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

<Abstract of published report>Two Flavonol Glycosides, Hexandrasides C and D, from the Underground Parts of Vancouveria hexandra.

Penelitian dalam skripsi ini yaitu membahas permasalahan mengenai bentuk perlindungan hukum terhadap anak korban perkosaan berdasarkan keadilan restoratif dalam sistem peradilan pidana anak serta kelemahan peraturan perundang-undangan dalam mengatur bentuk perlindungan hukum terhadap anak korban perkosaan. Banyak peraturan yang mengatur mengenai bentuk perlindungan hukum terhadap anak korban kejahatan yang dalam hal ini adalah perkosaan, yaitu diatur dalam KUHP, KUHAP, Undang-undang Nomor 11 tahun 2012 tentang Sistem Peradilan Pidana Anak, Undang-undang Nomor 23 Tahun 2002 Jo Undang-undang Nomor 35 Tahun 2014 tentang Perlindungan Anak, dan Undang-undang Nomor 13 Tahun 2006 Jo Undang-undang Nomor 31 Tahun 2014 tentang Perlindungan Saksi dan Korban. Namun terdapat kelemahan peraturan perundang-undangan dalam mengatur bentuk perlindungan hukum terhadap anak korban perkosaan sehingga bentuk perlindungan hukum antara  kepada pelaku dan korban lebih banyak ditujukan kepada pelaku.   Kata Kunci: Bentuk Perlindungan Hukum, Anak Korban Perkosaan, Keadilan Restoratif dalam Sistem Peradilan Pidana Ana

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

Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation

PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell–cell junctions, was impaired in Tie2Cre;Piezo1cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell–cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation

Vertical Distribution and Migration Patterns of Nautilus pompilius

Vertical depth migrations into shallower waters at night by the chambered cephalopod Nautilus were first hypothesized early in the early 20th Century. Subsequent studies have supported the hypothesis that Nautilus spend daytime hours at depth and only ascend to around 200 m at night. Here we challenge this idea of a universal Nautilus behavior. Ultrasonic telemetry techniques were employed to track eleven specimens of Nautilus pompilius for variable times ranging from one to 78 days at Osprey Reef, Coral Sea, Australia. To supplement these observations, six remotely operated vehicle (ROV) dives were conducted at the same location to provide 29 hours of observations from 100 to 800 meter depths which sighted an additional 48 individuals, including five juveniles, all deeper than 489 m. The resulting data suggest virtually continuous, nightly movement between depths of 130 to 700 m, with daytime behavior split between either virtual stasis in the relatively shallow 160–225 m depths or active foraging in depths between 489 to 700 m. The findings also extend the known habitable depth range of Nautilus to 700 m, demonstrate juvenile distribution within the same habitat as adults and document daytime feeding behavior. These data support a hypothesis that, contrary to previously observed diurnal patterns of shallower at night than day, more complex vertical movement patterns may exist in at least this, and perhaps all other Nautilus populations. These are most likely dictated by optimal feeding substrate, avoidance of daytime visual predators, requirements for resting periods at 200 m to regain neutral buoyancy, upper temperature limits of around 25°C and implosion depths of 800 m. The slope, terrain and biological community of the various geographically separated Nautilus populations may provide different permutations and combinations of the above factors resulting in preferred vertical movement strategies most suited for each population

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