Phase 1 Trial of Fruquintinib in Patients with Advanced Solid Tumors: Results of the Dose Escalation Phase.

Background: Fruquintinib (Fruq) is a potent, highly selective, novel vascular endothelial growth factor receptor (VEGFR) -1, -2, and -3 tyrosine kinase inhibitor. In the Phase III FRESCO trial1 that led to the drug approval in China, Fruq improved the median overall survival in patients with metastatic colorectal cancer (mCRC) in the third line or later setting when compared to placebo (9.3 vs 6.6 months); hazard ratio 0.65 (95% CI, 0.51-0.83; P \u3c .001), Methods: This is a Phase 1 open-label, dose escalation/dose expansion study conducted in the US (NCT03251378). The primary objectives are to evaluate the safety and tolerability of Fruq in pts with advanced solid tumors and to determine the recommended phase 2 dose (RP2D). A secondary objective is to evaluate anticancer activity. There were 2 dose cohorts: 3mg and 5 mg qd, each on a 3 weeks on, 1 week (3/1) off schedule. Results: Fourteen pts were enrolled: 7 (6 evaluable) pts in each dose cohort. Fruq was generally well-tolerated. There was 1 dose-limiting toxicity (DLT) of grade 4 hypertension in the 3 mg cohort, and no DLTs in the 5 mg cohort. The RP2D was 5 mg qd (3/1), which is also the approved dose in China. Two other serious adverse events were reported: colon obstruction and left breast cellulitis; neither was suspected to be drug-related. All 14 pts reported AEs; the most common were vomiting (57%), nausea (50%), constipation (50%, proteinuria (50%), hypertension (50%), dysphonia (43%), anorexia (36%), and dyspepsia (36%). Ten pts were evaluable for best objective response; results were partial response 3, stable disease 6, and disease progression 1. Objective response rate was 3/14 (21.4%) and disease control rate was 9/14 (64.3%). Mean duration on study drug was 5.3 months. Conclusion: Fruq is generally well-tolerated in heavily pretreated patients. The RP2D in US pts is 5 mg qd (3/1). The safety profile is consistent with that of other anti-angiogenic tyrosine kinase inhibitors. There is preliminary evidence of anticancer activity in pts with advanced solid tumors. The dose expansion phase of the study is ongoing. Further investigation of Fruq in pts with mCRC is planned. 1. JAMA 2018; 319:2486

Sexual violence in Iraq: Challenges for transnational feminist politics

The article discusses sexual violence by ISIS against women in Iraq, particularly Yezidi women, against the historical background of broader sexual and gender-based violence. It intervenes in feminist debates about how to approach and analyse sexual and wider gender-based violence in Iraq specifically and the Middle East more generally. Recognizing the significance of positionality, the article argues against dichotomous positions and for the need to look at both macrostructural configurations of power pertaining to imperialism, neoliberalism and globalization on the one hand, and localized expressions of patriarchy, religious interpretations and practices and cultural norms on the other hand. Finally, the article reflects on the question of what a transnational feminist solidarity might look like in relation to sexual violence by ISIS

Identification of Genes Required for Neural-Specific Glycosylation Using Functional Genomics

Glycosylation plays crucial regulatory roles in various biological processes such as development, immunity, and neural functions. For example, α1,3-fucosylation, the addition of a fucose moiety abundant in Drosophila neural cells, is essential for neural development, function, and behavior. However, it remains largely unknown how neural-specific α1,3-fucosylation is regulated. In the present study, we searched for genes involved in the glycosylation of a neural-specific protein using a Drosophila RNAi library. We obtained 109 genes affecting glycosylation that clustered into nine functional groups. Among them, members of the RNA regulation group were enriched by a secondary screen that identified genes specifically regulating α1,3-fucosylation. Further analyses revealed that an RNA–binding protein, second mitotic wave missing (Swm), upregulates expression of the neural-specific glycosyltransferase FucTA and facilitates its mRNA export from the nucleus. This first large-scale genetic screen for glycosylation-related genes has revealed novel regulation of fucTA mRNA in neural cells

Insight into the Regulation of Glycan Synthesis in Drosophila Chaoptin Based on Mass Spectrometry

BACKGROUND: A variety of N-glycans attached to protein are known to involve in many important biological functions. Endoplasmic reticulum (ER) and Golgi localized enzymes are responsible to this template-independent glycan synthesis resulting glycoforms at each asparagine residues. The regulation mechanism such glycan synthesis remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In order to investigate the relationship between glycan structure and protein conformation, we analyzed a glycoprotein of Drosophila melanogaster, chaoptin (Chp), which is localized in photoreceptor cells and is bound to the cell membrane via a glycosylphosphatidylinositol anchor. Detailed analysis based on mass spectrometry revealed the presence of 13 N-glycosylation sites and the composition of the glycoform at each site. The synthetic pathway of glycans was speculated from the observed glycan structures and the composition at each N-glycosylation site, where the presence of novel routes were suggested. The distribution of glycoforms on a Chp polypeptide suggested that various processing enzymes act on the exterior of Chp in the Golgi apparatus, although virtually no enzyme can gain access to the interior of the horseshoe-shaped scaffold, hence explaining the presence of longer glycans within the interior. Furthermore, analysis of Chp from a mutant (RNAi against dolichyl-phosphate alpha-d-mannosyltransferase), which affects N-glycan synthesis in the ER, revealed that truncated glycan structures were processed. As a result, the distribution of glycoforms was affected for the high-mannose-type glycans only, whereas other types of glycans remained similar to those observed in the control and wild-type. CONCLUSIONS/SIGNIFICANCE: These results indicate that glycan processing depends largely on the backbone structure of the parent polypeptide. The information we obtained can be applied to other members of the LRR family of proteins

Nautilus at Risk – Estimating Population Size and Demography of Nautilus pompilius

The low fecundity, late maturity, long gestation and long life span of Nautilus suggest that this species is vulnerable to over-exploitation. Demand from the ornamental shell trade has contributed to their rapid decline in localized populations. More data from wild populations are needed to design management plans which ensure Nautilus persistence. We used a variety of techniques including capture-mark-recapture, baited remote underwater video systems, ultrasonic telemetry and remotely operated vehicles to estimate population size, growth rates, distribution and demographic characteristics of an unexploited Nautilus pompilius population at Osprey Reef (Coral Sea, Australia). We estimated a small and dispersed population of between 844 and 4467 individuals (14.6–77.4 km−2) dominated by males (83∶17 male∶female) and comprised of few juveniles (<10%).These results provide the first Nautilid population and density estimates which are essential elements for long-term management of populations via sustainable catch models. Results from baited remote underwater video systems provide confidence for their more widespread use to assess efficiently the size and density of exploited and unexploited Nautilus populations worldwide