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The histiocytoses comprise a histopathologically and clinically diverse group of disorders bearing recurrent genomic alterations, commonly involving the BRAFgene and mitogen-activated protein kinase pathway. In the current study, a novel CLTC::SYKfusion in 3 cases of a histopathologically distinct histiocytic neoplasm arising as solitary soft tissue lesions in children identified by next-generation sequencing and fluorescence in situ hybridization is described. Morphologically, all 3 neoplasms were composed of sheets of cells with round-oval nuclei and vacuolated eosinophilic cytoplasm but, in contrast to classic juvenile xanthogranuloma (JXG), Touton giant cells were absent. A separate cohort of classic JXG cases subsequently profiled by fluorescence in situ hybridization were negative for the presence of a CLTC::SYKfusion suggesting that CLTC::SYKfusion-positive histiocytoma is genetically and histologically distinct from JXG. We postulate that the CLTC::SYKfusion leads to aberrant activation of the SYK kinase, which is involved in variable pathways, including mitogen-activated protein kinase. The identification of a novel CLTC::SYKfusion may pave the way for the development of targeted therapeutic options for aggressive disease.

Purpose: Surgeons now have a variety of treatment options for Dupuytren’s contracture including traditional partial fasciectomy (PF), percutaneous needle aponeurotomy (PNA), and collagenase Clostridium histolyticum(CCH) injection. An important factor in clinical decision making is the cost-effectiveness of the various modalities, as will be discussed in this article.Methods: A literature search was performed by 2 independent reviewers. A total of 14 articles and 3 abstracts met inclusion criteria. Papers were excluded for non-English language, insufficient breakdown of costs by treatment type, promotional materials, or works-in-progress. Cost data were extracted and subsequently converted to US dollars. Weighted means were used to objectively pool data that were sufficiently similar in methodology and population.Results: Seven observational cohort studies were pooled and found to have a weighted mean cost in favour of PNA at US$3335 per patient as compared to CCH at US$3673.14 and PF at US$4734.14. Two expected-value decision analysis models were in agreement that PF is not cost-effective, but they differed on whether PNA or CCH was the most cost-effective strategy. Two cost minimization studies agreed that CCH was less costly than PF by US$486. One cost–benefit analysis found no significant cost benefit to CCH or PF, but found significant indirect benefit to CCH. Overall 10 of 17 studies found CCH to be superior with respect to direct cost, indirect cost, or both. Only 2 of the 17 studies found PF to be the most cost-effective method. Of the 7 studies that considered PNA, 4 found it to be lowest cost.Conclusion: The vast majority of studies found PF to be the most costly treatment modality; however, it is still the treatment of choice in certain clinical scenarios. It is difficult to compare CCH to PNA, as many studies did not consider PNA. More studies, especially considering indirect costs, are required to be able to accurately determine which method is most cost-effective.

Weightlifting is a highly technical sport that is governed by interactions of phases to optimize the load lifted. Given the technicality of the snatch and the clean and jerk, understanding key stable components to identify errors and better prescribe relevant exercises are warranted. The aim of this article is to present an applied method of analysis for coaches that considers the biomechanical underpinnings of optimal technique through stable interactions of the kinetics and kinematics of the lifter and barbell at key phases of the lift. This article will also look to discuss variable components that may differentiate between athletes and therefore provide a foundation in what to identify when coaching weightlifting to optimize load lifted while allowing for individual variances.

Liquid biopsy, or the capacity to noninvasively isolate and analyze plasma tumor DNA (ptDNA) using blood samples, represents an important tool for modern oncology that enables increasingly safe, personalized, and robust cancer diagnosis and treatment. Here, we review advances in the development and implementation of liquid biopsy approaches, and we focus on the capacity of liquid biopsy to noninvasively detect oncological disease and enhance early detection strategies. In addition to noting the distinctions between mutation-targeted and mutation-agnostic approaches, we discuss the potential for genomic analysis and longitudinal testing to identify somatic lesions early and to guide intervention at more manageable disease stages.

Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling. Enhancing SYK activity by inducing expression of a constitutively active SYK mutant, SYK130E, increased growth factor-stimulated migration and invasion of ovarian cancer cells, which was abrogated by cortactin knockdown. Similarly, SYK inhibitors significantly decreased invasion of ovarian cancer cells across basement membrane in real-time transwell assays and in 3D tumor spheroid models. SYK inactivation by targeted gene knockout or by small molecule inhibition reduced actin polymerization. Collectively, this study reported a new mechanism by which SYK signaling regulates ovarian cancer cell motility and invasiveness, and suggest a target-based strategy to prevent or suppress the advancement of ovarian malignancies.

