Neurosarcoidosis is a rare complication, and cranial neuropathy is the most frequent manifestation of this disease. However, few cohesive reports have discussed multiple cranial neuropathies in Japanese patien...
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Δευτέρα 22 Οκτωβρίου 2018
Sarcoid uveitis in a patient with multiple neurological lesions: a case report and review of the literature
Downregulation of IGF1R Expression Inhibits Growth and Enhances Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cells In Vitro
Abstract
A lentivirus-mediated doxycycline-inducible pTRIPZ shRNAmir plasmid targeting IGF1R transcript was transfected into two head and neck squamous cell carcinoma (HNSCC) cell lines to silence IGF1R expression and to assess the effect of its downregulation on cisplatin sensitivity in vitro. In Cal27-regIGF1R and SCC25-regIGF1R cell lines, IGF1R protein expression was reduced by more than 90% after 72 h of incubation with doxycycline. Both basal and IGF-stimulated pIGF1R, pAKT, and pERK were significantly reduced, without influence on total AKT and ERK expression. Downregulation of the IGF1R was associated with decreased proliferation and cell viability in both cell lines. Reduced IGF1R expression was also associated with increased sub-G0/G1-phase and G0/G1-phase populations and decreased S-phase and G2/M-phase populations. IGF1R downregulation enhanced sensitivity to cisplatin with decrease of cisplatin IC50 from 15 to 7.1 in Cal27-regIGF1R cells and from 11 to 6.3 in SCC25-regIGF1R cells. Cisplatin exhibited increased pro-apoptotic activity by annexin V staining and PARP cleavage in both cells lines when cultured in doxycycline. Thus, in two HNSCC cell lines in vitro, reduced IGF1R expression results in reduced growth rate and increased sensitivity to cisplatin. Thus, IGF1R downregulation and/or inhibition may serve as a useful adjunct to platinum-based cytotoxic chemotherapy.
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EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma
Abstract
Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.
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The Prognostic Value of Inositol Polyphosphate 5-Phosphatase in Cutaneous Squamous Cell Carcinoma
Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in cancer development and progression. We found that low INPP5A expression is associated with aggressive tumors and poor outcomes. INPP5A is a novel tumor marker that may help in the management of cutaneous squamous cell carcinoma.
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Peroxisome Proliferator-Activated Receptor-{delta} Supports the Metabolic Requirements of Cell Growth in TCR{beta}-Selected Thymocytes and Peripheral CD4+ T Cells [IMMUNE SYSTEM DEVELOPMENT]
During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor– (PPARmut) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARmut thymocytes, studies in the OP9–delta-like 4 in vitro system of differentiation revealed that PPARmut double-negative 3 cells underwent fewer cell divisions. Naive CD4+ T cells from PPARmut mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-–deficient thymocytes and peripheral CD4+ T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell–restricted deficiency of Ppard starting at the double-positive stage of thymocyte development, although exhibiting defective CD4+ T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARmut mice. These findings implicate PPAR- as a regulator of the metabolic program during thymocyte and T cell growth.
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EU Panel Backs Drug for Rare Hereditary Angioedema
Lanadelumab would be the first monoclonal antibody for preventing recurrent attacks of HAE in patients ages 12 years and older.
International Approvals
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Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage-Th17 Cell Axis [TUMOR IMMUNOLOGY]
Intratracheal administration of a novel IL-10 formulation suppressed IL-17–driven, CD4+ T cell–dependent tumorigenesis in the LSL-K-rasG12D murine lung cancer model. Analysis of lung lymphocyte populations demonstrated that antitumor activity of IL-10 was associated with a 5-fold decline in Th17 cell prevalence and a concurrent suppression of inflammatory M1-like macrophage activity. Further phenotypic characterization revealed that macrophages and dendritic cells, but not Th17 cells, expressed IL-10RA on the cell surface with the CD11b+F4/80+CX3CR1+ interstitial macrophages representing the dominant IL-10RA+ subset. Consistent with these observations, in vitro stimulation of sorted CD4+ T cells with IL-10 did not affect their ability to produce IL-17, whereas similar treatment of purified interstitial macrophages resulted in a dramatic M1 to M2 phenotypic switch. Importantly, preconditioning of macrophages (but not of CD4+ T cells) with IL-10 led to potent suppression of CD4+ T cell IL-17 production in an in vitro coculture assay, suggesting that IL-10 suppressed Th17 cell activity primarily via its upstream effects on macrophages. In support of this notion, in vivo macrophage depletion resulted in a 5-fold decline in Th17 cell numbers and a concurrent 6-fold reduction in tumor burden. Collectively, these data demonstrate that in the LSL-K-rasG12D murine lung cancer model, inflammatory macrophage–Th17 cell axis is critical to tumorigenesis and that IL-10 blocks this process primarily via a direct effect on the former. Inhaled IL-10 formulations may be of use in prophylaxis against lung cancer in high-risk patients.
