The Rho‐associated (ROCK) serine/threonine kinases have emerged as central regulators of the actomyosin cytoskeleton, their main purpose being to promote contractile force generation. Aided by the ...discovery of effective inhibitors such as Y27632, their roles in cancer have been extensively explored with particular attention focused on motility, invasion and metastasis. Recent studies have revealed a surprisingly diverse range of functions of ROCK. These insights could change the way ROCK inhibitors might be used in cancer therapy to include the targeting of stromal rather than tumour cells, the concomitant blocking of ROCK and proteasome activity in K‐Ras‐driven lung cancers and the combination of ROCK with tyrosine kinase inhibitors for treating haematological malignancies such as chronic myeloid leukaemia. Despite initial optimism for therapeutic efficacy of ROCK inhibition for cancer treatment, no compounds have progressed into standard therapy so far. However, by carefully defining the key cancer types and expanding the appreciation of ROCK's role in cancer beyond being a cell‐autonomous promoter of tumour cell invasion and metastasis, the early promise of ROCK inhibitors for cancer therapy might still be realized.
ROCK kinases as downstream effectors of Rho GTPases have been implicated in numerous cellular processes including tumorigenesis. Therefore, interference with ROCK activity has been considered to be a potential therapeutic approach to fight cancer. This review highlights some of the recent findings that have extended our understanding of the role of ROCK signalling in cancer into unexpected and potentially clinically important areas.
ROCK kinases, which play central roles in the organization of the actin cytoskeleton, are tantalizing targets for the treatment of human diseases. Deletion of ROCK I in mice revealed a role in the ...pathophysiological responses to high blood pressure, and validated ROCK inhibition for the treatment of specific types of cardiovascular disease. To date, the only ROCK inhibitor employed clinically in humans is fasudil, which has been used safely in Japan since 1995 for the treatment of cerebral vasospasm. Clinical trials, mostly focusing on the cardiovascular system, have uncovered beneficial effects of fasudil for additional indications. Intriguing recent findings also suggest significant potential for ROCK inhibitors in the production and implantation of stem cells for disease therapies.
Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase.
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They belong to the AGC family of serine/threonine kinases
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and play vital ...roles in facilitating actomyosin cytoskeleton contractility downstream of RhoA and RhoC activation. Since their discovery, ROCK kinases have been extensively studied, unveiling their manifold functions in processes including cell contraction, migration, apoptosis, survival, and proliferation. Two mammalian ROCK homologs have been identified, ROCK1 (also called ROCK I, ROKβ, Rho-kinase β, or p160ROCK) and ROCK2 (also known as ROCK II, ROKα, or Rho kinase), hereafter collectively referred to as ROCK. In this review, we will focus on the structure, regulation, and functions of ROCK.
The 20 members of the Rho GTPase family are key regulators of a wide-variety of biological activities. In response to activation, they signal via downstream effector proteins to induce dynamic ...alterations in the organization of the actomyosin cytoskeleton. In this review, post-translational modifications, mechanisms of dysregulation identified in human pathological conditions, and the ways that Rho GTPases might be targeted for chemotherapy will be discussed.
Cancer cell metastasis is a multi-stage process involving invasion into surrounding tissue, intravasation, transit in the blood or lymph, extravasation, and growth at a new site. Many of these steps ...require cell motility, which is driven by cycles of actin polymerization, cell adhesion and acto-myosin contraction. These processes have been studied in cancer cells in vitro for many years, often with seemingly contradictory results. The challenge now is to understand how the multitude of in vitro observations relates to the movement of cancer cells in living tumour tissue. In this review we will concentrate on actin protrusion and acto-myosin contraction. We will begin by presenting some general principles summarizing the widely-accepted mechanisms for the co-ordinated regulation of actin polymerization and contraction. We will then discuss more recent studies that investigate how experimental manipulation of actin dynamics affects cancer cell invasion in complex environments and in vivo.
External loading of the ligamentous tissues induces mechanical creep, which modifies neuromuscular response to perturbations. It is not well understood how ligamentous creep affects athletic ...performance and contributes to modifications of knee biomechanics during functional tasks.
The purpose of this study was to examine the mechanical and neuromuscular responses to single leg drop landing perturbations before and after passive loading of the knee joint.
