A mouse model for oral squamous cell carcinoma

Despite recent advances, the prognosis of oral squamous cell carcinoma is still poor. Therapeutic options such as radiotherapy, chemotherapy, surgery and the novel treatment option gene therapy are being investigated in animal models. Diverse models have been studied to induce oral squamous cell carcinomas. The carcinogenic 4-nitroquinoline-1-oxide (4NQO) model has proven to be successful although until now it is unknown at what time point the established tumor is a representative squamous cell carcinoma and has a suitable volume for scientific treatment. For this end we applied 4NQO 3 times a week during 16 weeks and measured the volume of tumor tissue each week until the end of the experiment at 40 weeks. Concurrent histopathology at different time points up to the end of the experiment revealed that all mice bearing oral tumors were diagnosed with squamous cell carcinoma. Immunohistochemistry with markers cyclin D1 and E-cadherin revealed that the generated mouse oral tumors showed strong similarities with the described immunopathology in human oral tumors. The 4NQO model is a suitable alternative for preclinical gene therapy experiments with primary oral tumors. Future survey of therapeutic options in the carcinogenic 4NQO model should be conducted around 40 weeks after the start of the treatment

Effectiveness of an add-on guided internet-based emotion regulation training (E-TRAIN) in adolescents with depressive and/or anxiety disorders: study protocol for a multicenter randomized controlled trial

During adolescence, depressive and anxiety disorders are among the most common mental health disorders. Both disorders tend to persist, are predictive for other mental disorders, and are associated with severe impairment in diverse areas. Although Cognitive Behavioral Therapy (CBT) has proven to be an effective treatment, a considerable number of adolescents do not respond to CBT and residual symptoms often remain. Therefore, it is of great importance to improve treatment outcomes for depressed and/or anxious adolescents. Dysfunctional emotion regulation appears to be a transdiagnostic factor in the development and maintenance of aforementioned disorders. Enhancing emotion regulation skills may therefore reduce symptom severity. In light of this, we developed a guided internet-based emotion regulation training (E-TRAIN) that will be added to CBT. This study aims to evaluate the effectiveness of E-TRAIN + CBT compared to CBT alone on depressive and anxiety outcomes among adolescents with depressive and/or anxiety disorder. Methods: In this multicenter two-arm randomized controlled trial with parallel group design, we aim to include 138 adolescents, aged 13–19 years, referred for treatment and diagnosed with depressive and/or anxiety disorder. Participants will be allocated to either CBT or CBT + E-TRAIN. Assessments will take place at baseline, and at 3 (T1), 6 (T2) and 12 (T3) months after baseline. We will conduct multi-informant assessments: the adolescent, a parent/caregiver, and the CBT therapist will be asked to fill in questionnaires. The continuous primary outcome measure is self-reported depressive and anxiety symptoms at six months after baseline, measured with the RCADS25. Secondary outcome measures include anxiety or depression diagnosis based on a semi-structured clinical interview, emotion (dys) regulation, and parent-report measures of anxiety, depression and emotion (dys) regulation. Discussion: This study is the first randomized controlled trial to examine the additional value of a guided internet-based emotion regulation training to regular CBT in adolescents with depressive and/or anxiety disorders. If this intervention is effective, it can be implemented in mental health care and improve treatment for these young people. Trial registration: Registered on June 23, 2021 in The Netherlands Trial Register (NL9564). Retrospectively registered. Recruitment started in May 2021 and is ongoing

Qualitative evaluation of a form for standardized information exchange between orthopedic surgeons and occupational physicians

BACKGROUND: Both occupational physicians and orthopedic surgeons can be involved in the management of work relevant musculoskeletal disorders. These physicians hardly communicate with each other and this might lead to different advices to the patient. Therefore, we evaluated a standardized information exchange form for the exchange of relevant information between the orthopedic surgeon and the occupational physician. The main goals of this qualitative study are to evaluate whether the form improved information exchange, whether the form gave relevant information, and to generate ideas to further improve this information exchange. METHODS: The information exchange form was developed in two consensus meetings with five orthopedic surgeons and five occupational physicians. To evaluate the information exchange form, a qualitative evaluation was set up. Structured telephone interviews were undertaken with the patients, interviews with the physicians were face-to-face and semi-structured, based on a topic list. These interviews were recorded and literally transcribed. Each interview was analyzed separately in Atlas-Ti. RESULTS: The form was used for 8 patients, 7 patients agreed to participate in the qualitative evaluation. All three orthopedic surgeons involved and three of the six involved occupational physicians agreed to be interviewed. The form was transferred to 4 occupational physicians, the other 3 patients recovered before they visited the occupational physician. The information on the form was regarded to be useful. All orthopedic surgeons agreed that the occupational physician should take the initiative. Most physicians felt that the form should not be filled out for each patient visiting an orthopedic surgeon, but only for those patients who do not recover as expected. Orthopedic surgeons suggested that a copy of the medical information provided to the general practitioner could also be provided to occupational physicians. CONCLUSION: The information exchange form was regarded to be useful and could be used in practice. The occupational physician should take the initiative for using this form and most physicians felt the information should only be exchanged for patients who do not recover as expected. That means that the advantage of giving information early in the treatment is lost