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Proinflammatory Effects of Respiratory Syncytial Virus-Induced Epithelial HMGB1 on Human Innate Immune Cell Activation [INFECTIOUS DISEASE AND HOST RESPONSE]
High mobility group box 1 (HMGB1) is a multifunctional nuclear protein that translocates to the cytoplasm and is subsequently released to the extracellular space during infection and injury. Once released, it acts as a damage-associated molecular pattern and regulates immune and inflammatory responses. Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants and elderly, for which no effective treatment or vaccine is currently available. This study investigated the effects of HMGB1 on cytokine secretion, as well as the involvement of NF-B and TLR4 pathways in RSV-induced HMGB1 release in human airway epithelial cells (AECs) and its proinflammatory effects on several human primary immune cells. Purified HMGB1 was incubated with AECs (A549 and small alveolar epithelial cells) and various immune cells and measured the release of proinflammatory mediators and the activation of NF-B and P38 MAPK. HMGB1 treatment significantly increased the phosphorylation of NF-B and P38 MAPK but did not induce the release of cytokines/chemokines from AECs. However, addition of HMGB1 to immune cells did significantly induce the release of cytokines/chemokines and activated the NF-B and P38 MAPK pathways. We found that activation of NF-B accounted for RSV-induced HMGB1 secretion in AECs in a TLR4-dependent manner. These results indicated that HMGB1 secreted from AECs can facilitate the secretion of proinflammatory mediators from immune cells in a paracrine mechanism, thus promoting the inflammatory response that contributes to RSV pathogenesis. Therefore, blocking the proinflammatory function of HMGB1 may be an effective approach for developing novel therapeutics.
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Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets [INFECTIOUS DISEASE AND HOST RESPONSE]
Perforin-2, the product of the MPEG1 gene, limits the spread and dissemination of bacterial pathogens in vivo. It is highly expressed in murine and human phagocytes, and macrophages lacking Perforin-2 are compromised in their ability to kill phagocytosed bacteria. In this study, we used Salmonella enterica serovar Typhimurium as a model intracellular pathogen to elucidate the mechanism of Perforin-2's bactericidal activity. In vitro Perforin-2 was found to facilitate the degradation of Ags contained within the envelope of phagocytosed bacteria. In contrast, degradation of a representative surface Ag was found to be independent of Perforin-2. Consistent with our in vitro results, a protease-sensitive, periplasmic superoxide dismutase (SodCII) contributed to the virulence of S. Typhimurium in Perforin-2 knockout but not wild-type mice. In aggregate, our studies indicate that Perforin-2 breaches the envelope of phagocytosed bacteria, facilitating the delivery of proteases and other antimicrobial effectors to sites within the bacterial cell.
https://ift.tt/2NXoLK0
The Histone Demethylase LSD1 Regulates B Cell Proliferation and Plasmablast Differentiation [SYSTEMS IMMUNOLOGY]
B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM. LSD1-deficient PB exhibited derepression and superinduction of genes involved in immune system processes; a subset of these being direct Blimp-1 target–repressed genes. Cell cycle genes were globally downregulated without LSD1, which corresponded to a decrease in the proliferative capacity of LSD1-deficient activated B cells. PB lacking LSD1 displayed increased histone H3 lysine 4 monomethylation and chromatin accessibility at nB active enhancers and the binding sites of transcription factors Blimp-1, PU.1, and IRF4 that mapped to LSD1-repressed genes. Together, these data show that LSD1 is required for normal in vivo PB formation, distinguish LSD1 as a transcriptional rheostat and epigenetic modifier of B cell differentiation, and identify LSD1 as a factor responsible for decommissioning nB active enhancers.
https://ift.tt/2NYmcYu
The End of the Binary Era: Revisiting the Spectrum of Tuberculosis [BRIEF REVIEWS]
Human Mycobacterium tuberculosis infection was thought to result in either active symptomatic tuberculosis (TB) or latent asymptomatic infection. It is now clear that this binary classification is insufficient to describe the myriad of infection outcomes. In active TB, symptomatic disease can be mild to severe, with a range of lung and thoracic lymph node involvement or extrapulmonary manifestations. Most humans control the infection and develop latent TB infection, with differential risks of reactivation to active TB. However, some frequently exposed persons appear to be resistant to infection, whereas others may initially become infected yet subsequently eliminate all bacilli. The immunologic factors influencing these varied outcomes are still not clear, but likely involve a range of different responses. In this article, we review the data supporting the spectrum of M. tuberculosis infection in humans as well as data in nonhuman primates that allow dissection of the immune responses leading to the varied outcomes of infection.
https://ift.tt/2NWpGKR
Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus [IMMUNE SYSTEM DEVELOPMENT]
We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r–/– rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.
https://ift.tt/2NYEYyT
Cutting Edge: Local Proliferation of Uterine Tissue-Resident NK Cells during Decidualization in Mice [CUTTING EDGE]
NK cells accumulate in adult murine and human uteri during decidualization induced physiologically, pathologically, or experimentally. Adoptive transfer studies indicate that uterine NK (uNK) cells arise from circulating progenitors. However, virgin uteri contain few circulating NK1.1+CD49a– conventional NK cells, whereas NK1.1+CD49a+ tissue-resident NK (trNK) cells are abundant. In this study, we employed a novel, immune-competent NK cell–specific reporter mouse to track accumulation of uNK cells during unmanipulated pregnancies. We identified conventional NK and trNK cells accumulating in both decidua basalis and myometrium. Only trNK cells showed evidence of proliferation. In parabiosis studies using experimentally induced deciduomata, the accumulated uNK cells were proliferating trNK cells; migrating NK cells made no contribution. Together, these data suggest proliferating trNK cells are the source of uNK cells during endometrial decidualization.
https://ift.tt/2ODVDgl
HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface [INFECTIOUS DISEASE AND HOST RESPONSE]
HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4+ T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4+ T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4+ T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding–deficient Nef variant fails to impair CD4+ T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo.
