Miracle-dz/UniFAR-FTUs huggingface dataset:
Human Head and Neck Squamous Cell Carcinoma–Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells

One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC)–secreted Sema4D on myeloid cell differentiation. CD33+ cells cultured in HNSCC cell line–derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33+CD11b+HLA-DR−/low). The addition of anti-Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28. Importantly, CD33+ myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4+T-bet+ and CD8+T-bet+), as well as a decrease in regulatory T cells (CD4+CD25+FOXP3+). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies.
GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism

Expression of the inflammatory cytokine TNF is tightly controlled. During endotoxin tolerance, transcription of TNF mRNA is repressed, although not entirely eliminated. Production of TNF cytokine, however, is further controlled by posttranscriptional regulation. In this study, we detail a mechanism of posttranscriptional repression of TNF mRNA by GAPDH binding to the TNF 3′ untranslated region. Using RNA immunoprecipitation, we demonstrate that GAPDH–TNF mRNA binding increases when THP-1 monocytes are in a low glycolysis state, and that this binding can be reversed by knocking down GAPDH expression or by increasing glycolysis. We show that reducing glycolysis decreases TNF mRNA association with polysomes. We demonstrate that GAPDH–TNF mRNA binding results in posttranscriptional repression of TNF and that the TNF mRNA 3′ untranslated region is sufficient for repression. Finally, after exploring this model in THP-1 cells, we demonstrate this mechanism affects TNF expression in primary human monocytes and macrophages. We conclude that GAPDH–TNF mRNA binding regulates expression of TNF based on cellular metabolic state. We think this mechanism has potentially significant implications for treatment of various immunometabolic conditions, including immune paralysis during septic shock.
NK Cell Functional Impairment after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Reduced Levels of T-bet and Eomesodermin

NK cells play a major role in protection against tumor recurrence and infection after allogeneic hematopoietic stem cell transplantation (HSCT). It has been shown that NK cell function after HSCT is impaired, but underlying molecular mechanisms are not well-known. In this report we show that the level of T-bet and Eomesodermin (Eomes), two T-box transcription factors regulating lymphocyte effector functions, is strongly reduced in NK cells from HSCT recipients compared with healthy control subjects. Reduction of T-bet and Eomes expression appeared early and persisted for years after HSCT, affecting all peripheral blood NK cells independently of their differentiation status. Reduced T-bet levels in NK cells from allogeneic HSCT recipients significantly correlated with reduced perforin expression. Acute, but not chronic, graft-versus-host disease, as well as CMV reactivation, was associated with further downregulation of T-bet expression in NK cells. Lower levels of T-bet expression in NK cells were associated with less favorable outcome after HSCT as a result of increased nonrelapse mortality. Collectively, our results provide a possible molecular explanation for the previously reported functional exhaustion of NK cells after allogeneic HSCT and suggest an impact of the NK transcriptional machinery status on HSCT outcome.
Measuring hoof slip of the leading limb on jump landing over two different equine arena surfaces

The amount of hoof slip at the moment of impact can cause musculoskeletal injuries to the horse. Risk of injury is influenced by surface properties, however there is limited understanding of the effect on hoof slip during jump landing. The objectives of this study were to compare hoof slip on two different surfaces and investigate relationships between hoof slip and surface properties. A contact mat and hoof reference marker were designed and validated, the former to indicate the moment of impact and the latter to provide a visible reference marker on the lateral hoof wall. The leading right forelimb of six horses was recorded during jump landing on two different surfaces. Five trials, plus one where the forelimb landed on a contact mat were recorded at 500 Hz using a calibrated high speed camera positioned perpendicular to landing. Surface hardness, penetrability and traction were measured between horses. Horizontal displacement of the hoof reference marker was plotted and smoothed with a Butterworth fil.
Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells

