Biomechanics and the thermotolerance of development

Successful completion of development requires coordination of patterning events with morphogenetic movements. Environmental variability challenges this coordination. For example, developing organisms encounter varying environmental temperatures that can strongly influence developmental rates. We hypothesized that the mechanics of morphogenesis would have to be finely adjusted to allow for normal morphogenesis across a wide range of developmental rates. We formulated our hypothesis as a simple model incorporating time-dependent application of force to a viscoelastic tissue. This model suggested that the capacity to maintain normal morphogenesis across a range of temperatures would depend on how both tissue viscoelasticity and the forces that drive deformation vary with temperature. To test this model we investigated how the mechanical behavior of embryonic tissue (Xenopus laevis) changed with temperature; we used a combination of micropipette aspiration to measure viscoelasticity, electrically induced contractions to measure cellular force generation, and confocal microscopy to measure endogenous contractility. Contrary to expectations, the viscoelasticity of the tissues and peak contractile tension proved invariant with temperature even as rates of force generation and gastrulation movements varied three-fold. Furthermore, the relative rates of different gastrulation movements varied with temperature: the speed of blastopore closure increased more slowly with temperature than the speed of the dorsal-to-ventral progression of involution. The changes in the relative rates of different tissue movements can be explained by the viscoelastic deformation model given observed viscoelastic properties, but only if morphogenetic forces increase slowly rather than all at once. © 2014 von Dassow et al

Emergent mechanics of actomyosin drive punctuated contractions and shape network morphology in the cell cortex.

Filamentous actin (F-actin) and non-muscle myosin II motors drive cell motility and cell shape changes that guide large scale tissue movements during embryonic morphogenesis. To gain a better understanding of the role of actomyosin in vivo, we have developed a two-dimensional (2D) computational model to study emergent phenomena of dynamic unbranched actomyosin arrays in the cell cortex. These phenomena include actomyosin punctuated contractions, or "actin asters" that form within quiescent F-actin networks. Punctuated contractions involve both formation of high intensity aster-like structures and disassembly of those same structures. Our 2D model allows us to explore the kinematics of filament polarity sorting, segregation of motors, and morphology of F-actin arrays that emerge as the model structure and biophysical properties are varied. Our model demonstrates the complex, emergent feedback between filament reorganization and motor transport that generate as well as disassemble actin asters. Since intracellular actomyosin dynamics are thought to be controlled by localization of scaffold proteins that bind F-actin or their myosin motors we also apply our 2D model to recapitulate in vitro studies that have revealed complex patterns of actomyosin that assemble from patterning filaments and motor complexes with microcontact printing. Although we use a minimal representation of filament, motor, and cross-linker biophysics, our model establishes a framework for investigating the role of other actin binding proteins, how they might alter actomyosin dynamics, and makes predictions that can be tested experimentally within live cells as well as within in vitro models

Actomyosin meshwork mechanosensing enables tissue shape to orient cell force

Sculpting organism shape requires that cells produce forces with proper directionality. Thus, it is critical to understand how cells orient the cytoskeleton to produce forces that deform tissues. During Drosophila gastrulation, actomyosin contraction in ventral cells generates a long, narrow epithelial furrow, termed the ventral furrow, in which actomyosin fibres and tension are directed along the length of the furrow. Using a combination of genetic and mechanical perturbations that alter tissue shape, we demonstrate that geometrical and mechanical constraints act as cues to orient the cytoskeleton and tension during ventral furrow formation. We developed an in silico model of two-dimensional actomyosin meshwork contraction, demonstrating that actomyosin meshworks exhibit an inherent force orienting mechanism in response to mechanical constraints. Together, our in vivo and in silico data provide a framework for understanding how cells orient force generation, establishing a role for geometrical and mechanical patterning of force production in tissues.National Institute of General Medical Sciences (U.S.) (Grant R01GM105984)American Heart Association (Grant 14GRNT18880059)European Molecular Biology Organization (Grant ALTF 1082-2012

Validation of an Endometrial Tumor Diameter Model for Risk Assessment in the Absence of Lymph Node Mapping