https://ift.tt/2NW6CfX
A Novel Neutralizing Antibody Specific to the DE Loop of VP1 Can Inhibit EV-D68 Infection in Mice [ANTIGEN RECOGNITION AND RESPONSES]
Enterovirus D68 (EV-D68) belongs to the picornavirus family and was first isolated in CA, USA, in 1962. EV-D68 can cause severe cranial nerve system damage such as flaccid paralysis and acute respiratory diseases such as pneumonia. There are currently no efficient therapeutic methods or effective prophylactics. In this study, we isolated the mAb A6-1 from an EV-D68–infected rhesus macaque (Macaca mulatta) and found that the Ab provided effective protection in EV-D68 intranasally infected suckling mice. We observed that A6-1 bound to the DE loop of EV-D68 VP1 and interfered with the interaction between the EV-D68 virus and α2,6-linked sialic acids of the host cell. The production of A6-1 and its Ab properties present a bridging study for EV-D68 vaccine design and provide a tool for analyzing the process by which Abs can inhibit EV-D68 infection.
https://ift.tt/2NYmiPQ
Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque [INNATE IMMUNITY AND INFLAMMATION]
The rhesus macaque is an important animal model for AIDS and other infectious diseases; however, studies to address NK cell function in this species have been limited by the lack of defined ligands for killer cell Ig-like receptors (KIRs). To identify ligands for rhesus macaque KIRs, we adopted a novel approach based on a pair of stable cell lines. NFAT-responsive luciferase reporter cell lines expressing the extracellular domains of macaque KIRs fused to the transmembrane and cytoplasmic domains of CD28 and CD3 were incubated with target cells expressing individual MHC class I molecules, and ligand recognition was detected by the MHC class I–dependent upregulation of luciferase. Using this approach, we found that Mamu-KIR3DL01, -KIR3DL06, -KIR3DL08, and -KIR3DSw08 all recognize Mamu-Bw4 molecules but with differing allotype specificity. In contrast, Mamu-KIR3DL05 recognizes Mamu-A and Mamu-A–related molecules, including Mamu-A1*002 and -A3*13, Mamu-B*036, the product of a recombinant Mamu-B allele with α1 and α2 domain sequences derived from a MHC-A gene, and Mamu-AG*01, a nonclassical molecule expressed on placental trophoblasts that originated from an ancestral duplication of a MHC-A gene. These results reveal an expansion of the lineage II KIRs in macaques that recognize Bw4 ligands and identify a nonclassical molecule implicated in placental development and pregnancy as a ligand for Mamu-KIR3DL05. In addition to offering new insights into KIR–MHC class I coevolution, these findings provide an important foundation for investigating the role of NK cells in the rhesus macaque as an animal model for infectious diseases and reproductive biology.
https://ift.tt/2NWVH5B
WDFY4 Is Involved in Symptoms of Systemic Lupus Erythematosus by Modulating B Cell Fate via Noncanonical Autophagy [AUTOIMMUNITY]
Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout (Wdfy4-CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4-CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4-CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.
https://ift.tt/2OFnfll
EF Hand Domain Family Member D2 Is Required for T Cell Cytotoxicity [TUMOR IMMUNOLOGY]
Programmed cell death 1 (PD-1) is a major coinhibitory receptor and a member of the immunological synapse (IS). To uncover proteins that regulate PD-1 recruitment to the IS, we searched for cytoskeleton-related proteins that also interact with PD-1 using affinity purification mass spectrometry. Among these proteins, EF hand domain family member D2 (EFHD2), a calcium binding adaptor protein, was functionally and mechanistically analyzed for its contribution to PD-1 signaling. EFHD2 was required for PD-1 to inhibit cytokine secretion, proliferation, and adhesion of human T cells. Interestingly, EFHD2 was also required for human T cell–mediated cytotoxicity and for mounting an antitumor immune response in a syngeneic murine tumor model. Mechanistically, EFHD2 contributed to IS stability, lytic vesicles trafficking, and granzyme B secretion. Altogether, EFHD2 is an important regulator of T cell cytotoxicity and further studies should evaluate its role in T cell–mediated inflammation.
https://ift.tt/2NYmcrs
IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells [AUTOIMMUNITY]
Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.
https://ift.tt/2NUtbBC
High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia [CLINICAL AND HUMAN IMMUNOLOGY]
Killer-cell Ig-like receptor (KIR) genes are inherited as haplotypes. They are expressed by NK cells and linked to outcomes of infectious diseases and pregnancy in humans. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. In this article, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected in both peripheral blood and uterine NK cells. Using this new method, we demonstrate that both blood and uterine NK cells codominantly express KIR2DL1A and KIR2DL1B allotypes but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk.