The present study was undertaken to assess the health-related quality of life in patients with Dupuytren’s disease who undergo palmar fasciectomy.

Prion diseases exhibit different disease phenotypes in their natural hosts and when transmitted to rodents, and this variability is regarded as indicative of prion strain diversity. Phenotypic characterization of scrapie strains in sheep can be attempted by histological, immunohistochemical and biochemical approaches, but it is widely considered that strain confirmation and characterization requires rodent bioassay. Examples of scrapie strains obtained from original sheep isolates by serial passage in mice include ME7, 79A, 22A and 87V. In order to address aspects of prion strain stability across the species barrier, we transmitted the above murine strains to sheep of different breeds and susceptible Prnpgenotypes. The experiment included 40 sheep dosed by the oral route alone and 36 sheep challenged by combined subcutaneous and intracerebral routes. Overall, the combined route produced higher attack rates (~100%) than the oral route (~50%) and 2–4 times shorter incubation periods. Uniquely, 87V given orally was unable to infect any sheep. Overall, scrapie strains adapted and cloned in mice produce distinct but variable disease phenotypes in sheep depending on breed or Prnpgenotype. Further re-isolation experiments in mice are in progress in order to determine whether the original cloned murine disease phenotype will reemerge.

GDP-mannose transporters (GMT) carry GDP-mannose nucleotide sugars from the cytosol across the Golgi apparatus membrane for use as substrates in protein glycosylation in plants, animals and fungi. Genomes of some fungal species, such as the yeast Saccharomyces cerevisiae, contain only one gene encoding a GMT, while others, including Aspergillus nidulans, contain two (gmtAand gmtB). We previously showed that cell wall integrity and normal hyphal morphogenesis in A. nidulansdepend upon the function of GmtA and that GmtA localizes to a Golgi-like compartment. Cells bearing the calI11 mutation in gmtAalso have reduced cell surface mannosylation. Here we show that GmtB colocalizes with GmtA, suggesting that the role of GmtB is similar to that of GmtA, although the respective transcript levels differ during spore germination and early development. Transcript levels of gmtBare high in ungerminated spores and remain so throughout the first 16 h of germination. In contrast, transcript levels of gmtAare negligible in ungerminated spores but increase to levels comparable to those of gmtBduring germination. These observations suggest that although GmtA and GmtB reside within the same subcellular compartments, they nevertheless perform distinct functions at different stages of development.

The centrosome is the major organelle responsible for the nucleation and organization of microtubules into arrays.  Recent studies demonstrate that microtubules can nucleate outside the centrosome.  The molecular mechanisms controlling acentrosomal microtubule nucleation are currently poorly defined, and the function of this type of microtubule regulation in tumor cell biology is particularly unclear.  Since microtubule nucleation is initiated by the gamma-tubulin protein, we examined the regulation of gamma-tubulin in a panel of human breast tumor cell lines, ranging from non-tumorigenic to highly aggressive.  We have identified a more dispersive subcellular localization of gamma-tubulin in aggressive breast cancer cell lines, while gamma-tubulin localization remains largely centrosomal in non-invasive cell lines.  Delocalization of gamma-tubulin occurs independently from changes in protein expression and is therefore regulated at the post-translational level.  Subcellular fractionation revealed that tumor cell lines show an aberrantly increased release of gamma-tubulin into a soluble cytoplasmic fraction, with the most dramatic changes observed in tumor cell lines of greater metastatic potential.  Extraction of soluble gamma-tubulin revealed acentrosomal incorporation of gamma-tubulin in cytoplasmic microtubules and along cell junctions.  Moreover, acentrosomal delocalization of gamma-tubulin yielded resistance to colchicine-mediated microtubule collapse.  These findings support a model where the solubility of gamma-tubulin can be altered through post-translational modification and provides a new mechanism for microtubule dysregulation in breast cancer.  Gamma-tubulin which is delocalized from the centrosome can still clearly be incorporated into filaments, and defines a novel mechanism for tumor cells to develop resistance to microtubule-targeted chemotherapies.

Iatrogenic transmission by blood transfusion has been described in cases of human variant Creutzfeldt-Jakob disease (vCJD), experimental ovine bovine spongiform encephalopathy (BSE), and natural sheep scrapie, demonstrating that blood in these prion diseases is infectious. However, the possible effect of the transfusion, derived from differences in the inoculum (blood) and the route of infection (intravenous), on the pathologic phenotype of the disease in the recipients is not known. This study describes the neuropathologic phenotype of PrPd accumulation in sheep succumbing to neurologic disease after blood transfusion from donors experimentally infected with BSE; these were either clinically or subclinically affected at the time of donation. We demonstrate that blood can become infectious at early stages of ovine BSE infection and that the PrPd immunohistochemical phenotype is maintained after transfusion. This suggests that a change in the pathologic phenotype of vCJD would not be expected as a result of exposure to infected blood.

