Komplementäre Onkologie und Prognose

Zusammenfassung

Hintergrund

Maßnahmen außerhalb der konventionellen Medizin werden von Patienten genutzt, um die Heilungschancen zu verbessern.

Ziel

Dieser Beitrag versucht die Frage zu beantworten, ob komplementäronkologische Maßnahmen geeignet sind, eine Verbesserung der Heilungschancen bei malignen Tumorerkrankungen zu bewirken.

Material und Methoden

Es erfolgte eine umfangreiche Literaturrecherche.

Ergebnisse

Es besteht die Möglichkeit, dass es durch 1. verschiedene Ansätze möglich ist, die Verträglichkeit der Behandlung zu verbessern, wodurch sich seltener Therapieabbrüche und/oder eine höhere Dosisintensität ergibt, was nachweislich mit einer besseren Prognose einhergeht, 2. komplementäre Methoden die Wirksamkeit der Methoden der klassischer Medizin erhöhen können und 3. sich komplementäre Methoden zur Verhinderung des Rezidivs eignen können, nachdem die klassische Therapie beendet ist.

Schlussfolgerung

Voraussetzung für eine Verbesserung der Prognose scheinen rational begründbare Ansätze zu sein, die die Situation des Patienten, die Tumorentität und die Therapie berücksichtigen. Es finden sich keine Hinweise dafür, dass beliebige, irrationale oder esoterische Therapiekonzepte ebenfalls zu einer Prognoseverbesserung beitragen könnten.

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Roles of L-type calcium channels (CaV1.2) and the distal C-terminus (DCT) in differentiation and mineralization of rat dental apical papilla stem cells (rSCAPs)

Publication date: February 2017
Source:Archives of Oral Biology, Volume 74
Author(s): Qianqian Gao, Jianping Ge, Yanqin Ju, Changsheng Li, Jian Gao, Meisheng Wu, Shouliang Zhao
ObjectiveVoltage-gated inward Ca²⁺ currents (ICa) are triggered by cell depolarization and commonly produce transient increases in the cytoplasmic free Ca²⁺ concentration. The CaV1.2 distal C-terminus is susceptible to proteolytic cleavage, which yields a truncated CaV1.2 subunit and a cleaved C-terminal fragment (CCt or DCT). Stem cells from the apical papilla (SCAPs) has a capacity for differentiation into the odontoblastic-like cells in vitro and dentin forming in vivo, which makes SCAPs advantages in tissue engineering and regenerative endodontic. The aim of this study was to investigate the effect of CaV1.2 and its distal C-terminal fragment in the odontoblastic differentiation of rat SCAPs (stem cells from the apical papilla).DesignIn this study, we generated stable CaV1.2 knockdown and DCT over-expressed rSCAPs using short hairpin RNA and DCT gene containing Lentivirus vectors, respectively. The transfected apical papilla cells were induced to differentiate into the odontoblast-like cells, and the expression of markers for odontoblastic differentiation were analyzed by alizarin red staining, Real-time Polymerase chain reaction (RT-PCR), and Western blot analysis.ResultsThe knockdown of CaV1.2 and excess expression of DCT both suppressed the expression of DSPP, ALP in mRNA level and the formation of calcium nodules.ConclusionsOur results suggest that CaV1.2 and DCT play important roles in the differentiation of rSCAPs, DCT might act as a transcription factor and regulate the differentiation of rSCAPs.



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The effects of SOST on implant osseointegration in ovariectomy osteoporotic mice

Publication date: February 2017
Source:Archives of Oral Biology, Volume 74
Author(s): Rui Shu, Dongqing Ai, Ding Bai, Jinlin Song, Mengyuan Zhao, Xianglong Han
ObjectiveOsteoporosis is a risk factor for implant fixation failure. The inhibition of sclerostin effectively improves bone formation and bone remodeling. Therefore, this study investigated whether SOST deficiency enhances the osseointegration of implants in a mouse model of osteoporosis induced by ovariectomy (OVX).DesignOsteoporosis was induced in female C57BL/6 and SOST deficient mice by OVX. Titanium implants were placed in the bilateral distal aspects of the femurs. Implants underwent sandblasting and acid-etching after which the structure, surface roughness and chemical components were investigated using scanning electron microscopy (SEM) and energy spectrum analyses. Undecalcified slices, μ-CT, histology analyses and mechanical tests were used to evaluate the osseointegration of implants. The results were compared using one-way ANOVA between four groups.ResultsSandblasting and acid-etching increased the roughness of the implants. OVX surgery reduced bone formation around the implants in both WT and SOST^−/− mice. However, implant osseointegration was significantly improved in the SOST^−/− OVX mice compared to the WT OVX mice.ConclusionsInhibition of the SOST gene improved implant fixation in the OVX osteoporotic mice, which suggests a strategy for enhancing implant osseointegration in clinical patients with osteoporosis.



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Differential gene expression in the condylar cartilage of growing rabbits with temporomandibular joint anterior disk displacement—A transcriptomic study

Publication date: February 2017
Source:Archives of Oral Biology, Volume 74
Author(s): Shuhua Wang, Liquan Deng, Ye Li, Huiling Wu, Zhiyuan Gu
Internal derangement (ID) in the temporomandibular joint (TMJ) comprises a group of clinical problems with relatively high prevalence. However, the temporal changes in gene expression of condylar cartilage during continuous ID remain unclear. The aim of the current study is to investigate by microarray analysis, the differentially-expressed gene pattern in condylar cartilage of rabbits with ID from one to eight weeks of ID progression. Histological results (hematoxylin and eosin staining) indicated that abnormal collagen fiber arrangements, fragmentation of fibrils, and inflammatory cell-infiltration were detected from one to four weeks in joint disc specimens, while newly formed vessels, mucoid degeneration, meniscal tears, and the presence of osteoclasts and osteoblasts were observed at later time points. The microarray analysis revealed 6478 genes among all tested transcripts, to have a greater than two-fold expression change compared to controls. The inflammation-associated gene group including ace and il1β increased rapidly in the early stage of disease and decreased later. In contrast, bone construction-related genes showed low expression levels at first and increased at later period in the ID progression. The current study also found some genes such as hla2g, which have not been previously reported, to be potentially relevant within ID. Our findings provide useful insights into the pathological mechanism of ID in TMJ.