https://ift.tt/2OKWZpt
Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
Novel therapeutics against multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococcal lipooligosaccharide often expresses lacto-N-neotetraose (LNnT), which becomes sialylated in vivo, enhancing factor H (FH) binding and contributing to the organism's ability to resist killing by complement. We previously showed that FH domains 18–20 (with a D-to-G mutation at position 1119 in domain 19) fused to Fc (FHD1119G/Fc) displayed complement-dependent bactericidal activity in vitro and attenuated gonococcal vaginal colonization of mice. Gonococcal lipooligosaccharide phase variation can result in loss of LNnT expression. Loss of sialylated LNnT, although associated with a considerable fitness cost, could decrease efficacy of FHD1119G/Fc. Similar to N. meningitidis, gonococci also bind FH domains 6 and 7 through Neisserial surface protein A (NspA). In this study, we show that a fusion protein comprising FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/Fc) bound to 15 wild-type antimicrobial resistant isolates of N. gonorrhoeae and to each of six lgtA gonococcal deletion mutants. FH6,7/Fc mediated complement-dependent killing of 8 of the 15 wild-type gonococcal isolates and effectively reduced the duration and burden of vaginal colonization of three gonococcal strains tested in wild-type mice, including two strains that resisted complement-dependent killing but on which FH6,7/Fc enhanced C3 deposition. FH/Fc lost efficacy when Fc was mutated to abrogate C1q binding and in C1q–/– mice, highlighting the requirement of the classical pathway for its activity. Targeting gonococci with FH6,7/Fc provides an additional immunotherapeutic approach against multidrug-resistant gonorrhea.
https://ift.tt/2ODVBFf
Augmentation of Human Monocyte Responses to Lipopolysaccharide by the Protein S and Mer/Tyro3 Receptor Tyrosine Kinase Axis [IMMUNE REGULATION]
Resolution of the inflammatory response requires coordinated regulation of pro- and anti-inflammatory mediator production, together with clearance of recruited inflammatory cells. Many different receptors have been implicated in phagocytosis of apoptotic cells (efferocytosis), including Mer, a receptor tyrosine kinase that can mediate recognition and subsequent internalization of apoptotic cells. In this manuscript, we examine the expression and function of the Tyro3/Axl/Mer (TAM) family of receptors by human monocytes. We demonstrate that the Mer ligand, protein S, binds to the surface of viable monocytes via phosphatidylserine-dependent and -independent mechanisms. Importantly, we have identified a novel role for receptor tyrosine kinase signaling in the augmentation of monocyte cytokine release in response to LPS. We propose that low-level phosphatidylserine exposure on the plasma membrane of viable monocytes allows protein S binding that leads to TAM-dependent augmentation of proinflammatory cytokine production. Our findings identify a potentially important role for TAM-mediated signaling during the initiation phase of inflammation.
https://ift.tt/2NYlHO6
Short Leucine-Rich Proteoglycans Modulate Complement Activity and Increase Killing of the Respiratory Pathogen Moraxella catarrhalis [INFECTIOUS DISEASE AND HOST RESPONSE]
The respiratory pathogen Moraxella catarrhalis is a human-specific commensal that frequently causes acute otitis media in children and stimulates acute exacerbations in chronic obstructive pulmonary disease patients. The exact molecular mechanisms defining host–pathogen interactions promoting pathogenesis are not clearly understood. Limited knowledge hampers vaccine and immunotherapeutic development required to treat this emerging pathogen. In this study, we reveal in detail a novel antibacterial role displayed by short leucine-rich proteoglycans (SLRPs) in concert with complement. We show that fibromodulin (FMOD), osteoadherin (OSAD), and biglycan (BGN) but not decorin (DCN) enhance serum killing of M. catarrhalis. Our results suggest that M. catarrhalis binding to SLRPs is a conserved feature, as the overwhelming majority of clinical and laboratory strains bound all four SLRPs. Furthermore, we resolve the binding mechanism responsible for this interaction and highlight the role of the ubiquitous surface protein (Usp) A2/A2H in mediating binding to host SLRPs. A conserved immune evasive strategy used by M. catarrhalis and other pathogens is the surface acquisition of host complement inhibitors such as C4b-binding protein (C4BP). We observed that FMOD, OSAD, and BGN competitively inhibit binding of C4BP to the surface of M. catarrhalis, resulting in increased C3b/iC3b deposition, membrane attack complex (MAC) formation, and subsequently decreased bacterial survival. Furthermore, both OSAD and BGN promote enhanced neutrophil killing in vitro, both in a complement-dependent and independent fashion. In summary, our results illustrate that SLRPs, FMOD, OSAD, and BGN portray complement-modulating activity enhancing M. catarrhalis killing, defining a new antibacterial role supplied by SLRPs.
https://ift.tt/2OFvbmp
STAT6 and Furin Are Successive Triggers for the Production of TGF-{beta} by T Cells [IMMUNE REGULATION]
Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell–inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β–dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.
https://ift.tt/2OGvqxr
Growth Hormone Deficiency and Nonalcoholic Fatty Liver Disease with Insights from Humans and Animals: Pediatric Implications
Metabolic Syndrome and Related Disorders, Ahead of Print.
https://ift.tt/2ODMeW1
Plasma Growth Arrest-Specific 6 Protein and Genetic Variations in the GAS6 Gene in Patients with Metabolic Syndrome
Metabolic Syndrome and Related Disorders, Ahead of Print.
https://ift.tt/2ED6GBN
Safety of trifluridine/tipiracil in an open-label expanded-access program in elderly and younger patients with metastatic colorectal cancer
Abstract
Purpose
Trifluridine/tipiracil (FTD/TPI; TAS-102, Lonsurf®), a novel form of chemotherapy for metastatic colorectal cancer (mCRC), has shown clinical benefit in the global, phase III RECOURSE trial, regardless of patient age. Here, we report the safety and tolerability profile of FTD/TPI from an expanded-access program (EAP) in the US patients with mCRC whose disease has progressed on the standard therapies.
