Free Flap Selection and Outcomes of Soft Tissue Reconstruction Following Resection of Intra-oral Malignancy.

Introduction: Surgery to resect intra-oral malignancy is a well-established mode of primary treatment. The tissue requirement in this area is for a thin, pliable flap with minimal bulk and this has historically been provided by free tissue transfer with a radial forearm free flap (RFFF). More recently, a role for the anterolateral thigh free flap (ALTFF) has been described, although in populations with a westernized diet, body habitus may preclude use of an ALTFF due to flap thickness, relative to a radial forearm free flap. Methods: An analysis of data was performed retrospectively for 90 consecutive patients with intra-oral malignancy, requiring immediate soft tissue reconstruction by the senior author, at Addenbrooke's Hospital between July 2008 and April 2016. Cases requiring bony reconstruction were excluded. Data on patient age, sex, indication for surgery, tumor location and defect type, complications, success rates, and length of stay were recorded. Results: The majority of patients received an ALTFF (n = 56) with 38% receiving a RFFF (n = 34). Surgical resection took place in the floor of the mouth most frequently. These were closed with ALTFF and RFFF in 41 and 28 occasions, respectively. A success rate of 97% was observed in the RFFF group; 1 flap developed partial necrosis and required complete revision. In the ALTFF group, there was a 100% flap success rate. ALTFF usage resulted in a reduction in the number of intraoperative (p = 0.021) in addition a reduction in the number of days in ITU (p = 0.01) and post-operative clinic visits (p = 0.025). Conclusion: We present a series that used predominately the ALTFF to reconstruct intra-oral defects following resection of squamous cell carcinoma in a Western population. The results demonstrate that this treatment can produce at least as comparable results as to the use of a RFFF repair in this population, whilst avoiding the donor site morbidity and aesthetic compromise of a RFFF

From mesenchymal niches to engineered in vitro model systems: Exploring and exploiting biomechanical regulation of vertebrate hedgehog signalling

Tissue patterning is the result of complex interactions between transcriptional programs and various mechanical cues that modulate cell behaviour and drive morphogenesis. Vertebrate Hedgehog signalling plays key roles in embryogenesis and adult tissue homeostasis, and is central to skeletal development and the osteogenic differentiation of mesenchymal stem cells. The expression of several components of the Hedgehog signalling pathway have been reported to be mechanically regulated in mesodermal tissue patterning and osteogenic differentiation in response to external stimulation. Since a number of bone developmental defects and skeletal diseases, such as osteoporosis, are directly linked to aberrant Hedgehog signalling, a better knowledge of the regulation of Hedgehog signalling in the mechanosensitive bone marrow-residing mesenchymal stromal cells will present novel avenues for modelling these diseases and uncover novel opportunities for extracellular matrix-targeted therapies. In this review, we present a brief overview of the key molecular players involved in Hedgehog signalling and the basic concepts of mechanobiology, with a focus on bone development and regeneration. We also highlight the correlation between the activation of the Hedgehog signalling pathway in response to mechanical cues and osteogenesis in bone marrow-derived mesenchymal stromal cells. Finally, we propose different tissue engineering strategies to apply the expanding knowledge of 3D material-cell interactions in the modulation of Hedgehog signalling in vitro for fundamental and translational research applications

Bioinspired Precision Engineering of Three‐Dimensional Epithelial Stem Cell Microniches

Maintenance of the epithelium relies on stem cells residing within specialized microenvironments, known as epithelial crypts. Two‐photon polymerization (2PP) is a valuable tool for fabricating 3D micro/nanostructures for stem cell niche engineering applications. Herein, biomimetic gelatin methacrylate‐based constructs, replicating the precise geometry of the limbal epithelial crypt structures (limbal stem cell “microniches”) as an exemplar epithelial niche, are fabricated using 2PP. Human limbal epithelial stem cells (hLESCs) are seeded within the microniches in xeno‐free conditions to investigate their ability to repopulate the crypts and the expression of various differentiation markers. Cell proliferation and a zonation in cell phenotype along the z‐axis are observed without the use of exogenous signaling molecules. Significant differences in cell phenotype between cells located at the base of the microniche and those situated towards the rim are observed, demonstrating that stem cell fate is strongly influenced by its location within a niche and the geometrical details of where it resides. This study provides insight into the influence of the niche’s spatial geometry on hLESCs and demonstrates a flexible approach for the fabrication of biomimetic crypt‐like structures in epithelial tissues. This has significant implications for regenerative medicine applications and can ultimately lead to implantable synthetic “niche‐based” treatments