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Fingering a Natural Culprit During Antibody-Mediated Rejection.

No abstract available

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The International Liver Transplant Society (ILTS) Living Donor Liver Transplant Recipient Guideline.

No abstract available

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Tolerance and Efficacy with Simultaneous Use of Two Monoclonal Antibodies for a Patient with Hypereosinophilic Syndrome and Ulcerative Colitis

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy , Vol. 0, No. 0.


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Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition

Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAFV600-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAFV600-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P=0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD-1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited >6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (

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Synthetic Poly(L-Glutamic Acid)-conjugated CpG Exhibits Antitumor Efficacy With Increased Retention in Tumor and Draining Lymph Nodes After Intratumoral Injection in a Mouse Model of Melanoma

There is an urgent need for new clinically applicable drug-delivery methods to enhance accumulation of immune-activating drugs in tumors. We synthesized a poly(L-glutamic acid)-CpG ODN2216 conjugate (PG-CpG) and injected it intratumorally into C57BL/6 mice bearing subcutaneous B16-ovalbumin melanoma. PG-CpG elicited the same potent antitumoral activity as CpG with respect to reducing tumor growth and triggering antigen-specific CD8+ T-cell responses in this well-established solid tumor model. Moreover, PG-CpG was retained significantly longer in both tumor and draining lymph nodes than was free CpG after intratumoral injection. Specifically, 48 hours after injection, 26.5%±16.9% of the injected PG-CpG dose versus 4.72%±2.61% of free CpG remained at the tumor, and 1.53%±1.22% of the injected PG-CpG versus 0.37%±0.33% of free CpG was retained in the draining inguinal lymph nodes. These findings indicate that PG is an effective synthetic polymeric carrier for delivery of immunostimulatory agents to tumors and lymph nodes.

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The Characteristics of Naive-like T Cells in Tumor-infiltrating Lymphocytes From Human Lung Cancer

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TILs) or genetically modified lymphocytes from TILs is a new effective approach, but the application of TIL immunotherapy is still limited in many solid tumors. Knowledge of the classification and function of TILs is important to develop personalized immunotherapy with TILs in non–small lung cancer (NSCLC). In this study, we show the characteristics of T-cell subsets in TILs isolated from NSCLC. CD3+ CD8+ CD45RA+ T cells outnumbered CD3+ CD4+ CD45RA+ T cells in CD45RA+ TILs, but it was the opposite in CD45RO+ TILs. Effector memory CD4+ T cells predominated in CD4+ TILs; about 10% of the stem cell-like memory T cells (Tscm) were detected in TILs. To further analyze their functions, we stimulated TILs from NSCLC patients by mitogens to examine cytokine production. Our data demonstrated that naive-phenotype T cells in TILs secret IFN-γ in abundance; TNF-α-producing T cells were significantly increased in TILs; there were more IL-17-expressing CD4+ Tscm cells than other subtypes of CD4+T cells in TILs. Our findings indicate that the CD4+/CD8+ naive-phenotype T cells and Tscm cells in TILs from lung cancer exhibit distinct composition and strong cytokine production. Attributes of Tscm cells from a naive-like T-cell population in TILs are the promising cell type for adoptive cell therapy in human lung cancer.

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Blood loss and transfusion requirements with epsilon-aminocaproic acid use during cranial vault reconstruction surgery

To determine whether epsilon-aminocaproic acid (EACA) load of 50 mg∙kg−1 before skin incision, and infusion of 25 mg∙kg−1∙h−1 until skin closure during cranial vault reconstruction (CVR) were associated with decreased estimated blood loss and transfusion requirements.

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Clinical Response Rates From Interleukin-2 Therapy for Metastatic Melanoma Over 30 Years’ Experience: A Meta-Analysis of 3312 Patients

Interleukin-2 (IL-2), initially used in 1986, can induce clinical regression—complete responses (CR) and partial responses (PR) of metastatic malignant melanoma. IL-2 has been used alone or in combination, and in different dosage schedules, as an immunotherapeutic agent for melanoma treatment. This meta-analysis aimed to document and evaluate the spectrum of reported clinical response rates from the combined experience of almost 30 years of IL-2 clinical usage. Clinical trials using IL-2 for metastatic melanoma therapy that reported: dosage, combinations, study details, definitions and clinical CR, PR, and overall response (OR) rates were included. A meta-analysis was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. In total, 34 studies met inclusion criteria, with 41 separate treatment arms. For all IL-2 treatment modalities collectively, the CR rate was 4.0% [95% confidence interval (CI), 2.8–5.3], PR 12.5% (95% CI, 10.1–15.0), and OR 19.7% (95% CI, 15.9–23.5). CR pre-1994 was 2.7% versus 6.1% post-1994. High and intermediate-IL-2 dosage showed no CR difference, while low-dose IL-2 showed a nonstatistical trend toward an increased CR rate. The highest CR rate resulted from IL-2 combined with vaccine at 5.0%. The meta-analysis showed that IL-2 immunotherapy for advanced metastatic melanoma delivered a CR rate of 4% (range, 0–23%) across nearly 30 years of clinical studies, with gradual improvement over time. The significance is that, contrary to popular belief, the data demonstrated that CR rates were similar for intermediate versus high-IL-2 dosing.