Methods
A total of 549 patients (≥ 18 years) with histologically confirmed mCRC following two or more regimens of standard therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 participated in this open-label EAP. During the 28-day treatment cycle, patients took FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days of rest for 2 weeks, with a 14-day rest period. Data were collected for therapy duration, treatment discontinuation, and adverse events. Age-based post hoc analysis was performed to determine the safety of FTD/TPI in elderly (≥ 65 years) versus younger (< 65 years) patients.
Results
FTD/TPI-treated patients in this EAP had a similar therapy duration and time to treatment discontinuation to those in the RECOURSE trial. The safety profile in elderly patients was consistent with that in younger patients, with no unexpected safety concerns.
Conclusions
This USA-based, open-label EAP has confirmed a similar safety and tolerability profile for FTD/TPI to that observed in the RECOURSE trial. Furthermore, FTD/TPI is well tolerated and can be considered as a treatment option in elderly patients with mCRC.
Trial registration
NCT02286492.
https://ift.tt/2R5lvi0
Left ventricular geometry and periodontitis in patients with the metabolic syndrome
Abstract
Objective
The presence of periodontal disease (PD) in subjects affected by the metabolic syndrome (MetS) may affect their risk of developing cardiovascular disease. The aim of this cross-sectional study was to investigate the systemic impact of PD in MetS, by assessing measures of sub-clinical atherosclerosis and left ventricular mass and geometry.
Materials and methods
A total of 103 patients undergoing treatment for MetS were examined for confirmation of diagnosis, blood sampling, and measures of pulse wave velocity (PWV), carotid intima-media thickness (c-IMT), left ventricular mass index (LVM), and relative wall thickness (RWT). All subjects underwent a detailed dental assessment, including measurements of DMFT (decayed-missing-filled teeth) and periodontal parameters.
Results
Ten patients (10%) were diagnosed with healthy-mild periodontitis, 38 patients (37%) were diagnosed in the moderate periodontitis group, and 55 (53%) had severe periodontitis. A total of 37% of subjects were affected by dental caries. Linear regression analysis revealed that patients with severe PD had increased average ventricular RWT (adjusted p = 0.032). Average full mouth probing pocket depth (PPD) was also associated with RWT (adjusted p = 0.006). No associations between PD and c-IMT, PWV, and LVM were detected after adjusted analyses.
Conclusion
This study suggests that periodontitis may be associated with concentric left ventricular remodeling, a predictive index of cardiovascular events.
Clinical relevance
The presence of periodontitis in patients with MetS might have an effect on left ventricular geometry. These findings stress the importance of prevention, diagnosis, and management of periodontitis in patients with MetS.
Trail registration
NCT03297749
https://ift.tt/2ysU2Qu
Surfactant protein D alleviates eosinophil‐mediated airway inflammation and remodeling in patients with aspirin‐exacerbated respiratory disease
Allergy, EarlyView.
https://ift.tt/2Sa5gkM
Letter to the Editor Regarding Diagnostic Accuracy of the McGill Thyroid Nodule Score in Pediatric Patients
Clinical Endocrinology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2R1WCDy
Role of fibroblast growth factor 21 in gestational diabetes mellitus: A mini‐review
Clinical Endocrinology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2q4InT9
Impact of Intraoperative Parathyroid Hormone Monitoring on the Management of Patients with Primary Hyperparathyroidism
Clinical Endocrinology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2R1Wq7i
Laparoscopic Hand Assisted Adrenalectomy for Tumours larger than 5cm
Clinical Endocrinology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2q85oV7
Issue Information
Experimental Dermatology, Volume 27, Issue 11, Page 1192-1192, November 2018.
https://ift.tt/2EDvjOT
Clinical Snippets
Experimental Dermatology, Volume 27, Issue 11, Page i-i, November 2018.
https://ift.tt/2PhW1R0
Update zu HPV-assoziierten Kopf-Hals-Karzinomen – Highlights der ASCO-Jahrestagung 2018
Zusammenfassung
Steigende Inzidenzraten mit dem humanen Papillomvirus (HPV‑)assoziierter Oropharynxkarzinome (OPC) und die deutlich bessere Prognose solcher Tumoren bringen diese Tumorentität in den wissenschaftlichen Fokus. Auf dem diesjährigen Kongress der American Society of Clinical Oncology (ASCO) wurden 291 Arbeiten mit dem Schlüsselwort „HPV" präsentiert, von denen die Mehrheit den Kopf-Hals-Tumoren gewidmet war. Deintensivierte Behandlungen werden aufgrund der erheblichen Spättoxizität konventioneller Therapieregime zunehmend diskutiert, allerdings wurden Ergebnisse von großen prospektiven Phase-III-Studien nicht präsentiert. Jedoch wurden retrospektive Daten zum neuen TNM-Staging (Downstaging der meisten HPV-assoziierten Patienten) und zu weiteren Risikostratifizierungen gezeigt. Auch der alleinige immunhistologische Nachweis von p16 wurde diskutiert. Viele Arbeitsgruppen haben sich auch mit dem Thema der HPV-Assoziation und der prognostischen Relevanz nicht nur bei OPC, sondern auch bei Mundhöhlen‑, Larynx- und Hypopharynxkarzinomen beschäftigt. Neue prognostische Marker wie die Methylierungssignatur scheinen darüber hinaus vielversprechend. Weitere interessante therapeutische Aspekte sind die gleichwertigen Überlebensraten der alleinigen Chirurgie beim HPV-assoziierten OPC im Stadium I. Ein möglicher negativer Effekt auf das Überleben mit HPV-assoziierten OPC im Stadium III mit einer Cisplatindosis von ≤200 mg/m2 wurde diskutiert. Insgesamt werden die Ergebnisse der Deeskalationsstudien dringend erwartet, um Patienten mit HPV-assoziierten Kopf-Hals-Tumoren möglichst präzise und schonende Therapien zukommen zu lassen und so langfristig eine gute Lebensqualität zu sichern.
