Historically, women in Pakistan’s northwestern territories bordering Afghanistan have played a critical role in providing money and men to jihadist organizations such as the Taliban, Al-Qaeda, and “Islamic State in Iraq and Syria” (ISIS). Lack of education, too little exposure and a male-dominated conservative milieu constitute some of the ingredients of support for these outfits. This was true for over three decades and the phenomenon remained restricted to the rural, backward northwestern regions. But since the early 1990s, outfits such as the Al-Hudda Foundation – an exclusively women-focused organization – began serving as the initial hooks for middle- and upper-class women whom the Foundation targets. It brainwashes women into using hijab, and also into believing that they need to forge an alliance against the West and work for an Islamic, Sharia-based state. This advocacy turns many affluent women into religious radicals who can potentially work as the first line of recruits for extremist outfits like Daesh/IS. However small their numbers, these women represent a big threat to the global liberal values of society.

In this paper, we place the Trans-Atlantic Trade and Investment Partnership (TTIP) into broader geo-political and economic context given the current Trump Administration's withdrawal from the Trans Pacific Partnership (TPP) and the loss of momentum for TTIP. Both TPP and TTIP sought to provide key tactical solutions to the particular trade/investment problems participating states faced. For the U.S. government, these free trade agreements also represented a geo-political undertaking, an attempt to once again set trade rules in light of deadlock in the WTO. Ultimately, the inability of the Obama Administration to successfully complete negotiations for and ratification of these two deals does not alter the underlying motivations that led to them in the first place. The stagnation of these deals, however, has intensified geo-economic and geo-strategic concerns: opening the door to rival articulations of trade governance and undermining U.S. credibility with its partners.

Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.

Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).

Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.

Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

To functionally classify AU-rich elements (AREs) from six different cytokine mRNAs, we made use of two previously described HT1080-derived cellular mutants (slowA, slowC) that lack a function required for the rapid degradation of interleukin-3 (IL-3) mRNA. Here we show that the defect is specific for ARE-containing mRNAs, whereas nonsense-mediated decay is intact. Degradation of β-globin reporter transcripts mediated by the AREs of IL-3, GM-CSF, and TNFα, as well as by the structurally different and less potent AREs of IL-2 and IL-6, is impaired in both mutants. All these reporter transcripts are also sensitive to decay induced by ectopic expression of the RNA-binding protein tristetraprolin in the slowC background. Thus, we concluded that the mutants slowA and slowC define a common mRNA degradation pathway that targets cytokine AREs. In NIH3T3 cells, this decay pathway becomes incapacitated by upstream signaling from p38 MAP- or PI3-kinases, which independently stabilize cytokine ARE-containing transcripts. In contrast, c-fos ARE-directed mRNA degradation proceeds through a different pathway not affected by these kinases.