Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous mast cell tumours: A prospective study

BACKGROUND: Distant metastases in dogs with cutaneous mast cell tumors (cMCT) are rare and incurable. The aims of this prospective study were to clarify the clinico-pathological features of stage IV cMCTs and to identify possible prognostic factors for progression-free interval (PFI) and survival time (ST). MATERIAL AND METHODS: Dogs were eligible for recruitment if they had a previously untreated, histologically confirmed cMCT and if they underwent complete staging demonstrating stage IV disease. Dogs were uniformly followed-up, whereas treatment was not standardized and included no therapy, surgery, radiation therapy, chemotherapy, tyrosine-kinase inhibitors or a combination of these. RESULTS: 45 dogs with stage IV cMCT were enrolled. All dogs had distant metastatic disease, and 41 (91.1%) dogs had also metastasis in the regional lymph node. Histopathological grade and mutational status greatly varied among dogs. Median ST was 110 days. Notably, PFI and ST were independent of well-known prognostic factors, including anatomic site, histological grade, and mutational status. Conversely, tumor diameter >3\u2009cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis. CONCLUSION: Currently, there is no satisfactory treatment for stage IV cMCT. Asymptomatic dogs with tumor diameter <3\u2009cm and a low tumor burden, without bone marrow infiltration may be candidates for multimodal treatment. Stage IV dogs without lymph node metastasis may enjoy a surprisingly prolonged survival. The achievement of local tumor control seems to predict a better outcome in dogs with stage IV cMCT

Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions

The availability of therapeutic molecules to targets within cartilage depends on transport through the avascular matrix. We studied equilibrium partitioning and non-equilibrium transport into cartilage of Pf-pep, a 760 Da positively charged peptide inhibitor of the proprotein convertase PACE4. Competitive binding measurements revealed negligible binding of Pf-pep to sites within cartilage. Uptake of Pf-pep depended on glycosaminoglycan charge density, and was consistent with predictions of Donnan equilibrium given the known charge of Pf-pep. In separate transport experiments, the diffusivity of Pf-pep in cartilage was measured to be ~1 × 10[superscript −6] cm[superscript 2]/s, close to other similarly-sized non-binding solutes. These results suggest that small positively charged therapeutics will have a higher concentration within cartilage than in the surrounding synovial fluid, a desired property for local delivery; however, such therapeutics may rapidly diffuse out of cartilage unless there is additional specific binding to intra-tissue substrates that can maintain enhanced intra-tissue concentration for local delivery.National Institutes of Health (U.S.) (Grant AR45779)National Institutes of Health (U.S.) (Grant AR33236)Pfizer Inc

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

A lean six sigma framework for continuous and incremental improvement in the oil and gas sector

This article aims to explore synergies between Lean Production (LP) and Six Sigma principles in order to propose a Lean Six Sigma (LSS) framework for continuous and incremental improvement in the oil and gas sector. The Three-Dimensional LSS Framework seeks to provide various combinations about the integration between LP principles, DMAIC cycle and PDCA cycle to support operations management needs. Design/methodology/approach - The research method is composed of two main steps: (i) diagnostic of current problems and proposition of a conceptual framework that qualitatively integrates synergistic aspects of LP and Six Sigma; and (ii) analysis of the application of the construct through semi-structured interviews with leaders from oil and gas companies to assess and validate the proposed framework. Findings - As a result, a conceptual framework of LSS is developed contemplating the integration of LP and Six Sigma and providing a systemic and holistic approach to problemsolving through continuous and incremental improvement in the oil and gas sector. Originality/value - This research is different from previous studies because it integrates LP principles, DMAIC and PDCA cycles into a unique framework that fulfils a specific need of oil and gas sector. It presents a customized LSS framework that guides wastes and costs reduction, while enhances quality and reduces process variability to elevate efficiency in operations management of this sector. The paper type is an original research that present new and original scientific findings.N/

High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues.

International audienceBACKGROUND: Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent. FINDINGS: We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328-0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7). CONCLUSIONS: Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS

Trends and current aspects of reconstructive surgery for gynecological cancers

Gynecologic cancers can lead to gynecologic tract destruction with extension into both the gastrointestinal and urinary tracts. Recurrent disease can also affect the surrounding bony pelvis and pelvic musculature. As opposed to advanced ovarian cancer, where cytoreduction is the goal, in these scenarios, an oncologic approach to achieve negative margins is critical for benefit. Surgeries aimed at achieving a R0 resection in gynecologic oncology can have a significant impact on pelvic anatomy, and require reconstruction. Overall, it appears that these types of radical surgery are less frequently performed; however, when required, multidisciplinary teams at high-volume centers can potentially improve short-term morbidity. There are few data to examine the long-term, quality-of-life outcomes after reconstruction following oncologic resection in advanced and recurrent gynecologic cancers. In this review we outline considerations and approaches for reconstruction after surgery for gynecologic cancers. We also discuss areas of innovation, including minimally invasive surgery and the use of 3D surgical anatomy models for improved surgical planning. In the era of 'less is more', pelvic exenteration in gynecologic oncology is still indicated when there are no other curative-intent alternatives in persistent or recurrent gynecological malignancies confined to the pelvis or with otherwise unmanageable symptoms from fistula or radiation necrosis. Pelvic exenteration is one of the most destructive procedures performed on an elective basis, which inevitably carries a significant psychologic, sexual, physical, and emotional burden for the patient and caregivers. Such complex ultraradical surgery, which requires removal of the vagina, vulva, urinary tract, and/or gastrointestinal tract, subsequently needs creative and complex reconstructive procedures. The additional removal of sidewall or perineal structures, like pelvic floor muscles/vulva, or portions of the musculoskeletal pelvis, and the inclusion of intra-operative radiation further complicates reconstruction. This review paper will focus on the reconstruction aspects following pelvic exenteration, including options for urinary tract restoration, reconstruction of the vulva and vagina, as well as how to fill large empty spaces in the pelvis. While the predominant gastrointestinal outcome after exenteration in gynecologic oncology is an end colostomy, we also present some novel new options for gastrointestinal tract reconstruction at the end

Mass Spectrometry Imaging Disclosed Spatial Distribution of Defense-Related Metabolites in Triticum spp

Fusarium Head Blight is the most common fungal disease that strongly affects Triticum spp., reducing crop yield and leading to the accumulation of toxic metabolites. Several studies have investigated the plant metabolic response to counteract mycotoxins accumulation. However, information on the precise location where the defense mechanism is taking place is scarce. Therefore, this study aimed to investigate the specific tissue distribution of defense metabolites in two Triticum species and use this information to postulate on the metabolites’ functional role, unlocking the “location-to-function” paradigm. To address this challenge, transversal cross-sections were obtained from the middle of the grains. They were analyzed using an atmospheric-pressure (AP) SMALDI MSI source (AP-SMALDI5 AF, TransMIT GmbH, Giessen, Germany) coupled to a Q Exactive HF (Thermo Fisher Scientific GmbH, Bremen, Germany) orbital trapping mass spectrometer. Our result revealed the capability of (AP)-SMALDI MSI instrumentation to finely investigate the spatial distribution of wheat defense metabolites, such as hydroxycinnamic acid amides, oxylipins, linoleic and α-linoleic acids, galactolipids, and glycerolipids