Descriptive laboratory study. Male (n = 7) and female (n = 14) participants' (21.3 ± 2.1 yrs., 1.69 ± 0.09 m, 69.3 ± 13.0 kg) right hip, knee, and ankle kinematics were assessed during drop landings performed from a 30 cm height onto a force platform before and after a 10 min creep protocol. Electromyography (EMG) signals were recorded from rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM), semimembranosus (SM), and biceps femoris (BF) muscles. The creep protocol involved fixing the knee joint at 35° during static loading with perpendicular loads of either 200 N (males) or 150 N (females). Maximum, minimum, range of motion (ROM), and angular velocities were assessed for the hip, knee, and ankle joints, while normalized EMG (NEMG), vertical ground reaction forces (VGRF), and rate of force development (RFD) were assessed at landing using ANOVAs. Alpha was set at 0.05.
Maximum hip flexion velocity decreased (p < 0.01). Minimum knee flexion velocity increased (p < 0.02). Minimum knee ad/abduction velocity decreased (p < 0.001). Ankle ROM decreased (p < 0.001). aVGRF decreased (p < 0.02). RFD had a non-significant trend (p = 0.076). NAEMG was significant between muscle groups (p < 0.02).
Distinct changes in velocity parameters are attributed to the altered mechanical behavior of the knee joint tissues and may contribute to changes in the loading of the leg during landing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During the second meiotic cell division, egg cells discard one set of chromatids to the polar body to produce a large haploid gamete. Meiotic spindle rotation is a critical step to ensure proper ...polar body extrusion. In this issue, Bourdais et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202211029) have identified MRCKβ as an essential kinase for efficient spindle rotation. MRCK activates cortical myosin II rings overlying the spindle to prevent the notoriously sticky interaction between the cell cortex and chromatin to facilitate spindle rotation. Furthermore, Bourdais et al. found that the same MRCK-myosin II pathway also operates in zygotes to promote parental genome unification.
Analyzing variation in treatment effects across subsets of the population is an important way for social scientists to evaluate theoretical arguments. A common strategy in assessing such treatment ...effect heterogeneity is to include a multiplicative interaction term between the treatment and a hypothesized effect modifier in a regression model. Unfortunately, this approach can result in biased inferences due to unmodeled interactions between the effect modifier and other covariates, and including these interactions can lead to unstable estimates due to overfitting. In this paper, we explore the usefulness of machine learning algorithms for stabilizing these estimates and show how many off-the-shelf adaptive methods lead to two forms of bias: direct and indirect regularization bias. To overcome these issues, we use a post-double selection approach that utilizes several lasso estimators to select the interactions to include in the final model. We extend this approach to estimate uncertainty for both interaction and marginal effects. Simulation evidence shows that this approach has better performance than competing methods, even when the number of covariates is large. We show in two empirical examples that the choice of method leads to dramatically different conclusions about effect heterogeneity.
Staphylococcus epidermidis is a highly significant nosocomial pathogen mediating infections primarily associated with indwelling biomaterials (e.g., catheters and prostheses). In contrast to ...Staphylococcus aureus, virulence properties associated with S. epidermidis are few and biofilm formation is the defining virulence factor associated with disease, as demonstrated by animal models of biomaterial-related infections. However, other virulence factors, such as phenol-soluble modulins and poly-gamma-DL-glutamic acid, have been recently recognized that thwart innate immune system mechanisms. Formation of S. epidermidis biofilm is typically considered a four-step process consisting of adherence, accumulation, maturation and dispersal. This article will discuss recent advances in the study of these four steps, including accumulation, which can be either polysaccharide or protein mediated. It is hypothesized that studies focused on understanding the biological function of each step in staphylococcal biofilm formation will yield new treatment modalities to treat these recalcitrant infections.
Hypoglossal nerve stimulation (HGNS) therapy was approved in 2014 for the treatment of obstructive sleep apnea in patients who are intolerant to continuous positive airway pressure (CPAP) therapy, ...which is reported in up to 40–60% of patients. This therapy works via direct neurostimulation of the hypoglossal nerve in synchrony with respiration, to open the airway via tongue stiffening and protrusion. Studies have demonstrated significant reductions in both respiratory parameters such as disordered breathing indices, as well as subjective sleep complaints, such as daytime sleepiness, with the use of this therapy. This has increased the repertoire of treatment options for sleep providers to recommend to those patients that are intolerant to CPAP therapy.
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