Iatrogenic transmission by blood transfusion has been described in cases of human variant Creutzfeldt-Jakob disease (vCJD), experimental ovine bovine spongiform encephalopathy (BSE), and natural sheep scrapie, demonstrating that blood in these prion diseases is infectious. However, the possible effect of the transfusion, derived from differences in the inoculum (blood) and the route of infection (intravenous), on the pathologic phenotype of the disease in the recipients is not known. This study describes the neuropathologic phenotype of PrPdaccumulation in sheep succumbing to neurologic disease after blood transfusion from donors experimentally infected with BSE; these were either clinically or subclinically affected at the time of donation. We demonstrate that blood can become infectious at early stages of ovine BSE infection and that the PrPdimmunohistochemical phenotype is maintained after transfusion. This suggests that a change in the pathologic phenotype of vCJD would not be expected as a result of exposure to infected blood.

ABSTRACTMany tumor cells are impaired in adhesion-regulated apoptosis, which contributes to their metastatic potential. However, suppression of this apoptotic pathway in untransformed cells is not mediated only by adhesion to the extracellular matrix but also through the resulting ability to spread and adopt a distinct morphology. Since cell spreading is dependent on the integrity of the actin microfilament cytoskeleton, we sought to determine if actin depolymerization was sufficient to induce apoptosis, even in the presence of continuous attachment. For this study, we used a human mammary epithelial cell line (MCF10A), which is immortalized but remains adhesion dependent for survival. Treatment of MCF10A cells with latrunculin-A (LA), an inhibitor of actin polymerization, rapidly led to disruption of the actin cytoskeleton and caused cell rounding but preserved attachment. Initiation of apoptosis in LA-treated MCF10A cells was detected by mitochondrial localization of the Bax apoptotic protein, which was prevented by overexpression of Bcl-2. DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage in LA-treated MCF10A cells indicated progression to the execution phase of apoptosis. The MDA-MB-453 cell line, which was derived from a metastatic human mammary tumor, was resistant to PARP cleavage and loss of viability in response to actin depolymerization. Stable overexpression of Bcl-2 in the untransformed MCF10A cells was able to recapitulate the resistance to apoptosis found in the tumor cell line. We demonstrate that inhibition of actin polymerization is sufficient to stimulate apoptosis in attached MCF10A cells, and we present a novel role for Bcl-2 in cell death induced by direct disruption of the actin cytoskeleton.

Many tumor cells are impaired in adhesion-regulated apoptosis, which contributes to their metastatic potential. However, suppression of this apoptotic pathway in untransformed cells is not mediated only by adhesion to the extracellular matrix but also through the resulting ability to spread and adopt a distinct morphology. Since cell spreading is dependent on the integrity of the actin microfilament cytoskeleton, we sought to determine if actin depolymerization was sufficient to induce apoptosis, even in the presence of continuous attachment. For this study, we used a human mammary epithelial cell line (MCF10A), which is immortalized but remains adhesion dependent for survival. Treatment of MCF10A cells with latrunculin-A (LA), an inhibitor of actin polymerization, rapidly led to disruption of the actin cytoskeleton and caused cell rounding but preserved attachment. Initiation of apoptosis in LA-treated MCF10A cells was detected by mitochondrial localization of the Bax apoptotic protein, which was prevented by overexpression of Bcl-2. DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage in LA-treated MCF10A cells indicated progression to the execution phase of apoptosis. The MDA-MB-453 cell line, which was derived from a metastatic human mammary tumor, was resistant to PARP cleavage and loss of viability in response to actin depolymerization. Stable overexpression of Bcl-2 in the untransformed MCF10A cells was able to recapitulate the resistance to apoptosis found in the tumor cell line. We demonstrate that inhibition of actin polymerization is sufficient to stimulate apoptosis in attached MCF10A cells, and we present a novel role for Bcl-2 in cell death induced by direct disruption of the actin cytoskeleton.

In this paper, we study if the following properties are present in defect 3 blocks of symmetric group algebras kGn, where k has characteristic p (≥5):the Ext-quiver is bipartite;the p.i.m.'s have a common Loewy length 7.We obtain a criteria for a defect 3 block B of kGn to inherit these properties from a defect 3 block B˜ of kGn−1, with which it forms a [3:1]-pair. We also verify that the principal blocks of kGn (3p≤n≤4p−1) have these properties.