Designing topographically textured microparticles for induction and modulation of osteogenesis in mesenchymal stem cell engineering

Mesenchymal stem cells are the focus of intense research in bone development and regeneration. The potential of microparticles as modulating moieties of osteogenic response by utilizing their architectural features is demonstrated herein. Topographically textured microparticles of varying microscale features are produced by exploiting phase-separation of a readily soluble sacrificial component from polylactic acid. The influence of varying topographical features on primary human mesenchymal stem cell attachment, proliferation and markers of osteogenesis is investigated. In the absence of osteoinductive supplements, cells cultured on textured microparticles exhibit notably increased expression of osteogenic markers relative to conventional smooth microparticles. They also exhibit varying morphological, attachment and proliferation responses. Significantly altered gene expression and metabolic profiles are observed, with varying histological characteristics in vivo. This study highlights how tailoring topographical design offers cell-instructive 3D microenvironments which allow manipulation of stem cell fate by eliciting the desired downstream response without use of exogenous osteoinductive factors

A Two-stage Flow-based Intrusion Detection Model ForNext-generation Networks

The next-generation network provides state-of-the-art access-independent services over converged mobile and fixed networks. Security in the converged network environment is a major challenge. Traditional packet and protocol-based intrusion detection techniques cannot be used in next-generation networks due to slow throughput, low accuracy and their inability to inspect encrypted payload. An alternative solution for protection of next-generation networks is to use network flow records for detection of malicious activity in the network traffic. The network flow records are independent of access networks and user applications. In this paper, we propose a two-stage flow-based intrusion detection system for next-generation networks. The first stage uses an enhanced unsupervised one-class support vector machine which separates malicious flows from normal network traffic. The second stage uses a self-organizing map which automatically groups malicious flows into different alert clusters. We validated the proposed approach on two flow-based datasets and obtained promising results

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basi

Clarifying the role of three-dimensional transvaginal sonography in reproductive medicine: an evidenced-based appraisal

This overview describes and illustrates the clinical applications of three-dimensional transvaginal sonography in reproductive medicine. Its main applications include assessment of uterine anomalies, intrauterine pathology, tubal patency, polycystic ovaries, ovarian follicular monitoring and endometrial receptivity. It is also useful for detailed evaluation of failed and/or ectopic pregnancy. Three-dimensional color Doppler sonography provides enhanced depiction of uterine, endometrial, and ovarian vascularity

Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus

BACKGROUND: IL-10 has a potent inhibitory effect on osteoclastogenesis. In vitro and in vivo studies confirm the importance of this cytokine in bone metabolism, for instance IL-10-deficient mice develop the hallmarks of osteoporosis. Although it is known that IL-10 directly inhibits osteoclastogenesis at an early stage, preventing differentiation of osteoclast progenitors to preosteoclasts, the precise mechanism of its action is not yet clear. Several major pathways regulate osteoclastogenesis, with key signalling genes such as p38, TRAF6, NF-κB and NFATc1 well established as playing vital roles. We have looked at gene expression in eleven of these genes using real-time quantitative PCR on RNA extracted from RANKL-treated RAW264.7 monocytes. RESULTS: There was no downregulation by IL-10 of DAP12, FcγRIIB, c-jun, RANK, TRAF6, p38, NF-κB, Gab2, Pim-1, or c-Fos at the mRNA level. However, we found that IL-10 significantly reduces RANKL-induced NFATc1 expression. NFATc1 is transcribed from two alternative promoters in Mus musculus and, interestingly, only the variant transcribed from promoter P1 and beginning with exon 1 was downregulated by IL-10 (isoform 1). In addition, immunofluorescence studies showed that IL-10 reduces NFATc1 levels in RANKL-treated precursors and suppresses nuclear translocation. The inhibitory effect of IL-10 on tartrate-resistant acid phosphatase-positive cell number and NFATc1 mRNA expression was reversed by the protein kinase C agonist phorbol myristate acetate, providing evidence that interleukin-10 disrupts NFATc1 activity through its effect on Ca(2+ )mobilisation. CONCLUSION: IL-10 acts directly on mononuclear precursors to inhibit NFATc1 expression and nuclear translocation, and we provide evidence that the mechanism may involve disruption of Ca(2+ )mobilisation. We detected downregulation only of the NFATc1 isoform 1 transcribed from promoter P1. This is the first report indicating that one of the ways in which IL-10 directly inhibits osteoclastogenesis is by suppressing NFATc1 activity