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model

<p>Abstract</p> <p>Background</p> <p>Antibodies directed against haemagglutinin, measured by the haemagglutination inhibition (HI) assay are essential to protective immunity against influenza infection. An HI titre of 1:40 is generally accepted to correspond to a 50% reduction in the risk of contracting influenza in a susceptible population, but limited attempts have been made to further quantify the association between HI titre and protective efficacy.</p> <p>Methods</p> <p>We present a model, using a meta-analytical approach, that estimates the level of clinical protection against influenza at any HI titre level. Source data were derived from a systematic literature review that identified 15 studies, representing a total of 5899 adult subjects and 1304 influenza cases with interval-censored information on HI titre. The parameters of the relationship between HI titre and clinical protection were estimated using Bayesian inference with a consideration of random effects and censorship in the available information.</p> <p>Results</p> <p>A significant and positive relationship between HI titre and clinical protection against influenza was observed in all tested models. This relationship was found to be similar irrespective of the type of viral strain (A or B) and the vaccination status of the individuals.</p> <p>Conclusion</p> <p>Although limitations in the data used should not be overlooked, the relationship derived in this analysis provides a means to predict the efficacy of inactivated influenza vaccines when only immunogenicity data are available. This relationship can also be useful for comparing the efficacy of different influenza vaccines based on their immunological profile.</p

Mycoplasma Contamination Revisited: Mesenchymal Stromal Cells Harboring Mycoplasma hyorhinis Potently Inhibit Lymphocyte Proliferation In Vitro

Mesenchymal stromal cells (MSC) have important immunomodulatory effects that can be exploited in the clinical setting, e.g. in patients suffering from graft-versus-host disease after allogeneic stem cell transplantation. In an experimental animal model, cultures of rat T lymphocytes were stimulated in vitro either with the mitogen Concanavalin A or with irradiated allogeneic cells in mixed lymphocyte reactions, the latter to simulate allo-immunogenic activation of transplanted T cells in vivo. This study investigated the inhibitory effects of rat bone marrow-derived MSC subsequently found to be infected with a common mycoplasma species (Mycoplasma hyorhinis) on T cell activation in vitro and experimental graft-versus-host disease in vivo.We found that M. hyorhinis infection increased the anti-proliferative effect of MSC dramatically, as measured by both radiometric and fluorimetric methods. Inhibition could not be explained solely by the well-known ability of mycoplasmas to degrade tritiated thymidine, but likely was the result of rapid dissemination of M. hyorhinis in the lymphocyte culture.This study demonstrates the potent inhibitory effect exerted by M. hyorhinis in standard lymphocyte proliferation assays in vitro. MSC are efficient vectors of mycoplasma infection, emphasizing the importance of monitoring cell cultures for contamination

Designing a spoken dialogue interface to an intelligent cognitive assistant for people with dementia

Intelligent cognitive assistants support people who need help performing everyday tasks by detecting when problems occur and providing tailored and context-sensitive assistance. Spoken dialogue interfaces allow users to interact with intelligent cognitive assistants while focusing on the task at hand. In order to establish\ud requirements for voice interfaces to intelligent cognitive assistants, we conducted three focus groups with people with dementia, carers, and older people without a diagnosis of dementia. Analysis of the focus group data showed that voice and interaction style should be chosen based on the preferences of the user, not those of the carer. For people with dementia, the intelligent cognitive assistant should act like a patient,encouraging guide, while for older people without dementia, assistance should be to the point and not patronising. The intelligent cognitive assistant should be able to adapt to cognitive decline

Epigenetic Dysregulation in Mesenchymal Stem Cell Aging and Spontaneous Differentiation

BACKGROUND: Mesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation

Mesenchymal Stromal Cells Engage Complement and Complement Receptor Bearing Innate Effector Cells to Modulate Immune Responses

Infusion of human third-party mesenchymal stromal cells (MSCs) appears to be a promising therapy for acute graft-versus-host disease (aGvHD). To date, little is known about how MSCs interact with the body's innate immune system after clinical infusion. This study shows, that exposure of MSCs to blood type ABO-matched human blood activates the complement system, which triggers complement-mediated lymphoid and myeloid effector cell activation in blood. We found deposition of complement component C3-derived fragments iC3b and C3dg on MSCs and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. MSCs bound low amounts of immunoglobulins and lacked expression of complement regulatory proteins MCP (CD46) and DAF (CD55), but were protected from complement lysis via expression of protectin (CD59). Cell-surface-opsonization and anaphylatoxin-formation triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation in blood. The complement-activating properties of individual MSCs were furthermore correlated with their potency to inhibit PBMC-proliferation in vitro, and both effector cell activation and the immunosuppressive effect could be blocked either by using complement inhibitor Compstatin or by depletion of CD14/CD11b-high myeloid effector cells from mixed lymphocyte reactions. Our study demonstrates for the first time a major role of the complement system in governing the immunomodulatory activity of MSCs and elucidates how complement activation mediates the interaction with other immune cells

Human Cord Blood Stem Cell-Modulated Regulatory T Lymphocytes Reverse the Autoimmune-Caused Type 1 Diabetes in Nonobese Diabetic (NOD) Mice

Background: The deficit of pancreatic islet b cells caused by autoimmune destruction is a crucial issue in type 1 diabetes (T1D). It is essential to fundamentally control the autoimmunity for treatment of T1D. Regulatory T cells (Tregs) play a pivotal role in maintaining self-tolerance through their inhibitory impact on autoreactive effector T cells. An abnormality of Tregs is associated with initiation of progression of T1D. Methodology/Principal Findings: Here, we report that treatment of established autoimmune-caused diabetes in NOD mice with purified autologous CD4 + CD62L + Tregs co-cultured with human cord blood stem cells (CB-SC) can eliminate hyperglycemia, promote islet b-cell regeneration to increase b-cell mass and insulin production, and reconstitute islet architecture. Correspondingly, treatment with CB-SC-modulated CD4 + CD62L + Tregs (mCD4CD62L Tregs) resulted in a marked reduction of insulitis, restored Th1/Th2 cytokine balance in blood, and induced apoptosis of infiltrated leukocytes in pancreatic islets. Conclusions/Significance: These data demonstrate that treatment with mCD4CD62L Tregs can reverse overt diabetes