University of Zurich

About: University of Zurich is a education organization based out in Zurich, Switzerland. It is known for research contribution in the topics: Population & Medicine. The organization has 50842 authors who have published 124042 publications receiving 5304521 citations. The organization is also known as: UZH & Uni Zurich.

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

Abstract: Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial

Abstract: Importance Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76;P Conclusions and Relevance In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration clinicaltrials.gov Identifier:NCT00916409

Organometallic Anticancer Compounds

Abstract: The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics). Figure 1 Summary of the typical classes of organometallic compounds used in medicinal chemistry. In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

Wave breaking for nonlinear nonlocal shallow water equations

Abstract: WAVE BREAKING FOR NONLINEAR NONLOCAL SHALLOW WATER EQUATIONS 233 THEOREM 2.1. Let T>O and vE C 1 ([0, T); H 2(R)). Then for every t~ [0, T) there exists at least one point ~(t)ER with ,~(t) := in~ Ivy(t, x)] = ~ ( t , ~(t)), and the function m is almost everywhere differentiable on (0, T) with dm dt (t)=vt~(t,~(t)) a.e. on (O,T). Proof. Let c>0 stand for a generic constant. Fix te[0, T) and define m(t):=infxcR[v~(t,x)]. If m(t))O we have that v(t , . ) is nondecreasing on R and therefore v(t,. ) 0 (recall v(t,. )cL2(R)) , so that we may assume re(t)<0. Since vx(t,. ) c H I ( R ) we see that limlxl~ ~ Vx(t, x)=0 so that there exists at least a ~(t) e R with re(t) =v~(t, ~(t)). Let now s, tC [0, T) be fixed. If re(t) <~rn(s) we have 0 < re(s) .~(t) = i n f [~x (~, x ) ] ~ ( t , ~(t)) <. ~=(~, ~(t)) -~x(t, ~(t)), and by the Sobolev embedding HI(R) C L ~ ( R ) we conclude that Im(8)-.~(t)l ~< Ivx(t)-v~(s)lL~(~) < c Iv~(t)-v~(8)l.l(R). Hence the mean-value theorem for functions with values in Banach spaces-Hi(R) in the present case--yields (see [12]) jm(t)-m(s)l<~clt-s j m a x [IVt~(T)JHI(R)], t, se[O,T). O~T~max{s,t} Since vt~cC([O,T), Hi(R)) , we see that m is locally Lipschitz on [0, T) and therefore Rademacher's theorem (cf. [14]) implies that m is almost everywhere differentiable on (0,T). Fix tC(0, T). We have that v~(t+h)-vx(t)h vt~(t) Hl(R) ---~0 as h--*O, and therefore vx( t+h ,y ) -vx ( t , y ) sup vtx(t,y) --~0 as h---~O, (2.1) ycl~ h in view of the continuous embedding H 1 ( R ) c L ~ (R). 234 A. C O N S T A N T I N AND J. E S C H E R By the definition of m, m(t+h) = v~(t+h, ((t+h)) <. v~(t+h, ((t)). Consequently, given h>0 , we obtain m( t+h) -m( t ) <<. h Letting h--~O + and using (2.1), we find lim sup m(t+h) -m( t ) h~_~0 + h

Foundations of Human Sociality - Economic Experiments and Ethnographic: Evidence From Fifteen Small-Scale Societies

Abstract: 1. Introduction and Guide to the Volume 2. Overview and Synthesis 3. Measuring Social Norms and Preferences Using Experimental Games: A Guide for Social Sciences 4. Coalitional Effects on Reciprocal Fairness in the Ultimatum Game: A Case from the Ecuadorian Amazon 5. Comparative Experimental Evidence from Machiguenga, Mapuche, Huinca, and American Populations Shows Substantial Variation Among Social Groups in Bargaining and Public Goods Behavior 6. Dictators and Ultimatums in an Egalitarian Society of Hunter-Gatherers - the Hadza of Tanzania 7. Does Market Exposure Affect Economic Game Behavior? The Ultimatum Game and the Public Goods Game Among the Tsimane of Bolivia 8. Market Integration, Reciprocity, and Fairness in Rural Papua New Guinea: Results from a Two-Village Ultimatum Game Experiment 9. Ultimatum Game with an Ethnicity Manipulation: Results from Khovdiin Bulgan Sum, Mongolia 10. Kinship, Familiarity, and Trust: An Experimental Investigation 11. Community Structure, Mobility, and the Strength of Norms in an Africa Society: the Sangu of Tanzania 12. Market Integration and Fairness: Evidence from Ultimatum, Dictator, and Public Goods Experiments in East Africa 13. Economic Experiments to Examine Fairness and Cooperation among the Ache Indians of Paraguay 14. The Ultimatum Game, Fairness, and Cooperation among Big Game Hunters