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

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.

Regional differences in clear cell metastatic renal cell carcinoma patients across the USA

Purpose To test for regional differences in clear cell metastatic renal cell carcinoma (ccmRCC) patients across the USA. Methods The Surveillance, Epidemiology, and End Results (SEER) database (2000–2018) was used to tabulate patient (age at diagnosis, sex, race/ethnicity), tumor (N stage, sites of metastasis) and treatment characteristics (proportions of nephrectomy and systemic therapy), according to 12 SEER registries. Multinomial regression models, as well as multivariable Cox regression models, tested the overall mortality (OM) adjusting for those patient, tumor and treatment characteristics. Results In 9882 ccmRCC patients, registry-specific patient counts ranged from 4025 (41%) to 189 (2%). Differences across registries existed for sex (24–36% female), race/ethnicity (1–75% non-Caucasian), N stage (N1 25–35%, NX 3–13%), proportions of nephrectomy (44–63%) and systemic therapy (41–56%). Significant inter-registry differences remained after adjustment for proportions of nephrectomy (46–63%) and systemic therapy (35–56%). Unadjusted 5-year OM ranged from 73 to 85%. In multivariable analyses, three registries exhibited significantly higher OM (SEER registry 5: hazard ratio (HR) 1.20, p = 0.0001; SEER registry 7:HR 1.15, p = 0.008M SEER registry 10: HR 1.15, p = 0.04), relative to the largest reference registry (n = 4025). Conclusion Important regional differences including patient, tumor and treatment characteristics exist, when ccmRCC patients included in the SEER database are studied. Even after adjustment for these characteristics, important OM differences persisted, which may require more detailed analyses to further investigate these unexpected differences

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

Complex Interactions between GSK3 and aPKC in Drosophila Embryonic Epithelial Morphogenesis

Generally, epithelial cells must organize in three dimensions to form functional tissue sheets. Here we investigate one such sheet, the Drosophila embryonic epidermis, and the morphogenetic processes organizing cells within it. We report that epidermal morphogenesis requires the proper distribution of the apical polarity determinant aPKC. Specifically, we find roles for the kinases GSK3 and aPKC in cellular alignment, asymmetric protein distribution, and adhesion during the development of this polarized tissue. Finally, we propose a model explaining how regulation of aPKC protein levels can reorganize both adhesion and the cytoskeleton

An apicobasal gradient of Rac activity determines protrusion form and position

Each cell within a polarised epithelial sheet must align and correctly position a wide range of subcellular structures, including actin-based dynamic protrusions. Using in vivo inducible transgenes that can sense or modify Rac activity, we demonstrate an apicobasal gradient of Rac activity that is required to correctly form and position distinct classes of dynamic protrusion along the apicobasal axis of the cell. We show that we can modify the Rac activity gradient in genetic mutants for specific polarity proteins, with consequent changes in protrusion form and position and additionally show, using photoactivatable Rac transgenes, that it is the level of Rac activity that determines protrusion form. Thus, we demonstrate a mechanism by which polarity proteins can spatially regulate Rac activity and the actin cytoskeleton to ensure correct epithelial cell shape and prevent epithelial-to-mesenchymal transitions

A Modifier Screen for Bazooka/PAR-3 Interacting Genes in the Drosophila Embryo Epithelium

The development and homeostasis of multicellular organisms depends on sheets of epithelial cells. Bazooka (Baz; PAR-3) localizes to the apical circumference of epithelial cells and is a key hub in the protein interaction network regulating epithelial structure. We sought to identify additional proteins that function with Baz to regulate epithelial structure in the Drosophila embryo.The baz zygotic mutant cuticle phenotype could be dominantly enhanced by loss of known interaction partners. To identify additional enhancers, we screened molecularly defined chromosome 2 and 3 deficiencies. 37 deficiencies acted as strong dominant enhancers. Using deficiency mapping, bioinformatics, and available single gene mutations, we identified 17 interacting genes encoding known and predicted polarity, cytoskeletal, transmembrane, trafficking and signaling proteins. For each gene, their loss of function enhanced adherens junction defects in zygotic baz mutants during early embryogenesis. To further evaluate involvement in epithelial polarity, we generated GFP fusion proteins for 15 of the genes which had not been found to localize to the apical domain previously. We found that GFP fusion proteins for Drosophila ASAP, Arf79F, CG11210, Septin 5 and Sds22 could be recruited to the apical circumference of epithelial cells. Nine of the other proteins showed various intracellular distributions, and one was not detected.Our enhancer screen identified 17 genes that function with Baz to regulate epithelial structure in the Drosophila embryo. Our secondary localization screen indicated that some of the proteins may affect epithelial cell polarity by acting at the apical cell cortex while others may act through intracellular processes. For 13 of the 17 genes, this is the first report of a link to baz or the regulation of epithelial structure

The neurobiology of Etruscan shrew active touch

The Etruscan shrew, Suncus etruscus, is not only the smallest terrestrial mammal, but also one of the fastest and most tactile hunters described to date. The shrew's skeletal muscle consists entirely of fast-twitch types and lacks slow fibres. Etruscan shrews detect, overwhelm, and kill insect prey in large numbers in darkness. The cricket prey is exquisitely mechanosensitive and fast-moving, and is as big as the shrew itself. Experiments with prey replica show that shape cues are both necessary and sufficient for evoking attacks. Shrew attacks are whisker guided by motion- and size-invariant Gestalt-like prey representations. Shrews often attack their prey prior to any signs of evasive manoeuvres. Shrews whisk at frequencies of approximately 14 Hz and can react with latencies as short as 25–30 ms to prey movement. The speed of attacks suggests that shrews identify and classify prey with a single touch. Large parts of the shrew's brain respond to vibrissal touch, which is represented in at least four cortical areas comprising collectively about a third of the cortical volume. Etruscan shrews can enter a torpid state and reduce their body temperature; we observed that cortical response latencies become two to three times longer when body temperature drops from 36°C to 24°C, suggesting that endothermy contributes to the animal's high-speed sensorimotor performance. We argue that small size, high-speed behaviour and extreme dependence on touch are not coincidental, but reflect an evolutionary strategy, in which the metabolic costs of small body size are outweighed by the advantages of being a short-range high-speed touch and kill predator

Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model

BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by cystathionine β-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis. METHODS: To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention. RESULTS: hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca(2+)/PO(4)(3- )and lower Ca(2+)/CO(3)(2- )molar ratios than in controls. Mineral crystallization was unchanged. CONCLUSION: In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We also conclude that the hCySH-supplemented chick is a promising model for study of the connective tissue abnormalities associated with homocystinuria and an important alternative model to the CBS knock-out mouse