Human Vγ9Vδ2 T cells are activated through their TCR by neighboring cells producing phosphoantigens. Zoledronate (ZOL) treatment induces intracellular accumulation of the phosphoantigens isopentenyl pyrophosphate and ApppI. Few attempts have been made to use immunomanipulation of Vγ9Vδ2 lymphocytes in chronic viral infections. Although Vγ9Vδ2 T cells seem to ignore human CMV (HCMV)–infected cells, we examined whether they can sense HCMV when a TCR stimulus is provided with ZOL. Fibroblasts treated with ZOL activate Vγ9Vδ2 T cells to produce IFN-γ but not TNF. Following the same treatment, HCMV-infected fibroblasts stimulate TNF secretion and an increased production of IFN-γ, indicating that Vγ9Vδ2 cells can sense HCMV infection. Increased lymphokine production was observed with most clinical isolates and laboratory HCMV strains, HCMV-permissive astrocytoma, or dendritic cells, as well as “naive” and activated Vγ9Vδ2 cells. Quantification of intracellular isopentenyl pyrophosphate/ApppI following ZOL treatment showed that HCMV infection boosts their accumulation. This was explained by an increased capture of ZOL and by upregulation of HMG-CoA synthase and reductase transcription. Using an experimental setting where infected fibroblasts were cocultured with γδ cells in submicromolar concentrations of ZOL, we show that Vγ9Vδ2 cells suppressed substantially the release of infectious particles while preserving uninfected cells. Vγ9Vδ2 cytotoxicity was decreased by HCMV infection of targets whereas anti–IFN-γ and anti-TNF Abs significantly blocked the antiviral effect. Our experiments indicate that cytokines produced by Vγ9Vδ2 T cells have an antiviral potential in HCMV infection. This should lead to in vivo studies to explore the possible antiviral effect of immunostimulation with ZOL in this context.
Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice

The class B scavenger receptors BI (SR-BI) and BII (SR-BII) are high-density lipoprotein receptors that recognize various pathogens, including bacteria and their products. It has been reported that SR-BI/II null mice are more sensitive than normal mice to endotoxin-induced inflammation and sepsis. Because the SR-BI/II knockout model demonstrates multiple immune and metabolic disorders, we investigated the role of each receptor in the LPS-induced inflammatory response and tissue damage using transgenic mice with pLiv-11–directed expression of human SR-BI (hSR-BI) or human SR-BII (hSR-BII). At 6 h after i.p. LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of proinflammatory cytokines and 2- to 3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared with wild-type (WT) mice. LPS-stimulated inducible NO synthase expression was 3- to 6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower high-density lipoprotein plasma levels, both transgenic strains responded to LPS by a 5-fold increase of plasma corticosterone levels, which were only moderately lower than in WT animals. LPS treatment resulted in MAPK activation in tissues of all mice; however, the strongest response was detected for hepatic extracellular signal–regulated protein kinase 1 and 2 and kidney JNK of both transgenic mice. Histological examination of hepatic and renal tissue from LPS-challenged mice revealed more injury in hSR-BII, but not hSR-BI, transgenic mice versus WT controls. Our findings demonstrate that hSR-BII, and to a lesser extent hSR-BI, significantly increase LPS-induced inflammation and contribute to LPS-induced tissue injury in the liver and kidney, two major organs susceptible to LPS toxicity.
Immune Modulation after Total Hip Surgery

Background: Major trauma affects the immune system, and immunosuppression may render the patients susceptible to septic complications. The purpose of this study was to investigate lipopolysaccharide (LPS)-induced releases of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in whole blood in patients undergoing total hip replacement. Methods: Seven patients (6 females) who underwent elective total hip replacement were included. Ex vivo LPS-induced releases of TNF-α and IL-6 were measured in a whole blood assay at days 1, 6, 9 and 12 postoperatively, using low- and high-dose LPS incubation. At the same time, white blood cell counts were analyzed. Results: The amount of TNF-α release was significantly reduced at days 6 and 12. Compared to monocyte counts, TNF-α release was significantly decreased also at day 9 in low- and high-dose LPS stimulation. IL-6 in plasma was significantly increased at day 1 and normalized thereafter. There were no differences in LPS-induced IL-6 levels compared to the levels before surgery. Conclusion: This in vivo/ex vivo study shows a reduced capacity of whole blood to release LPS-induced TNF-α at day 6 through to day 12 after major orthopedic surgery. Attenuated TNF-α release may contribute to an increased postoperative susceptibility to gram-negative sepsis.
Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type–Specific Manner