https://ift.tt/2EEFItw
Condom catheter induced penile skin erosion
Abstract
Condom catheters are known to be discrete, reliable, comfortable and very easy to use which makes them preferable to bladder catheter (Saint et al. (Urinary catheters: What type do men and their nursesprefer? J Am Geriatr SOC 1999;47:1453–1457); Hirsh et al. (Do condom catheter collecting systems cause urinary tract infection? J Am Med Assoc 1979;2:0–1)). Condom catheters are widely used in the management of male urinary incontinence, bedridden patient and geriatric population. They are considered to be safe, however, they are associated with complications in care of an incorrect use. In our hospital setup a 73-year-old male bedridden patient attended the surgical opd with complain of penile skin erosion following condom catheter application for 4 days for which dressing was done to remove the slough for 2 days then circumcision was done. Henceforth, although a less known complications are associated with the condom catheter but if not attended promptly can lead to a grave condition like penile gangrene, necrosis, death (Özkan et al. (Penile strangulation and necrosis due to condom catheter. Int Wound J 2015;12:248–9. doi: 10.1111/iwj.12102. Epub 2013 Jun 11); Johnson (The condom catheter: urinary tract infection and other complications. South Med J 1983;76:579–82)).https://ift.tt/2PKf0kh
Follicular carcinoma arising in a large ectopic lingual thyroid: a case report and review of literature
Abstract
Ectopic lingual thyroid has been described, however, follicular carcinoma arising within it is an extremely rare entity with only 40 cases reported in the literature. Lingual thyroid carcinoma is undistinguishable from benign enlargement of lingual thyroid, the later should also be differentiated from many oropharyngeal pathologies including but not limited to thyroglossal duct cyst, lipoma, dermoid cyst and salivary gland tumors. Ectopic lingual nature of thyroid tissue can be diagnosed with scintigraphy scan; however, malignant transformation confirms just after pathological examination. Surgical excision remains the best therapy with transoral approach being the most appropriate and favorable among others due to its cosmetic results and lower incidence of infection. Herein, we report a case of an adult female who was diagnosed to have follicular carcinoma of an ectopic lingual thyroid tissue mass. Concerning the size of the mass it was the largest of all reported cases of ectopic thyroid gland.https://ift.tt/2CZF8oz
A rare case of paratesticular leiomyosarcoma
Abstract
Paratesticular leiomyosarcoma is a rare tumour. It is seldom diagnosed pre-operatively and subsequent secondary resection is often required. Current treatment consensus comprises inguinal radical orchidectomy with high ligation of the spermatic cord. We present a case of a 74-year-old male with a 3-year history of a painless right-sided scrotal mass which following excision was found to be an epididymal leiomyosarcoma. A review of literature and treatment is presented in this article.https://ift.tt/2PMpeAx
Assessing the effect of multibracket appliance treatment on tooth color by using electronic measurement
Abstract
Background
The purpose of this study was to investigate how tooth color is affected by multibracket appliance (MBA) treatment.
Methods
The color of teeth #14 to #24 of 15 patients with MBA was measured on body and gingival tooth segments using the spectrophotometer Shade Inspector™. Colors of both segments were recorded before start of MBA treatment (baseline T0), end of MBA treatment (T1; 2 years ±0.3), and 3 months after T1 (T2). A 2D color system and a 3D system served as reference systems.
Multilevel models were used to analyze color change within segments and to compare the difference in color change between segments (treatment effect).
Results
2D system. Changes within tooth segments from T0 to T2 were at worst 2.0 units (ΔE in the gingival segment), which is less than the threshold of 2.7 units for a clinically meaningful difference. Confidence intervals for the treatment effect indicated no clinically important differences in color change between body and gingival segments.
3D system. Changes within tooth segments from T0 to T2 were at worst 2.3 units (ΔE in the body segment), which is less than the threshold of 2.7 units for a clinically meaningful difference. Confidence intervals for the treatment effect indicated no clinically important differences in color change between body and gingival segments.
Thus, MBA treatment did not lead to clinically relevant changes in tooth color.
Conclusion
Within the limitation of this study the MBA treatment can be seen as a safe method with respect to tooth color.