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Comparison of the Macintosh and Airtraq laryngoscopes in morbidly obese patients: a randomized and prospective study

Morbid obesity is associated with a difficult management of the airway. There is no agreement on these patients being difficult to intubate, but if they are difficult to ventilate with facial mask, then the fast control of their airway becomes a priority. This study compares the quickness and success in tracheal intubation, glottic view, hemodynamic response, and complications from the use of the Macintosh and Airtraq laryngoscopes in morbidly obese patients for scheduled surgery.

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Durable Response of Metastatic Squamous Cell Carcinoma of the Skin to Ipilimumab Immunotherapy

A 72-year-old male patient was receiving second-line chemotherapy for metastatic squamous cell carcinoma of the skin (SCCS) when he was diagnosed with concurrent metastatic melanoma (BRAFG469E mutant). Chemotherapy was ceased and he was treated with 4 cycles of ipilimumab immunotherapy. The patient experienced clinical benefit and durable remission in both malignancies and remains free of cancer progression 8 months after the last cycle of ipilimumab. Response of SCCS to ipilimumab has not been previously described, however this case and recent reports of pembrolizumab efficacy confirm the critical role of the immune system in SCCS pathogenesis and suggest further exploration of checkpoint immunotherapy for the treatment of this disease.

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Comparison of laryngeal mask airway vs tracheal intubation: a systematic review on airway complications

To determine whether the laryngeal mask airway (LMA) has advantages over the tracheal tube (TT) in terms of incidence of cough, sore throat, laryngospasm, dysphagia, dysphonia, and blood staining. This is a systematic literature review performed at the Universtity Medical Center of Utrecht. The online databases PubMed, Embase, and the Cochrane Library were searched for relevant randomized controlled trials. Two independent reviewers selected relevant articles after title, abstract, and full text screening.

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EMA Begins Review of Select Injectable Allergy Medications

Injectable allergy medications containing methylprednisolone may pose risks to those who are allergic to cows' milk.
News Alerts

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Effect of sensor location on regional cerebral oxygen saturation measured by INVOS 5100 in on-pump cardiac surgery

Abstract

Purpose

Near-infrared spectroscopy sensors often cannot be attached at the commercially recommended locations because combined use of neurological monitoring systems is common during on-pump cardiac surgery. The primary purpose of this study was to compare the incidence of regional cerebral oxygen desaturation and regional cerebral oxygen saturation values detected using near-infrared spectroscopy between the upper and lower forehead during on-pump cardiac surgery.

Methods

A prospective observational study was conducted with 25 adult patients scheduled for elective on-pump cardiac surgery. Regional cerebral oxygen saturations at the left upper and lower forehead and other clinical measurements were monitored intraoperatively. McNemar's test was used to analyze differences in the incidence of cerebral regional oxygen desaturation between the left upper and lower forehead. Two-way repeated measures ANOVA with post hoc Bonferroni correction was used to compare the regional cerebral oxygen saturation at each time point.

Results

There was a significantly higher incidence of regional cerebral oxygen desaturation at the upper than lower forehead only at 1 h after initiation of aortic cross-clamping. There were significant differences between the left upper and lower regional cerebral oxygen saturation values throughout the observation period.

Conclusion

Regional cerebral oxygen saturation was significantly lower at the upper than lower forehead during on-pump cardiac surgery. However, disagreements in detection of cerebral regional oxygen desaturation were only significant at 1 h after initiation of aortic cross-clamping.

Trial registration

WHO-ICTRP, Clinical Research Information Service (CRiS). ID: KCT0000971. URL: http://ift.tt/2gKaxwO.

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Correction: In This Issue [CORRECTIONS]

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Retraction: Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells [LETTERS OF RETRACTION]

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Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice [IMMUNOTHERAPY AND VACCINES]

Targeting cancer through the use of effector T cells bearing chimeric Ag receptors (CARs) leads to elimination of tumors in animals and patients, but recognition of normal cells or excessive activation can result in significant toxicity and even death. CAR T cells based on modified NKG2D receptors are effective against many types of tumors, and their efficacy is mediated through direct cytotoxicity and cytokine production. Under certain conditions, their ligands can be expressed on nontumor cells, so a better understanding of the potential off-tumor activity of these NKG2D CAR T cells is needed. Injection of very high numbers of activated T cells expressing CARs based on murine NKG2D or DNAM1 resulted in increased serum cytokines (IFN-, IL-6, and MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells—perforin and GM-CSF. Host immune cells also contributed to this toxicity, and mice with severe immune cell defects remained healthy at the highest CAR T cell dose. These data demonstrate that specific CAR T cell effector mechanisms and the host immune system are required for this cytokine release–like syndrome in murine models.

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Retraction: Regulation of Tumor Cell Sensitivity to TRAIL-Induced Apoptosis by the Metastatic Suppressor Raf Kinase Inhibitor Protein via Yin Yang 1 Inhibition and Death Receptor 5 Up-Regulation [LETTERS OF RETRACTION]

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Mucosal and Systemic {gamma}{delta}+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

T cells act as a first line of defense against invading pathogens. However, despite their abundance in mucosal tissue, little information is available about their functionality in this compartment in the context of HIV/SIV infection. In this study, we evaluated the frequency, phenotype, and functionality of V1 and V2 T cells from blood, rectum, and the female reproductive tract (FRT) of rhesus macaques to determine whether these cells contribute to control of SIV infection. No alteration in the peripheral V1/V2 ratio in SIV-infected macaques was observed. However, CD8⁺ and CD4⁺CD8⁺ V1 T cells were expanded along with upregulation of NKG2D, CD107, and granzyme B, suggesting cytotoxic function. In contrast, V2 T cells showed a reduced ability to produce the inflammatory cytokine IFN-. In the FRT of SIV⁺ macaques, V1 and V2 showed comparable levels across vaginal, ectocervical, and endocervical tissues; however, endocervical V2 T cells showed higher inflammatory profiles than the two other regions. No sex difference was seen in the rectal V1/V2 ratio. Several peripheral V1 and/or V2 T cell subpopulations expressing IFN- and/or NKG2D were positively correlated with decreased plasma viremia. Notably, V2 CD8⁺ T cells of the endocervix were negatively correlated with chronic viremia. Overall, our results suggest that a robust V1 and V2 T cell response in blood and the FRT of SIV-infected macaques contribute to control of viremia.