Relative effects of sensory modalities and importance of fatty acid sensitivity on fat perception in a real food model

Fat can be perceived through mouthfeel, odour and taste, but the influence of these modalities on fat perception remains undefined. Fatty acids are stimuli. Individual’s sensitivity to fatty acids varies. Studies show association between fatty acid sensitivity, dietary intake and BMI, but results are conflicting. Therefore, this study examined this association, and the effects of modalities on fat perception. Two sub-studies conducted. In Study 1 (n=46), fat intensity was assessed by milk/cream mixtures varying by five fat levels. Fat intensity was rated under four conditions: mouthfeel-odour masked, mouthfeel masked, odour masking and no masking. Mouthfeel masking was achieved using thickener and paraffin, odour masking using nose-clips. Fatty acid sensitivity was measured by 3-AFC-staircase method using milk containing oleic acid (0.31-31.4mM). In Study 2 (n=51), more fat levels were added in fat intensity rating. A 2-AFC discrimination test was used to confirm whether fat levels could be distinguished. In the sensitivity test, a wider range of oleic acid was included. Fat intensity was rated higher without nose-clips (p<0.0001), implying that odour increased fat perception. Samples with mouthfeel-masked were rated higher, showing that increased viscosity and lubricity enhanced fat perception (p<0.0001). Participants could distinguish fat levels based on “taste” in rating tests and 2-AFC-tests. Participants were divided into high/medium/low-sensitivity groups. No significant difference found in fat intensity between groups, however, high-sensitivity group discriminated more fat levels. No association between sensitivity groups, nutrient intake or BMI found

Multicenter retrospective analysis of 581 patients with primary intestinal non-hodgkin lymphoma from the Consortium for Improving Survival of Lymphoma (CISL)

<p>Abstract</p> <p>Background</p> <p>Primary intestinal non-Hodgkin lymphoma (NHL) is a heterogeneous disease with regard to anatomic and histologic distribution. Thus, analyses focusing on primary intestinal NHL with large number of patients are warranted.</p> <p>Methods</p> <p>We retrospectively analyzed 581 patients from 16 hospitals in Korea for primary intestinal NHL in this retrospective analysis. We compared clinical features and treatment outcomes according to the anatomic site of involvement and histologic subtypes.</p> <p>Results</p> <p>B-cell lymphoma (n = 504, 86.7%) was more frequent than T-cell lymphoma (n = 77, 13.3%). Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (n = 386, 66.4%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) was the second most common subtype (n = 61, 10.5%). B-cell lymphoma mainly presented as localized disease (Lugano stage I/II) while T-cell lymphomas involved multiple intestinal sites. Thus, T-cell lymphoma had more unfavourable characteristics such as advanced stage at diagnosis, and the 5-year overall survival (OS) rate was significantly lower than B-cell lymphoma (28% versus 71%, P < 0.001). B symptoms were relatively uncommon (20.7%), and bone marrow invasion was a rare event (7.4%). The ileocecal region was the most commonly involved site (39.8%), followed by the small (27.9%) and large intestines (21.5%). Patients underwent surgery showed better OS than patients did not (5-year OS rate 77% versus 57%, P < 0.001). However, this beneficial effect of surgery was only statistically significant in patients with B-cell lymphomas (P < 0.001) not in T-cell lymphomas (P = 0.460). The comparison of survival based on the anatomic site of involvement showed that ileocecal regions had a better 5-year overall survival rate (72%) than other sites in consistent with that ileocecal region had higher proportion of patients with DLBCL who underwent surgery. Age > 60 years, performance status ≥ 2, elevated serum lactate dehydrogenase, Lugano stage IV, presence of B symptoms, and T-cell phenotype were independent prognostic factors for survival.</p> <p>Conclusions</p> <p>The survival of patients with ileocecal region involvement was better than that of patients with involvement at other sites, which might be related to histologic distribution, the proportion of tumor stage, and need for surgical resection.</p