Differences in the rate of lymph node invasion in men with clinically localized prostate cancer might be related to the continent of origin

OBJECTIVETo test whether the rate of lymph node invasion (LNI) differs between patients treated with radical prostatectomy (RP) at a European or a North American centre.PATIENTS AND METHODSIn all, 1385 men had RP with bilateral lymphadenectomy for clinically localized prostate cancer (587 from Dallas, Texas and 798 from Milan, Italy). Univariate and multivariate analyses focused on the association between the continent of origin and the rate of LNI, after controlling for prostate‐specific antigen (PSA) level, clinical stage, biopsy Gleason sum and the number of examined and removed lymph nodes.RESULTSEuropean men had higher PSA levels (9.1 vs 7.8 ng/mL), a higher proportion of palpable cancers (44.5 vs 32.8%), more nodes removed (mean 14.9 vs 7.8) and a higher rate of LNI (9.0% vs 1.2%; all differences P < 0.001). In multivariate analyses that controlled for PSA level and clinical variables, European men had an 8.9‐fold higher risk of LNI (P < 0.001) than their counterparts from the USA. Among preoperative variables, the continent of origin was the third most informative predictor of LNI (67.5%), after biopsy Gleason sum (74.3%) and the number of examined lymph nodes (71.0%), and improved the ability to predict LNI by 4.7%.CONCLUSIONMen treated at a European centre had a 7.3–8.9‐fold higher rate of LNI, despite adjusting for all clinical and pathological variables. It remains to be shown what predisposes European men to a higher rate of LNI

Serum sclerostin levels in renal cell carcinoma patients with bone metastases

Sclerostin has been proposed as a potent inhibitor of bone formation. Sclerostin antibodies are under clinical development to treat osteoporosis and metastatic bone disease. Serum sclerostin level is elevated in multiple myeloma, an osteolytic malignancy, where it might serve as predictive marker for the use of sclerostin-directed antibodies. As renal cell carcinoma (RCC) patients often present with osteolytic metastases, we aimed to investigate serum sclerostin levels in RCC patients. Our study included 53 RCC patients (19 with bone metastases, 25 with visceral metastases and 9 with localized disease) and 53 age- and gender-matched non-osteoporotic controls. Frozen serum samples were subjected to sclerostin quantitative sandwich ELISA. The mean serum sclerostin levels of RCC patients and controls were 45.8 pmol/l and 45.1 pmol/l, respectively (p = 0.86). Analysis of variance showed no difference between the subgroups of RCC patients with regard to visceral or bone metastases or localized disease (p = 0.22). There was no significant association between eGFR (estimated glomerular filtration rate) and serum sclerostin levels in RCC patients (r = 0.05; p = 0.74) and controls (r = 0.06; p = 0.68). Our results indicate that serum sclerostin levels appear not to be a valuable biomarker to assess the occurrence of bone metastases in RCC patients

ПОБОЧНЫЕ ЭФФЕКТЫ СОРАФЕНИБА, СУНИТИНИБА И ТЕМСИРОЛИМУСА И ИХ ЛЕЧЕНИЕ У БОЛЬНЫХ МЕТАСТАТИЧЕСКИМ ПОЧЕЧНО-КЛЕТОЧНЫМ РАКОМ

Objective: to provide a systematic review of the adverse reactions of sorafenib, sunitinib, and temsirolimus and to outline actions for their prevention and correction.Materials and methods. To provide a description of the main methods to decrease the toxicity of these drugs, the authors made a systemat- ic review of their adverse reactions, by using the publications available in the PubMed database, monographs on the medicines, and instruc- tions for their medical use. Results. The frequency of their adverse reactions varied from &lt; 1 to 72%. Grades III—IV side effects are noted more rarely; their incidence is &lt; 1 to 13% for sorafenib, &lt; 1 to 16% for sunitinib, and 1 to 20% for temsirolimus. Sinitinib causes most grades III—IV adverse reactions and sofafenib does the least. However, close comparative studies of the safety of these kinase inhibitors are still lacking. Virtually all side effects can be effectively prevented and treated.  Conclusion. The prevention, timely recognition, and treatment of the adverse reactions of these agents are of great importance, which allows avoidance of the unneeded dosage reduction that may result in worse therapeutic efficiency.   Цель исследования — представить систематический обзор побочных эффектов сорафениба, сунитиниба и темсиролимуса, а также в общих чертах описать меры по их предупреждению и коррекции. Материалы и методы. Для того чтобы представить описание основных методов, направленных на снижение токсичности этих препаратов, нами проведен систематический обзор побочных эффектов на основе публикаций в базе данных PubMed, монографий по лекарственным препаратам и инструкций по их медицинскому применению.Результаты. Частота развития побочных эффектов варьирует от &lt; 1 до 72%. Побочные эффекты III—IV степени отмечаются реже, частота их возникновения от &lt; 1 до 13% для сорафениба, от &lt; 1 до 16% — для сунитиниба и от 1 до 20% — для темсиролимуса. Сунитиниб вызывает наибольшее количество побочных эффектов III—IV степени, а сорафениб — наименьшее. Однако все еще отсутствуют тщательные сравнительные клинические исследования безопасности этих ингибиторов киназ. Практически все побочные эффекты можно эффективно предупреждать и лечить.Заключение. Большое значение имеют профилактика, своевременное распознавание и лечение побочных эффектов этих препаратов, что позволяет избежать ненужного снижения дозы, грозящего ослаблением эффективности лечения.