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Generation of Immunity against Pathogens via Single-Domain Antibody-Antigen Constructs [NOVEL IMMUNOLOGICAL METHODS]

mAbs specific for surface proteins on APCs can serve as Ag-delivery vehicles that enhance immunogenicity. The practical use of such constructs is limited by the challenge of expressing and modifying full-sized mAbs. We generated single-domain Ab fragments (VHHs) specific for class II MHC (MHCII), CD11b, and CD36. VHH sequences were modified by inclusion of a C-terminal sortase motif to allow site-specific conjugation with various Ag payloads. We tested T cell activation using VHHs that target distinct APC populations; anti-MHCII adducts elicited strong activation of CD4⁺ T cells, whereas anti-CD11b showed CD8⁺ T cell activation superior to targeting via MHCII and CD36. Differences in Ag presentation among constructs were unrelated to dendritic cell subtype or routing to acidic compartments. When coupled to antigenic payloads, anti-MHCII VHH primed Ab responses against GFP, ubiquitin, an OVA peptide, and the α-helix of influenza hemagglutinin's stem; the last afforded protection against influenza infection. The versatility of the VHH scaffold and sortase-mediated covalent attachment of Ags suggests their broader application to generate desirable immune responses.

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Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells [TUMOR IMMUNOLOGY]

Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20⁺ B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab')₂ fragments, as well as C1q-binding–deficient IgG mutants, retained an ability to induce CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted of specific complement components demonstrated that the observed lytic activity, which we termed "accessory CDC," remained to be dependent on C1 and the classical pathway. We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR^– B cell lines. A direct relationship between BCR expression and accessory CDC was established by transfecting the BCR into CD20⁺ cells: OFA-F(ab')₂ fragments were able to induce CDC in the CD20⁺BCR⁺ cell population, but not in the CD20⁺BCR^– population. Importantly, OFA-F(ab')₂ fragments were able to induce CDC ex vivo in malignant B cells isolated from patients with mantle cell lymphoma and Waldenström macroglobulinemia. In summary, accessory CDC represents a novel effector mechanism that is dependent on type I CD20 Ab–induced BCR clustering. Accessory CDC may contribute to the excellent capacity of type I CD20 Abs to induce CDC, and thereby to the antitumor activity of such Abs in the clinic.

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The Analysis of CD83 Expression on Human Immune Cells Identifies a Unique CD83+-Activated T Cell Population [IMMUNE REGULATION]

CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4⁺, CD8⁺ T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.

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HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism [IMMUNOTHERAPY AND VACCINES]

The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb V_HDJ_H and V_LJ_L knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti–HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.

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Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide [AUTOIMMUNITY]

Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcR and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox. Three major Src family kinases found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-A^q. Unexpectedly we found they are not required for T cell functions induced by A9/I-A^q, nor are they required for APL stimulation of cytokines. On the other hand, the induction of the second messenger inositol trisphosphate and the mobilization of calcium are clearly triggered by the APL A9/I-A^q stimulation and are required for cytokine production, albeit the cytokines induced are different from those produced after activation of the canonical pathway. DBA/1 mice doubly deficient in IL-4 and IL-10 were used to confirm that these two cytokines are important for the APL-induced attenuation of arthritis. These studies provide a basis for exploring the effectiveness of analog peptides and the inhibitory T cells they induce as therapeutic tools for autoimmune arthritis.

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The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis [IMMUNE REGULATION]

The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-B ligand (RANKL)–mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow–derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR^–/– mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-B, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos–dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR^–/– mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.

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Age-Associated B Cells with Proinflammatory Characteristics Are Expanded in a Proportion of Multiple Sclerosis Patients [AUTOIMMUNITY]

Immune aging occurs in the elderly and in autoimmune diseases. Recently, IgD^–CD27^– (double negative, DN) and CD21^–CD11c⁺ (CD21^low) B cells were described as age-associated B cells with proinflammatory characteristics. This study investigated the prevalence and functional characteristics of DN and CD21^low B cells in multiple sclerosis (MS) patients. Using flow cytometry, we demonstrated a higher proportion of MS patients younger than 60 y with peripheral expansions of DN (8/41) and CD21^low (9/41) B cells compared with age-matched healthy donors (1/33 and 2/33, respectively), which indicates an increase in age-associated B cells in MS patients. The majority of DN B cells had an IgG⁺ memory phenotype, whereas CD21^low B cells consisted of a mixed population of CD27^– naive, CD27⁺ memory, IgG⁺, and IgM⁺ cells. DN B cells showed similar (MS patients) or increased (healthy donors) MHC-II expression as class-switched memory B cells and intermediate costimulatory molecule expression between naive and class-switched memory B cells, indicating their potential to induce (proinflammatory) T cell responses. Further, DN B cells produced proinflammatory and cytotoxic cytokines following ex vivo stimulation. Increased frequencies of DN and CD21^low B cells were found in the cerebrospinal fluid of MS patients compared with paired peripheral blood. In conclusion, a proportion of MS patients showed increased peripheral expansions of age-associated B cells. DN and CD21^low B cell frequencies were further increased in MS cerebrospinal fluid. These cells could contribute to inflammation by induction of T cell responses and the production of proinflammatory cytokines.