Abstract.: We give a complete classification of the classical Schur algebras and the infinitesimal Schur algebras which have tame representation type. In combination with earlier work of some of the authors on semisimplicity and finiteness, this completes the classification of representation type of all classical and infinitesimal Schur algebras in all characteristics.

This paper describes the adoption and implementation of the programme of Assertive Discipline at an outer London comprehensive school. Observations aimed at discovering to what extent the innovation was successful are presented and discussed. Seven potential problems are identified and considered along with implications for future practice. A persistent theme is the inadequacy of systems perspectives in explaining organisational change. In conclusion, it is recommended that the implementation of innovations must be evaluated from a variety of different perspectives.

Integrin-mediated cell adhesion triggers intracellular signaling cascades, including tyrosine phosphorylation of intracellular proteins. We show in this report that p120cbl(Cbl), the 120-kDa c-cblproto-oncogene product, becomes tyrosine-phosphorylated during integrin-mediated macrophage cell adhesion to extracellular matrix substrata and anti-integrin antibodies. This tyrosine phosphorylation does not occur when cells attach to polylysine, to which cells adhere in a nonspecific fashion. It also does not take place when adhesion-induced reorganization of the cytoskeleton is inhibited with cytochalasin D. In contrast to the rapid and transient tyrosine phosphorylation of Cbl by CSF-1 stimulation, tyrosine phosphorylation of Cbl by cell attachment was gradual and persistent. Tyrosine-phosphorylated Cbl was found to form complexes with the SH2 domain-containing signaling proteins Src and phosphatidylinositol 3-kinase; in vitrokinase assays demonstrated that these kinases were active in the Cbl complexes following integrin ligand binding. Furthermore, Cbl was found to translocate to the plasma membrane in response to cell adhesion to fibronectin. These observations suggest that Cbl serves as a docking protein and may transduce signals to downstream signaling pathways following integrin-mediated cell adhesion in macrophages.

ABSTRACTTyrosine kinase receptors lead to rapid activation of phosphatidylinositol 3-kinase (PI3 kinase) and the subsequent formation of phosphatidylinositides (PtdIns) 3,4-P2 and PtdIns 3,4,5-P3, which are thought to be involved in signaling for glucose transporter GLUT4 translocation, cytoskeletal rearrangement, and DNA synthesis. However, the specific role of each of these PtdIns in insulin and growth factor signaling is still mainly unknown. Therefore, we assessed, in the current study, the effect of SH2-containing inositol phosphatase (SHIP) expression on these biological effects. SHIP is a 5' phosphatase that decreases the intracellular levels of PtdIns 3,4,5-P3. Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin-induced GLUT4 translocation by 100 ± 21% (mean ± the standard error) at submaximal (3 ng/ml) and 64 ± 5% at maximal (10 ng/ml) insulin concentrations (P< 0.05 and P< 0.001, respectively). A catalytically inactive mutant of SHIP had no effect on insulin-induced GLUT4 translocation. Furthermore, SHIP also abolished GLUT4 translocation induced by a membrane-targeted catalytic subunit of PI3 kinase. In addition, insulin-, insulin-like growth factor I (IGF-I)-, and platelet-derived growth factor-induced cytoskeletal rearrangement, i.e., membrane ruffling, was significantly inhibited (78 ± 10, 64 ± 3, and 62 ± 5%, respectively; P< 0.05 for all) in 3T3-L1 adipocytes. In a rat fibroblast cell line overexpressing the human insulin receptor (HIRc-B), SHIP inhibited membrane ruffling induced by insulin and IGF-I by 76 ± 3% (P< 0.001) and 68 ± 5% (P< 0.005), respectively. However, growth factor-induced stress fiber breakdown was not affected by SHIP expression. Finally, SHIP decreased significantly growth factor-induced mitogen-activated protein kinase activation and DNA synthesis. Expression of the catalytically inactive mutant had no effect on these cellular responses. In summary, our results show that expression of SHIP inhibits insulin-induced GLUT4 translocation, growth factor-induced membrane ruffling, and DNA synthesis, indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions.

