therapy is critical for the control of many tumors and lung is an important dose-limiting organ that impacts radiation dose prescribed to avoid irreversible pulmonary fibrosis in cancer survivors. Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible lung disease caused by aberrantly activated lung (myo)fibroblasts. The presence of pro-fibrotic, apoptosis-resistant fibroblasts in IPF promotes progressive fibrosis and may have a role in other diseases, if these resistant cells are selected for as a consequence of treatment. However, the pathological response of IPF fibroblasts to radiation compared to non-IPF lung fibroblasts is not known. To address this, we examined fibroblast viability following radiation in lung fibroblasts from IPF and non-IPF patients and the underlying mechanism that protects IPF fibroblasts from radiation-induced death. IPF fibroblasts are significantly more resistant to apoptosis compared to non-IPF lung fibroblasts, suggesting that resistance to radiation-induced cell death is a predominant mechanism leading to lung fibrosis. Analysis of γH2AX induction demonstrated that radiation-induced DNA damage is reduced in IPF fibroblasts and correlates to the activation of the transcription factor forkhead box M1 (FoxM1) and subsequent upregulation of DNA repair proteins RAD51 and BRCA2. FoxM1 activation occurs secondary to FoxO3a suppression in IPF fibroblasts while restoration of FoxO3a function sensitizes IPF fibroblasts to radiation-induced cell death and downregulates FoxM1, RAD51, and BRCA2. Our findings support that increased FoxO3a/FoxM1-dependent DNA repair may be integral to the preservation of death-resistant fibrotic fibroblasts after radiation and that selective targeting of radioresistant fibroblasts may mitigate fibrosis

The politics of cross-border engagement: Mexican emigrants and the Mexican state

Reacting to migrants’ many, ongoing involvements with their home communities, sending states have increasingly adopted policies designed to resolve the problems of citizens living abroad and to respond to expatriates’ search for engagement, doing so in ways that best meet home state leaders’ goals. This paper seeks to understand the factors shaping this interaction between sending states and emigrants abroad by studying two contrasting aspects of the Mexican experience – expatriate voting, a relatively new development, and provision of the matrícula consular, a long-standing component of traditional consular services, though one that has recently been transformed. Focusing on the complex set of interactions linking migrants, sending states, and receiving states, the paper identifies the key differences and similarities between these two policies. Both policies suffered from a capacity deficit inherent in sending state efforts to connect with nationals living in a territory that the home country cannot control; both also generated conflict over membership and rights. Nonetheless, Mexico’s efforts to resolve the immigrants’ identification problems in the receiving society proved useful to millions; by contrast, a tiny proportion of emigrants took advantage of the first opportunity to vote from abroad. These diverging experiences demonstrate that sending states can exercise influence when intervening on the receiving society side, where the embeddedness of the immigrant population provides a source of leverage. By contrast, the search to re-engage the emigrants back home encounters greater difficulties and yields poorer results, as the emigrants’ extra-territorial status impedes the effort to sustain the connection to the people and places left behind. In the end, the paper shows that extension to the territory  3of another state yields far more constraints than those found on home soil as well as unpredictable reactions from receiving states and their peoples, not to speak of nationals who no longer perceive the migrants as full members of the society they left