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Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects [CLINICAL AND HUMAN IMMUNOLOGY]

Diverse Ab effector functions mediated by the Fc domain have been commonly associated with reduced risk of infection in a growing number of nonhuman primate and human clinical studies. This study evaluated the anti-HIV Ab effector activities in polyclonal serum samples from HIV-infected donors, VAX004 vaccine recipients, and healthy HIV-negative subjects using a variety of primary and cell line–based assays, including Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cell-mediated viral inhibition, and Ab-dependent cellular phagocytosis. Additional assay characterization was performed with a panel of Fc-engineered variants of mAb b12. The goal of this study was to characterize different effector functions in the study samples and identify assays that might most comprehensively and dependably capture Fc-mediated Ab functions mediated by different effector cell types and against different viral targets. Deployment of such assays may facilitate assessment of functionally unique humoral responses and contribute to identification of correlates of protection with potential mechanistic significance in future HIV vaccine studies. Multivariate and correlative comparisons identified a set of Ab-dependent cell-mediated viral inhibition and phagocytosis assays that captured different Ab activities and were distinct from a group of ADCC assays that showed a more similar response profile across polyclonal serum samples. The activities of a panel of b12 monoclonal Fc variants further identified distinctions among the ADCC assays. These results reveal the natural diversity of Fc-mediated Ab effector responses among vaccine recipients in the VAX004 trial and in HIV-infected subjects, and they point to the potential importance of polyfunctional Ab responses.

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CD8{alpha}{beta}+ {gamma}{delta} T Cells: A Novel T Cell Subset with a Potential Role in Inflammatory Bowel Disease [CLINICAL AND HUMAN IMMUNOLOGY]

T cells have been attributed a wide variety of functions, which in some cases may appear as contradictory. To better understand the enigmatic biology of T cells it is crucial to define the constituting subpopulations. T cells have previously been categorized into two subpopulations: CD8αα⁺ and CD8^– cells. In this study we have defined and characterized a novel subset of human T-cells expressing CD8αβ. These CD8αβ⁺ T cells differed from the previously described T cell subsets in several aspects, including the degree of enrichment within the gut mucosa, the activation status in blood, the type of TCR variant used in blood, and small but significant differences in their response to IL-2 stimulation. Furthermore, the novel subset expressed cytotoxic mediators and CD69, and produced IFN- and TNF-α. In patients with active inflammatory bowel disease the mucosal frequencies of CD8αβ⁺ T cells were significantly lower as compared with healthy controls, correlated negatively with the degree of disease activity, and increased to normal levels as a result of anti–TNF-α therapy. In conclusion, our results demonstrate that CD8αβ⁺ T cells constitute a novel lymphocyte subset, which is strongly enriched within the gut and may play an important role in gut homeostasis and mucosal healing in inflammatory bowel disease.

http://ift.tt/2h3t0YD

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma [IMMUNE REGULATION]

Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus–mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-α, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye.

http://ift.tt/2h3ttKo

First-in-Human Study in Healthy Subjects with FR104, a Pegylated Monoclonal Antibody Fragment Antagonist of CD28 [CLINICAL AND HUMAN IMMUNOLOGY]

FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin. Subjects were followed up over a maximum of 113 d. Overall, the pharmacokinetics of FR104 after a single and double infusions was approximately linear at doses ≥0.200 mg/kg. CD28 receptor occupancy by FR104 was saturated at the first sampling time point (0.5 h) at doses above 0.02 mg/kg and returned to 50% in a dose-dependent manner, by day 15 (0.020 mg/kg) to 85 (1.500 mg/kg). FR104 was well tolerated, with no evidence of cytokine-release syndrome and no impact on blood lymphocyte subsets. Inhibition of anti-keyhole limpet hemocyanin Ab response was dose-dependent in FR104 recipients and was already apparent at a dose of 0.02 mg/kg. Abs to FR104 were detected in 22/46 (48%) of FR104 recipients and only 1/46 (2.2%) was detected during drug exposure. In conclusion, selective blockade of CD28 with FR104 was safe and well tolerated at the doses tested. The observed immunosuppressive activity indicated that FR104 has potential to show clinical activity in the treatment of immune-mediated diseases.

http://ift.tt/2gRaG2a

Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses [IMMUNE REGULATION]

Dendritic cells (DCs) have been implicated as important regulators of innate and adaptive inflammation in many diseases, including atherosclerosis. However, the molecular mechanisms by which DCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies have shown an important anti-inflammatory role for the transcription factor Krüppel-like factor 2 (KLF2) in regulating activation of various cell types that participate in atherosclerotic lesion development, including endothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockout mouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in the context of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surface expression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferation and apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr^–/– mice aggravated atherosclerosis compared with control mice, most likely due to heightened vascular inflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokine production, and increased cell death in atherosclerotic lesions. Taken together, these data indicate that KLF2 governs the degree of DC activation and hence the intensity of proatherogenic T cell responses.

http://ift.tt/2h3zCq4

Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells [NOVEL IMMUNOLOGICAL METHODS]