Purpose: This study aimed to assess the optimal tumor diameter for predicting lymphatic metastasis and to determine intraoperatively the need for lymph node dissection in patients with endometrioid endometrial cancer. Methods: Military beneficiaries diagnosed with stage I–III endometrioid endometrial cancer during 2003–2016 who had at least 7 pelvic and/or paraaortic lymph nodes removed during the time of hysterectomy were studied. Tumor diameter was compared against the presence of positive nodes, using the prior models of 20 mm (ie, Mayo model) and 50 mm (ie, Milwaukee model), to determine the false-negative rate of each threshold. A separate analysis was completed to determine the optimal diameter for our population. Receiver operating characteristic curve analysis models of tumor diameter were evaluated for model fit and predictive power of lymph node involvement. Results: Of the 1224 patients with endometrioid endometrial cancer included, 13% (n = 160) had positive lymph node involvement. Tumor sizes ranged from 1 mm to 100 mm. In contrast to Mayo and Milwaukee models (ie, Mayo, Milwaukee), the optimal tumor diameter independent of myometrial invasion and grade of tumor to predict lymph node metastasis was found to be 35 mm. Conclusions: Endometrioid endometrial cancer tumor diameter of 35 mm was found to be the optimal threshold for lymphadenectomy when the operating surgeon has no knowledge of tumor invasion

Validation of an Endometrial Tumor Diameter Model for Risk Assessment in the Absence of Lymph Node Mapping

Purpose: This study aimed to assess the optimal tumor diameter for predicting lymphatic metastasis and to determine intraoperatively the need for lymph node dissection in patients with endometrioid endometrial cancer. Methods: Military beneficiaries diagnosed with stage I–III endometrioid endometrial cancer during 2003–2016 who had at least 7 pelvic and/or paraaortic lymph nodes removed during the time of hysterectomy were studied. Tumor diameter was compared against the presence of positive nodes, using the prior models of 20 mm (ie, Mayo model) and 50 mm (ie, Milwaukee model), to determine the false-negative rate of each threshold. A separate analysis was completed to determine the optimal diameter for our population. Receiver operating characteristic curve analysis models of tumor diameter were evaluated for model fit and predictive power of lymph node involvement. Results: Of the 1224 patients with endometrioid endometrial cancer included, 13% (n = 160) had positive lymph node involvement. Tumor sizes ranged from 1 mm to 100 mm. In contrast to Mayo and Milwaukee models (ie, Mayo, Milwaukee), the optimal tumor diameter independent of myometrial invasion and grade of tumor to predict lymph node metastasis was found to be 35 mm. Conclusions: Endometrioid endometrial cancer tumor diameter of 35 mm was found to be the optimal threshold for lymphadenectomy when the operating surgeon has no knowledge of tumor invasion

Satisfaction and effectiveness of a digital health tool to improve health behavior counseling among adolescent and young adult cancer survivors: a randomized controlled pilot trial

Abstract Background This pilot study examined the preliminary effectiveness of the PREVENT digital intervention that supports health care teams in delivering health behavior counseling on cancer survivors’ motivation to change behavior, their physical activity and food intake behaviors, and cardiovascular health (CVH). Methods Clinicians (physicians, nurse practitioners) at three urban cancer survivorship clinics were trained to use PREVENT. Patients were randomized to the PREVENT intervention or a wait-list routine care control group. Eligibility criteria for patients included: between ages 12–39, overweight or obese, were at least 6-months post-active cancer treatment, and had sufficient English proficiency. Results Fifty-five participants were enrolled; 27 were randomized to the PREVENT intervention and 28 to wait-list routine care control. The majority of the participants (82%) identified as non-Hispanic white, with an average age of 19.8 (SD ± 5.2) years. Patients that received the PREVENT intervention had greater increases in their self-efficacy, vigorous activity and number of food recommendations met than those who received routine clinical care. Changes in willingness, knowledge, and CVH outcomes were not significant. Conclusions The PREVENT digital intervention may provide improvements in preventive behaviors among AYA cancer survivors by supporting care teams with delivering evidence-based, tailored behavior change recommendations and resources to support patient health. Trial registration This trial ( NCT04623190 ) was registered on 11/02/2022