Tuba, a Cdc42 GEF, is required for polarized spindle orientation during epithelial cyst formation

An RNAi screen picks Tuba out of the GTPase exchange factor (GEF) orchestra as a regulator of cell polarity in epithelial morphogenesis. (See also a companion paper from Rodriguez-Fraticelli et al., in this issue.

Two TPX2-Dependent Switches Control the Activity of Aurora A

Aurora A is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. Its activation could be regulated by ATP cycle and its activator TPX2. To understand the activation mechanism of Aurora A, a series of 20 ns molecular dynamics (MD) simulations were performed on both the wild-type kinase and its mutants. Analyzing the three dynamic trajectories (Aurora A-ATP, Aurora A-ADP, and Aurora A-ADP-TPX2) at the residue level, for the first time we find two TPX2-dependent switches, i.e., switch-1 (Lys-143) and switch-2 (Arg-180), which are tightly associated with Aurora A activation. In the absence of TPX2, Lys-143 exhibits a “closed” state, and becomes hydrogen-bonded to ADP. Once TPX2 binding occurs, switch-1 is forced to “open” the binding site, thus pulling ADP away from Aurora A. Without facilitation of TPX2, switch-2 exits in an “open” conformation which accompanies the outward-flipping movement of P·Thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. However, with the binding of TPX2, switch-2 is forced to undergo a “closed” movement, thus capturing P·Thr288 into a buried position and locking its active conformation. Analysis of two Aurora A (K143A and R180A) mutants for the two switches further verifies their functionality and reliability in controlling Aurora activity. Our systems therefore suggest two switches determining Aurora A activation, which are important for the development of aurora kinase inhibitors

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Two TPX2-Dependent Switches Control the Activity of Aurora A

Aurora A is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. Its activation could be regulated by ATP cycle and its activator TPX2. To understand the activation mechanism of Aurora A, a series of 20 ns molecular dynamics (MD) simulations were performed on both the wild-type kinase and its mutants. Analyzing the three dynamic trajectories (Aurora A-ATP, Aurora A-ADP, and Aurora A-ADP-TPX2) at the residue level, for the first time we find two TPX2-dependent switches, i.e., switch-1 (Lys-143) and switch-2 (Arg-180), which are tightly associated with Aurora A activation. In the absence of TPX2, Lys-143 exhibits a “closed” state, and becomes hydrogen-bonded to ADP. Once TPX2 binding occurs, switch-1 is forced to “open” the binding site, thus pulling ADP away from Aurora A. Without facilitation of TPX2, switch-2 exits in an “open” conformation which accompanies the outward-flipping movement of P·Thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. However, with the binding of TPX2, switch-2 is forced to undergo a “closed” movement, thus capturing P·Thr288 into a buried position and locking its active conformation. Analysis of two Aurora A (K143A and R180A) mutants for the two switches further verifies their functionality and reliability in controlling Aurora activity. Our systems therefore suggest two switches determining Aurora A activation, which are important for the development of aurora kinase inhibitors

Cdc42 Regulates Apical Junction Formation in Human Bronchial Epithelial Cells through PAK4 and Par6B

A systematic screen of Cdc42 targets was carried out in human bronchial epithelial cells. Two kinases, PAK4 and Par6B/aPKC, were identified and are required for maturation of primordial junctions into apical junctions. PAK4 recruitment to primordial junctions is Cdc42-dependent, but maintenance at junctions during maturation is Par6B-dependent

Radiating on Oceanic Islands: Patterns and Processes of Speciation in the Land Snail Genus Theba (Risso 1826)

Island radiations have played a major role in shaping our current understanding of allopatric, sympatric and parapatric speciation. However, the fact that species divergence correlates with island size emphasizes the importance of geographic isolation (allopatry) in speciation. Based on molecular and morphological data, we investigated the diversification of the land snail genus Theba on the two Canary Islands of Lanzarote and Fuerteventura. Due to the geological history of both islands, this study system provides ideal conditions to investigate the interplay of biogeography, dispersal ability and differentiation in generating species diversity. Our analyses demonstrated extensive cryptic diversification of Theba on these islands, probably driven mainly by non-adaptive allopatric differentiation and secondary gene flow. In a few cases, we observed a complete absence of gene flow among sympatrically distributed forms suggesting an advanced stage of speciation. On the Jandía peninsula genome scans suggested genotype-environment associations and potentially adaptive diversification of two closely related Theba species to different ecological environments. We found support for the idea that genetic differentiation was enhanced by divergent selection in different environments. The diversification of Theba on both islands is therefore best explained by a mixture of non-adaptive and adaptive speciation, promoted by ecological and geomorphological factors