Acute hepatitis C virus (HCV) infection culminates in viral persistence in the majority of cases. Abs that recognize the envelope glycoproteins E1 and E2 are generated during the late stages of acute infection, yet their contribution to spontaneous viral clearance remains controversial. Investigation of the humoral responses during acute HCV infection have been limited by the inability to directly identify and characterize HCV-specific B cells. In this study we describe the development of a novel tetramer of the E2 glycoprotein ectodomain (J6, genotype 2a strain), which allowed us to visualize E2-specific B cells longitudinally in the peripheral blood of HCV-infected individuals. HCV-specific class-switched memory B cells were detected in 3 out of 7 participants during late acute infection, with a mean frequency of 0.63% for positive samples (range 0.16–0.67%) and in 7 out of 7 participants with chronic infection with a mean frequency of 0.47% (range 0.20–0.78%). In a cross-sectional study, E2 tetramer positive population was detected in 28 out of 31 chronically infected individuals. Deep sequencing of the BCR from E2-specific class-switched memory B cells sorted from two independent participants revealed a focused repertoire suggestive of clonal selection. Tetramer-specific B cells exhibited skewed CDR3 length distribution and increased mutation frequency compared with naive B cells. This BCR profile is indicative of clonal expansion and affinity maturation. E2 tetramer allows for specific and sensitive ex vivo characterization of rare HCV-specific B cells in infected individuals, and will enable researchers to gain a better understanding of humoral immunity in HCV infection.

http://ift.tt/2h3CJOw

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7 [INNATE IMMUNITY AND INFLAMMATION]

Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

http://ift.tt/2h3tOg9

Duck Tembusu Virus Nonstructural Protein 1 Antagonizes IFN-{beta} Signaling Pathways by Targeting VISA [INFECTIOUS DISEASE AND HOST RESPONSE]

Duck Tembusu virus (DTMUV) is an emergent infectious pathogen that has caused severe disease in ducks and huge economic losses to the poultry industry in China since 2009. Previously, we showed that DTMUV inhibits IFN-β induction early in infection; however, the mechanisms of the inhibition of innate immune responses remain poorly understood. In this study, we screened DTMUV-encoded structural and nonstructural proteins using reporter assays and found that DTMUV NS1 markedly suppressed virus-triggered IFN-β expression by inhibiting retinoic acid–inducible gene I–like receptor signaling. Moreover, we found that DTMUV NS1 specifically interacted with the C-terminal domain of virus-induced signaling adaptor and impaired the association of retinoic acid–inducible gene I or melanoma differentiation-associated gene 5 and virus-induced signaling adaptor, thereby downregulating the retinoic acid–inducible gene I–like receptor–mediated signal transduction and cellular antiviral responses, leading to evasion of the innate immune response. Together, our findings reveal a novel mechanism manipulated by DTMUV to circumvent the host antiviral immune response.

http://ift.tt/2gRc6tz

Calendrier

Publication date: December 2016
Source:Annales de Dermatologie et de Vénéréologie, Volume 143, Issue 12





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Editorial board

Publication date: December 2016
Source:Annales de Dermatologie et de Vénéréologie, Volume 143, Issue 12





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Les morphées : une diversité unique

Publication date: December 2016
Source:Annales de Dermatologie et de Vénéréologie, Volume 143, Issue 12
Author(s): A. Petit




http://ift.tt/2gPC4Qr

Apport de la dermatoscopie et de la microscopie confocale par réflectance dans le diagnostic de pili migrans

Publication date: Available online 2 December 2016
Source:Annales de Dermatologie et de Vénéréologie
Author(s): E. Couty, E. Cinotti, B. Labeille, A.-C. Biron Schneider, C. Jaffelin, A. Leclercq, F. Cambazard, J.-L. Perrot




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Les tatouages traditionnels chez les Lu

Publication date: December 2016
Source:Annales de Dermatologie et de Vénéréologie, Volume 143, Issue 12
Author(s): E. Clyti, S. Sayasone, K. Chanthavisouk, M. Strobel




http://ift.tt/2gPGXZD

Comprehensive Genetic Analysis of Japanese Autosomal Dominant Sensorineural Hearing Loss Patients

by Yoh-ichiro Iwasa, Shin-ya Nishio, Shin-ichi Usami

Background

In general, autosomal dominant inherited hearing loss does not have a founder mutation, with the causative mutation different in each family. For this reason, there has been a strong need for efficient diagnosis methods for autosomal dominant sensorineural hearing loss (ADSNHL) patients. This study sought to verify the effectiveness of our analysis algorithm for the screening of ADSNHL patients as well as the usefulness of the massively parallel DNA sequencing (MPS).

Subjects and Methods

Seventy-five Japanese ADSNHL patients from 53 ENT departments nationwide participated in this study. We conducted genetic analysis of 75 ADSNHL patients using the Invader assay, TaqMan genotyping assay and MPS-based genetic screening.

Results

A total of 46 (61.3%) ADSNHL patients were found to have at least one candidate gene variant.

Conclusion

We were able to achieve a high mutation detection rate through the combination of the Invader assay, TaqMan genotyping assay and MPS. MPS could be used to successfully identify mutations in rare deafness genes.

http://ift.tt/2gvDP4G

Zespół alergii jamy ustnej (zespół pyłkowo-pokarmowy), anafilaksja i alergologia molekularna. Nowe endotypy, nowe horyzonty

Publication date: Available online 1 December 2016
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Łukasz Błażowski, Katarzyna Gregorczyk-Maślanka, Ryszard Kurzawa
The main symptoms of oral allergy syndrome (OAS) usually involve oral cavity, but in the case of pollen food syndrome (PFS), symptoms may lead to development of systemic reactions. Precise diagnostics of primary sensitizer and triggering symptoms allow to give proper recommendations for the patient, which are crucial for diminishing the risk of anaphylaxis. Based on the case of a 12-year-old patient, the rules of component-resolved diagnostics and the benefits of PFS endotypes identification were discussed.