The insulin-responsive aminopeptidase (IRAP) is a constituent of the vesicles that contain the insulin-regulated glucose transporter (Glut4). Like Glut4, IRAP translocates to the cell surface in response to insulin. Microinjection into 3T3-L1 adipocytes of a glutathione S-transferase (GST) fusion protein containing the cytosolic portion of IRAP (GST-IRAP-(1–109)), resulted in translocation of Glut4 to the cell surface. Immunostaining of 3T3-L1 adipocytes for Glut4 showed that the percentage of cells with substantial cell surface Glut4 was 10% in unstimulated cells, 8% following injection of GST, and 27% following injection of GST-IRAP-(1–109). Increased cell surface Glut4 occurred within 5–10 min following injection and was maintained for at least 4 h. A fusion protein containing only 28 amino acids from IRAP (GST-IRAP-(55–82)) was as effective in increasing cell surface Glut4 as stimulation with 100 nminsulin (44% versus43%, respectively). In contrast to insulin-stimulated Glut4 translocation, the redistribution of Glut4 following injection of GST-IRAP-(55–82) was not blocked by wortmannin or co-injection with a SH2 domain from the regulatory subunit of phosphatidylinositol 3-kinase. These data suggest that the amino terminus of IRAP interacts with a retention/sorting protein that also regulates the distribution of Glut4 in insulin-responsive cells.

Tyrosine kinase receptors lead to rapid activation of phosphatidylinositol 3-kinase (PI3 kinase) and the subsequent formation of phosphatidylinositides (PtdIns) 3,4-P2 and PtdIns 3,4,5-P3, which are thought to be involved in signaling for glucose transporter GLUT4 translocation, cytoskeletal rearrangement, and DNA synthesis. However, the specific role of each of these PtdIns in insulin and growth factor signaling is still mainly unknown. Therefore, we assessed, in the current study, the effect of SH2-containing inositol phosphatase (SHIP) expression on these biological effects. SHIP is a 5′ phosphatase that decreases the intracellular levels of PtdIns 3,4,5-P3. Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin-induced GLUT4 translocation by 100 ± 21% (mean ± the standard error) at submaximal (3 ng/ml) and 64 ± 5% at maximal (10 ng/ml) insulin concentrations (P< 0.05 and P< 0.001, respectively). A catalytically inactive mutant of SHIP had no effect on insulin-induced GLUT4 translocation. Furthermore, SHIP also abolished GLUT4 translocation induced by a membrane-targeted catalytic subunit of PI3 kinase. In addition, insulin-, insulin-like growth factor I (IGF-I)-, and platelet-derived growth factor-induced cytoskeletal rearrangement, i.e., membrane ruffling, was significantly inhibited (78 ± 10, 64 ± 3, and 62 ± 5%, respectively; P< 0.05 for all) in 3T3-L1 adipocytes. In a rat fibroblast cell line overexpressing the human insulin receptor (HIRc-B), SHIP inhibited membrane ruffling induced by insulin and IGF-I by 76 ± 3% (P< 0.001) and 68 ± 5% (P< 0.005), respectively. However, growth factor-induced stress fiber breakdown was not affected by SHIP expression. Finally, SHIP decreased significantly growth factor-induced mitogen-activated protein kinase activation and DNA synthesis. Expression of the catalytically inactive mutant had no effect on these cellular responses. In summary, our results show that expression of SHIP inhibits insulin-induced GLUT4 translocation, growth factor-induced membrane ruffling, and DNA synthesis, indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions.

The Early Devonian Yackandandah Granite in northeast Victoria was emplaced along the western boundary of the Omeo Metamorphic Complex. Deformation of probable mid-Devonian age resulted in the formation of a ductile shear zone in the granite, termed the Kiewa shear zone. Displacement of granite boundaries and shear-zone fabrics, including excellently developed S-C fabrics, indicate that the shear zone accommodated ∼7 km of sinistral strike-slip displacement, with no evidence for thrusting as suggested in previous studies. Detailed mapping of fabrics across the shear zone suggest that ∼ 70% of strain was accommodated by the formation of the finite strain foliation (S-planes), with the remaining strain accommodated by discrete slip along C-planes parallel to the shear-zone boundary.

Let n and n denote the symmetric and alternating groups of degree n∈ℕ respectively. Let p be a prime number and let F be an arbitrary field of characteristic p. We say that a partition of n is p-regular if no p (non-zero) parts of it are equal; otherwise we call it p-singular. Let SλF denote the Specht module corresponding to λ. For λ a p-regular partition of n let DλF denote the unique irreducible top factor of SλF. Denote by ΔλF =DλF ↓n its restriction to n. Recall also that, over F, the ordinary quiver of the modular group algebra FG is a finite directed graph defined as follows: the vertices are labelled by the set of all simple FG-modules, L1, ..., Lr, and the number of arrows from Li to Lj equals dimFExtFG(Li, Lj). The quiver gives important information about the block structure of G.

Cytoskeleton stiffness, which is affected by the abundance of detyrosinated tubulin, regulates mechanosensitivity in osteocytes.