https://ift.tt/2ytJwIt
Pre-Operative Pregabalin for Post-Operative Pain in Head and Neck Cancer Surgery
Conditions: Head and Neck Cancer; Pain, Postoperative
Interventions: Drug: Pregabalin 150mg; Other: Placebo
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2NVWDak
Interventions: Drug: Pregabalin 150mg; Other: Placebo
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2NVWDak
Study on Association Between Treatment of Allergic Rhinitis and Cognitive Ability in Children
Condition: Allergic Rhinitis
Intervention: Other: No intervention
Sponsor: Chinese University of Hong Kong
Recruiting
https://ift.tt/2q7Lslf
Intervention: Other: No intervention
Sponsor: Chinese University of Hong Kong
Recruiting
https://ift.tt/2q7Lslf
Robotic-assisted Esophagectomy vs. Video-Assisted Thoracoscopic Esophagectomy(REVATE) Trial
Condition: Esophageal Squamous Cell Carcinoma
Interventions: Procedure: Robot esophagectomy (RE); Procedure: Video-assisted thoracoscopic esophagectomy (VATE)
Sponsor: Chang Gung Memorial Hospital
Not yet recruiting
https://ift.tt/2NVJ8HD
Interventions: Procedure: Robot esophagectomy (RE); Procedure: Video-assisted thoracoscopic esophagectomy (VATE)
Sponsor: Chang Gung Memorial Hospital
Not yet recruiting
https://ift.tt/2NVJ8HD
Stellate Ganglion Block in Head and Neck Cancer Surgery
Conditions: Head and Neck Cancer; Pain, Postoperative
Intervention: Procedure: Stellate ganglion block
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2q3LUB1
Intervention: Procedure: Stellate ganglion block
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2q3LUB1
Pre-Operative Pregabalin for Post-Operative Pain in Head and Neck Cancer Surgery
Conditions: Head and Neck Cancer; Pain, Postoperative
Interventions: Drug: Pregabalin 150mg; Other: Placebo
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2NVWDak
Interventions: Drug: Pregabalin 150mg; Other: Placebo
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2NVWDak
Study on Association Between Treatment of Allergic Rhinitis and Cognitive Ability in Children
Condition: Allergic Rhinitis
Intervention: Other: No intervention
Sponsor: Chinese University of Hong Kong
Recruiting
https://ift.tt/2q7Lslf
Intervention: Other: No intervention
Sponsor: Chinese University of Hong Kong
Recruiting
https://ift.tt/2q7Lslf
Robotic-assisted Esophagectomy vs. Video-Assisted Thoracoscopic Esophagectomy(REVATE) Trial
Condition: Esophageal Squamous Cell Carcinoma
Interventions: Procedure: Robot esophagectomy (RE); Procedure: Video-assisted thoracoscopic esophagectomy (VATE)
Sponsor: Chang Gung Memorial Hospital
Not yet recruiting
https://ift.tt/2NVJ8HD
Interventions: Procedure: Robot esophagectomy (RE); Procedure: Video-assisted thoracoscopic esophagectomy (VATE)
Sponsor: Chang Gung Memorial Hospital
Not yet recruiting
https://ift.tt/2NVJ8HD
Stellate Ganglion Block in Head and Neck Cancer Surgery
Conditions: Head and Neck Cancer; Pain, Postoperative
Intervention: Procedure: Stellate ganglion block
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2q3LUB1
Intervention: Procedure: Stellate ganglion block
Sponsor: Augusta University
Not yet recruiting
https://ift.tt/2q3LUB1
Exposure of remote organs and associated cancer risks from tangential and multi-field breast cancer radiotherapy
Abstract
Purpose
With the ever-increasing cure rates in breast cancer, radiotherapy-induced cancers have become an important issue. This study aimed to estimate secondary cancer risks for different treatment techniques, taking into account organs throughout the body.
Material and methods
Organ doses were evaluated for a tangential three-dimensional conformal (3D-CRT) and a multi-field intensity-modulated radiotherapy (IMRT) plan using a validated, Monte Carlo-based treatment planning system. Effects of wedges and of forward versus inverse planning were systematically investigated on the basis of phantom measurements. Organ-specific cancer risks were estimated using risk coefficients derived from radiotherapy patients or from the atomic bomb survivors.
Results
In the 3D-CRT plan, mean organ doses could be kept below 1 Gy for more remote organs than the lung, heart, and contralateral breast, and decreased to a few cGy for organs in the lower torso. Multi-field IMRT led to considerably higher mean doses in organs at risk, the difference being higher than 50% for many organs. Likewise, the peripheral radiation burden was increased by external wedges. No difference was observed for forward versus inverse planning. Despite the lower doses, the total estimated secondary cancer risk in more remote organs was comparable to that in the lung or the contralateral breast. For multi-field IMRT it was 75% higher than for 3D-CRT without external wedges.
Conclusion
Remote organs are important for assessment of radiation-induced cancer risk. Remote doses can be reduced effectively by application of a tangential field configuration and a linear accelerator set-up with low head scatter radiation.
https://ift.tt/2S8QRFF
Susceptibility mapping of the dural sinuses and other superficial veins in the brain
Publication date: Available online 21 October 2018
Source: Magnetic Resonance Imaging
Author(s): Sagar Buch, Yongsheng Chen, E. Mark Haacke
Abstract
Quantitative susceptibility mapping (QSM) is a means to obtain direct measurements of local tissue susceptibility distribution. Usually the focus is on imaging tissues in the brain, and the region of the brain studied is dictated by an eroded skull stripped mask. Producing the pristine local phase behavior for regions at the edge of the brain has been difficult in the past. For structures such as the superior sagittal sinus (SSS) that run alongside the surface of the brain and under the skull bones, a considerable part of the external phase from the dipole effect is lost due to the short T2* of the bones. In this paper, we propose a method that seeks to reconstruct the susceptibility distribution inside the dural sinuses by ensuring that the entire geometry of the dural sinuses is preserved with the help of an MR angiogram and venogram (MRAV). Having a geometrical model of the vessels makes it possible to estimate the missing phase outside the brain as well, by using the forward phase model and, hence, allowing a complete phase map to be reconstructed. Fifteen healthy volunteers were scanned using a susceptibility weighted imaging (SWI) sequence with interleaved rephased-dephased echoes. QSM results were compared between the conventional techniques and the proposed method of phase preservation outside the brain and inside the dural sinuses. This method demonstrates the reconstruction of the SSS, whereas conventional methods are either unable to preserve this structure or unable to provide complete phase information. The mean and standard deviation inside the SSS for all volunteers was 435 ± 5 ppb (this is the inter-subject error). To validate the proposed approach, the mean susceptibility inside the straight sinus showed good agreement between conventional approach and the proposed method. The results presented in this study indicate the potential of generating the susceptibility map for the whole brain, including the SSS (as well as potentially all the cortical veins).
https://ift.tt/2PM3d4R
Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer
Abstract
Background
Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer.