http://ift.tt/2fU8iFr

Od Redaktora Naczelnego

Publication date: Available online 1 December 2016
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Rafał Pawliczak




http://ift.tt/2gPkJqN

Nadwrażliwość na diazepam (Relanium)

Publication date: Available online 1 December 2016
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Michał Abramowicz, Jerzy Kruszewski
Diazepam – a benzodiazepine derivative is a quite commonly administered drug. Despite a fairly long list of diazepam's common side effects, hypersensitivity to this drug including anaphylactic shock almost does not occur. The paper presents a case of 60-year-old patient after a documented anaphylactic shock. The suggested cause was an intravenous administration of diazepam during the induction of anesthesia for the planned surgery. During the hospitalization, hypersensitivity to diazepam was confirmed by positive reactions in intradermal tests with diazepam.



http://ift.tt/2fU6rAy

Effectiveness of omalizumab therapy in patients with highly severe allergic asthma treated in Department of Pulmonology in Krakow

Publication date: Available online 2 December 2016
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Agnieszka Gawlewicz-Mroczka, Weronika Zastrzeżyńska, Marek Przybyszowski, Adam Cmiel, Krzysztof Sładek
Immunoglobulin E plays an important role in allergic diseases. In patients with allergic asthma, exposure to allergens releases a wide range of proinflamatory mediators, which are responsible for acute and chronic symptoms of the disease. IgE has become an attractive target in allergic asthma. In 2006, in Europe omalizumab became available.ObjectivesOur knowledge of who will derive the highest benefit from omalizumab therapy is still limited. The aim of this study was to evaluate the efficacy of omalizumab during one year of therapy carried out under real-life conditions in Polish patients with severe allergic asthma. We also attempted to identify predictors for very good responses to treatment.MethodsWe enrolled 15 patients due to inclusion criteria of the program for severe allergic asthma funded by the National Health Insurance. All the patients were assessed for asthma control, quality of life, daily dose of oral and inhaled corticosteroids, asthma exacerbation rate, and lung function. The effectiveness of the treatment was analyzed after 16 weeks and one year following the inclusion each patient to the therapy. The patients were divided into two groups according to their response to the treatment: very good and good, based on the GETE scale.ResultsOmalizumab decreased the severity of symptoms, improved asthma control and quality of life in patients. It helped to reduce episodes of asthma exacerbation and the use of systemic corticosteroids. At present, the overall assessment by physicians is still the best and most reliable method of identifying responders to the omalizumab therapy.



http://ift.tt/2gVQVoL

Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran

Primary immunodeficiency (PID) is a heterogeneous group of inheritable genetic disorders with increased susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy. Timely precise diag...

http://ift.tt/2gPgsDA

Lipopolysaccharides-stimulated macrophage products enhance Withaferin A-induced apoptosis via activation of caspases and inhibition of NF-κB pathway in human cancer cells

Publication date: January 2017
Source:Molecular Immunology, Volume 81
Author(s): Liang Piao, Zhao Canguo, Lu Wenjie, Cheng Xiaoli, Shi Wenli, Lu Li
Macrophages, as a major cellular component in tumor microenvironment, play an important role in tumor progression. However, their roles in modulation of cytotoxic chemotherapy are still not fully understood. Here, we investigated the influence of Lipoplysaccharides (LPS)-stimulated macrophage products (LSMP) on Withaferin A (WA), a natural compound that derived from the medicinal plant Withania somnifera, as an antitumor agent in human breast cancer cells MDA-MB-231 and prostate cancer cells PC-3. Our results revealed that LSMP may enhance WA-induced apoptosis in both cell lines, the underlying mechanisms of which are closely associated with activation of caspase-8, −9 and −3, cleavage of poly ADP-ribose polymerase (PARP), as well as specifically inhibiting the translocation of nuclear factor-κB (NF-κB) and down-regulation of anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and inhibitor of apoptosis protein (cIAP1/2). These findings demonstrate that macrophages in tumor microenvironment can modulate tumor responses to chemotoxic agents, providing an effective strategy that targets macrophages to enhance the antitumor efficacy of cytotoxic chemotherapy.



http://ift.tt/2gOYeCu

Room temperature structure of human IgG4-Fc from crystals analysed in situ

Publication date: January 2017
Source:Molecular Immunology, Volume 81
Author(s): Anna M. Davies, Theo Rispens, Pleuni Ooijevaar-de Heer, Rob C. Aalberse, Brian J. Sutton
The Fc region of IgG antibodies (Cγ2 and Cγ3 domains) is responsible for effector functions such as antibody-dependent cell-mediated cytotoxicity and phagocytosis, through engagement with Fcγ receptors, although the ability to elicit these functions differs between the four human IgG subclasses. A key determinant of Fcγ receptor interactions is the FG loop in the Cγ2 domain. High resolution cryogenic IgG4-Fc crystal structures have revealed a unique conformation for this loop, which could contribute to the particular biological properties of this subclass. To further explore the conformation of the IgG4 Cγ2 FG loop at near-physiological temperature, we solved a 2.7Å resolution room temperature structure of recombinant human IgG4-Fc from crystals analysed in situ. The Cγ2 FG loop in one chain differs from the cryogenic structure, and adopts the conserved conformation found in IgG1-Fc; however, this conformation participates in extensive crystal packing interactions. On the other hand, at room temperature, and free from any crystal packing interactions, the Cγ2 FG loop in the other chain adopts the conformation previously observed in the cryogenic IgG4-Fc structures, despite both conformations being accessible. The room temperature human IgG4-Fc structure thus provides a more complete and physiologically relevant description of the conformation of this functionally critical Cγ2 FG loop.