The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll–IL-1R domain–containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane and endosomes, for activation of TIRAP-MyD88 and TICAM-2–TICAM-1, respectively. LPS-induced endocytosis of TLR4 is mandatory for TICAM-1–mediated signaling including IFN-β production. Several molecules/mechanisms such as CD14, clathrin, and phosphatidylinositol metabolism have been reported to act as inducers of TLR4 translocation. However, the molecular mechanism of spatiotemporal regulation of TLR4 signaling remains unresolved. We have previously shown that Raftlin is essential for clathrin-dependent endocytosis of TLR3 ligand in human epithelial cells and myeloid dendritic cells (DCs). In this article, we demonstrate that Raftlin also mediated LPS-induced TLR4 internalization and TICAM-1 signaling in human monocyte-derived DCs and macrophages (Mo-Mϕs). When Raftlin was knocked down, LPS-induced TLR4-mediated IFN-β promoter activation, but not NF-κB activation, was decreased in HEK293 cells overexpressing TLR4/MD-2 or TLR4/MD-2/CD14. LPS-induced IFN-β production by monocyte-derived DCs and Mo-Mϕs was significantly decreased by knockdown of Raftlin. Upon LPS stimulation, Raftlin moved from the cytoplasm to the plasma membrane in Mo-Mϕs, where it colocalized with TLR4. Raftlin associated with clathrin-associated adaptor protein–2 in resting cells and transiently bound to TLR4 and clathrin at the cell surface in response to LPS. Thus, Raftlin appears to modulate cargo selection as an accessary protein of clathrin-associated adaptor protein–2 in clathrin-mediated endocytosis of TLR3/4 ligands.
Trial Watch

Immunostimulatory monoclonal antibodies (mAbs) exert antineoplastic effects by eliciting a novel or reinstating a pre-existing antitumor immune response. Most often, immunostimulatory mAbs activate T lymphocytes or natural killer (NK) cells by inhibiting immunosuppressive receptors, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1), or by engaging co-stimulatory receptors, like CD40, tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40) or TNFRSF18 (best known as GITR). The CTLA4-targeting mAb ipilimumab has been approved by the US Food and Drug Administration for use in patients with unresectable or metastatic melanoma in 2011. The therapeutic profile of ipilimumab other CTLA4-blocking mAbs, such as tremelimumab, is currently being assessed in subjects affected by a large panel of solid neoplasms. In the last few years, promising clinical results have also been obtained with nivolumab, a PD-1-targeting mAb formerly known as BMS-936558. Accordingly, the safety and efficacy of nivolumab and other PD-1-blocking molecules are being actively investigated. Finally, various clinical trials are underway to test the therapeutic potential of OX40- and GITR-activating mAbs. Here, we summarize recent findings on the therapeutic profile of immunostimulatory mAbs and discuss clinical trials that have been launched in the last 14 months to assess the therapeutic profile of these immunotherapeutic agents.
CENTRAL NERVOUS SYSTEM TUMORS A CLINICOPATHOLOGICAL STUDY

A total of 127 patients with CNS tumors were evaluated clinically and by imaging techniques (using MRI and CT-scan), followed by intraoperative cytological examination and then histopathological evaluation of the resected tumor tissues. The aim of the study was histopathological diagnosis and typing of CNS tumors and assessment of the possible diagnostic roles of cytology and the available imaging techniques. Results: Patients ages ranged from 3-72 years with a mean age of 40 years and a male to female ratio of 1.6:1. Majority had intracranial tumors (91.3%). Parietal lobe (21%) was the predominant affected region. Most tumors were malignant (61.4%). Astrocytomas (44.1%) were the commonest tumors, followed by meningiomas (24.4%). Cytology was found to be a valid supplementary diagnostic procedure to the available histologic tests for a rapid intraoperative diagnosis. The accuracy rate was 87% with a sensitivity of (92.6%) and a specificity of (100%), while the accuracy rate of imaging techniques was 69.3%.
Content validity of workplace-based portfolios: A multi-centre study

Abstract Background: Portfolios are used as tools to coach and assess students in the workplace. This study sought to evaluate the content validity of portfolios as reflected in their capacity to adequately assess achieved competences of medical students during clerkships. Methods: We reviewed 120 workplace portfolios at three medical universities (Belgium and the Netherlands). To validate their content, we developed a Validity Inventory for Portfolio Assessment (VIPA) based on the CanMEDS roles. Two raters evaluated each portfolio and indicated for each VIPA item whether the portfolio provided sufficient information to enable satisfactory assessment of the item. We ran a descriptive analysis on the validation data and computed Cohen’s Kappa to investigate interrater agreement. Results: The portfolios adequately covered the items pertaining to the communicator (90%) and professional (87%) roles. Coverage of the medical expert, collaborator, scholar and manager roles ranged between 75% and 85%. The health advocate role, covering 59%, was clearly less well represented. This role also exhibited little interrater agreement (Kappa < 0.4). Conclusions: This study lends further credence to the evidence that portfolios can indeed adequately assess the different CanMEDS roles during clerkships, the health advocate role, which was less well represented in the portfolio content, excepted.
STAT3 Impairs STAT5 Activation in the Development of IL-9–Secreting T Cells

Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9–secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9–secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.
Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination

The functional role of the ELR+ chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein–positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain, and spinal cord that correlated with increased frequency of Ly6G+CD11b+ neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells, and there was no difference in control of JHMV replication compared with control mice, indicating that T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1-transgenic mice reduced the severity of demyelination in mice, arguing for a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and that neutrophils can contribute to this process in a model of viral-induced neurologic disease.
HBV load in treated and untreated individuals

Abstract HHIVll infected patients with chronic HBV coinfection are at increased risk of developingg liver enzyme elevation (LEE) when highly active anti-retroviral therapyy (HAART) is initiated, relative to patients without HBV. coinfection. A majorr proportion of HAART regimens contains lamivudine (3TC), able to inhibit replicationn of both HIV and HBV. The objective of the present study was to study biochemicall and virological determinant s of LEE in the first year following administration off antiretroviral regimens including 3TC, among HBsAg positive HIVl infected individuals. AA retrospective study with 29 HIVl infected individuals successfull y treated for HIVl withh antiretroviral regimens including 3TC was performed. Serum samples were tested for HBVV DNA, HBsAg, HBeAg, ALT and AST at baseline and at least three times within one yearr after start of treatment . LEE was defined as an absolut e increase of 100 U/l or more relativee to the baseline value for either ALT or AST, and severe LEE was defined as an absolutee increase to levels above 250 U/l for both ALT and AST. Amongg 29 patients with a significant HIVl RNA decline, 10 developed LEE related to reductionn of HBV DNA (p = 0.002) but not to HBeAg clearance. Severe LEE (n=4) was significantlyy related to HBeAg clearance (p = 0.008), with a trend toward a relationshi p withh HBV DNA reduction. In these severe cases a rise in CD8 T cells, but not CD4 T cells,, was seen in the first year following 3TC treatment . None of these 10 patients had symptomati cc LEE or clinical signs related to LEE, and no obvious cause of LEE was identifiedd by screening their medical records. Inn conclusion, temporar y LEE in HBV/HIVl coinfected individuals following initiation of 3TCC containing antiretroviral treatment is linked to a combined drug-related effect on HIVll replication and anti-HBV immune response .
Twelve tips for postgraduate or undergraduate medics building a basic microsurgery simulation training course

Abstract Microsurgery is used in a variety of surgical specialties, including Plastic Surgery, Maxillofacial Surgery, Ophthalmic Surgery, Otolaryngology and Neurosurgery. It is considered one of the most technically challenging fields of surgery. Microsurgical skills demand fine, precise and controlled movements, and microsurgical skill acquisition has a steep initial learning curve. Microsurgical simulation provides a safe environment for skill acquisition before operating clinically. The traditional starting point for anyone wanting to pursue microsurgery is a basic simulation training course. We present twelve tips for postgraduate and undergraduate medics on how to set up and run a basic ex-vivo microsurgery simulation training course suitable for their peers.
THE BABY BLUES AND POSTNATAL DEPRESSION

The Baby Bluesadalah depresi ringan yang terjadi pada ibu-ibu dalam masa beberapa jam setelah melahirkan, sampai beberapa hari setelah melahirkan, dan kemudian dia akan hilang dengan sendirinya jika diberikan pelayanan psikologis yang baik. Banyak para ibu-ibu setelah melahirkan mengalami emosi yang berlebihan dan merasa sangat sedih sekali, dan diiringi tangisan tanpa alasan yang jelas. Dalam masa ini tidak mungkin lagi kita akan melihat ibu tersenyum atau tertawa. Sebagian ibu merasa sangat khawatir, cemas, dan tegang. Masalah â€“ masalah kecil saja jika tidak cepat diatasi pada masa hamil, atau sebelum melahirkan dapat menimbulkan Baby Blues.