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Miniatures and Animism: The communicative role of Inka carved stone conopa

Sillar, B; (2016) Miniatures and Animism: The communicative role of Inka carved stone conopa. Journal of Anthropological Research , 72 (4) pp. 408-415. 10.1086/689294 .

http://ift.tt/2fRXhES

The unsung impact of currency risk on the performance of international real property investment

Addae-Dapaah, K; Tan Yong Hwee, W; (2009) The unsung impact of currency risk on the performance of international real property investment. Review of Financial Economics , 18 (1) pp. 56-65. 10.1016/j.rfe.2008.04.002 . Green open access

http://ift.tt/2gNgnk8

Exchange Rate Volatility and International Real Estate Diversification: A Comparison of Emerging and Developed Economies

Addae-Dapaah, K; Loh, H; (2005) Exchange Rate Volatility and International Real Estate Diversification: A Comparison of Emerging and Developed Economies. Journal of Real Estate Portfolio Management , 11 (3) pp. 225-240.

http://ift.tt/2fS8WTT

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons

Caubit, X; Gubellini, P; Andrieux, J; Roubertoux, PL; Metwaly, M; Jacq, B; Fatmi, A; Caubit, X; Gubellini, P; Andrieux, J; Roubertoux, PL; Metwaly, M; Jacq, B; Fatmi, A; Had-Aissouni, L; Kwan, KY; Salin, P; Carlier, M; Liedén, A; Rudd, E; Shinawi, M; Vincent-Delorme, C; Cuisset, JM; Lemaitre, MP; Abderrehamane, F; Duban, B; Lemaitre, JF; Woolf, AS; Bockenhauer, D; Severac, D; Dubois, E; Zhu, Y; Sestan, N; Garratt, AN; Kerkerian-Le Goff, L; Fasano, L; - view fewer (2016) TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nature Genetics , 48 (11) pp. 1359-1369. 10.1038/ng.3681 .

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Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort

Zaniew, M; Bökenkamp, A; Kołbuc, M; La Scola, C; Baronio, F; Niemirska, A; Szczepańska, M; Zaniew, M; Bökenkamp, A; Kołbuc, M; La Scola, C; Baronio, F; Niemirska, A; Szczepańska, M; Bürger, J; La Manna, A; Miklaszewska, M; Rogowska-Kalisz, A; Gellermann, J; Zampetoglou, A; Wasilewska, A; Roszak, M; Moczko, J; Krzemień, A; Runowski, D; Siteń, G; Załuska-Leśniewska, I; Fonduli, P; Zurrida, F; Paglialonga, F; Gucev, Z; Paripovic, D; Rus, R; Said-Conti, V; Sartz, L; Chung, WY; Park, SJ; Lee, JW; Park, YH; Ahn, YH; Sikora, P; Stefanidis, CJ; Tasic, V; Konrad, M; Anglani, F; Addis, M; Cheong, HI; Ludwig, M; Bockenhauer, D; - view fewer (2016) Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort. Nephrology Dialysis Transplantation 10.1093/ndt/gfw350 . (In press).

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Indoor Air Quality and Office Property Value

Addae-Dapaah, K; Wai, TK; Bin Dollah, MJ; Foo, Y; (2010) Indoor Air Quality and Office Property Value. The Journal of Sustainable Real Estate , 2 (1) pp. 91-115. Green open access

http://ift.tt/2gNdW0Z

Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome.

Forsythe, E; Sparks, K; Best, S; Borrows, S; Hoskins, B; Sabir, A; Barrett, T; Forsythe, E; Sparks, K; Best, S; Borrows, S; Hoskins, B; Sabir, A; Barrett, T; Williams, D; Mohammed, S; Goldsmith, D; Milford, DV; Bockenhauer, D; Foggensteiner, L; Beales, PL; - view fewer (2016) Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome. Journal of the American Society of Nephrology 10.1681/ASN.2015091029 . (In press).

http://ift.tt/2fS3PTZ

Definition of important early morbidities related to paediatric cardiac surgery

Brown, KL; Pagel, C; Brimmell, R; Bull, K; Davis, P; Franklin, RC; Hoskote, A; Brown, KL; Pagel, C; Brimmell, R; Bull, K; Davis, P; Franklin, RC; Hoskote, A; Khan, N; Rodrigues, W; Thorne, S; Smith, L; Chigaru, L; Utley, M; Wray, J; Tsang, V; Mclean, A; - view fewer (2016) Definition of important early morbidities related to paediatric cardiac surgery. Cardiology in the Young 10.1017/S1047951116001256 . (In press). Green open access

http://ift.tt/2gNarHR

Hemodynamic Disturbances in the Early Phase After Subarachnoid Hemorrhage: Regional Cerebral Blood Flow Studied by Bedside Xenon-enhanced CT.

Background: The mechanisms leading to neurological deterioration and the devastating course of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) are still not well understood. Bedside xenon-enhanced computerized tomography (XeCT) enables measurements of regional cerebral blood flow (rCBF) during neurosurgical intensive care. In the present study, CBF characteristics in the early phase after severe SAH were explored and related to clinical characteristics and early clinical course outcome. Materials and Methods: Patients diagnosed with SAH and requiring mechanical ventilation were prospectively enrolled in the study. Bedside XeCT was performed within day 0 to 3. Results: Data from 64 patients were obtained. Median global CBF was 34.9 mL/100 g/min (interquartile range [IQR], 26.7 to 41.6). There was a difference in CBF related to age with higher global CBF in the younger patients (30 to 49 y). CBF was also related to the severity of SAH with lower CBF in Fisher grade 4 compared with grade 3. rCBF disturbances and hypoperfusion were common; in 43 of the 64 patients rCBF

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Buttressing the Pediatric Endotracheal Tube in Neonates: A Simple but Useful Technique.

No abstract available

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