Materials and methods
This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer.
Results
Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit.
Conclusions
Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.
https://ift.tt/2NWpcEo
Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1
Publication date: November 2018
Source: Molecular Immunology, Volume 103
Author(s): Lihua Shi, Song Li, Kelly Maurer, Zhe Zhang, Michelle Petri, Kathleen E. Sullivan
Abstract
We observed increased expression of ADAMDEC1 RNA in monocytes from patients with systemic lupus erythematosus. The precise role of ADAMDEC1 is uncertain and uniquely among metalloproteinases it utilizes a zinc-coordinating aspartic acid residue which allows it to escape inhibition by tissue inhibitor of metalloprotease-3 (TIMP-3). A closely related gene encodes the protein ADAM28, which is not up-regulated in lupus. We leveraged the ability to look at both gene's promoters and enhancers simultaneously. ADAMDEC1 was up-regulated by LPS while ADAM28 was not upregulated in the short term. We identified MAP kinases and NFκB as critical cell pathways regulating the expression of ADAMDEC1. These same pathways were implicated in driving the expression of the ADAMDEC1 upstream enhancer RNAs. We demonstrated that binding of the enhancer RNAs produced from the upstream enhancer were critically important and that p300 bound to both the RNA from the enhancer and the DNA at the enhancer. P300 binding to the enhancer was dependent on NFκB. These data define the critical pathways regulating the expression of ADAMDEC1 and extend our knowledge of the roles of enhancer RNAs and mechanistically links p300 and enhancer RNAs.
Graphical abstract
https://ift.tt/2CxndV3
Comparison of natural ostiodilatation and endoscopic sinus surgery in the same patient with chronic sinusitis
Publication date: Available online 22 October 2018
Source: Brazilian Journal of Otorhinolaryngology
Author(s): Ahmet Kutluhan, Hüseyin Çetin, Hayati Kale, Özmen Kara, Halil İbrahim Mişe, Tolga Oğuzhan, Kadir Şinasi Bulut
Abstract
Introduction
Chronic rhinosinusitis is a broad clinical syndrome characterized by mucosal inflammation of the nose and paranasal sinuses. In order for the paranasal sinuses to maintain their physiological functions; the ostiomeatal complex drainage pathways must be open. Surgical procedures are an important treatment option in patients who do not respond adequately to medical treatment. Although the methods and instruments used in functional endoscopic sinus surgery have continued to improve in recent years, the scar tissue formed during operation disrupts the drainage of the sinuses and reduces postoperative success. The natural ostiodilatation method, which is performed by balloon sinoplasty method, has become more and more popular in recent years.
Objectives
To compare the technique of balloon sinoplasty with the classical functional endoscopic sinus surgery method by considering the severity of chronic sinusitis on the same patient.
Methods
Total of 61 chronic sinusitis patients was included in the study. Paranasal sinus tomography of the patients was taken and according to the Lund–Mackay scoring, chronic sinusitis levels were determined. Cases were divided into two groups: Group 1 (severe chronic sinusitis group) and Group 2 (mild chronic sinusitis).
Results
There was no statistically significant difference in the results of comparison of sinuses which underwent balloon sinoplasty and classical functional endoscopic sinus surgery in Group 2 after Lund–Mackay scores. However in Group 1, the results of the comparison of postoperative Lund–Mackay scores of the balloon sinoplasty and the classical endoscopic operation were statistically significantly lower than those of the face half operated with the classical functional endoscopic sinus surgery.
Conclusion
The success of balloon sinoplasty in patients with mild sinusitis is the same as in classic functional endoscopic sinus surgery. However, as the severity of sinusitis increases, the efficacy of balloon sinoplasty decreases.
Resumo
Introdução
A rinossinusite crônica é uma síndrome clínica ampla, caracterizada por inflamação da mucosa nasal e seios paranasais. Para que os seios paranasais mantenham suas funções fisiológicas, as vias de drenagem do complexo ostiomeatal devem estar abertas. Os procedimentos cirúrgicos são uma importante opção de tratamento em pacientes que não respondem adequadamente ao tratamento clínico. Embora os métodos e instrumentos utilizados na cirurgia endoscópica funcional dos seios paranasais venham melhorando continuamente, o tecido cicatricial formado durante a cirurgia interrompe a drenagem dos seios nasais e reduz o sucesso pós-operatório. O método natural de dilatação ostial, que é realizado através da técnica de sinuplastia com balão, tem se tornado cada vez mais popular nos últimos anos.
Objetivos
Comparar a técnica de sinuplastia com balão com o método convencional de cirurgia endoscópica, no mesmo paciente, considerando a gravidade da rinossinusite crônica,.
Método
Um total de 61 pacientes com rinossinusite crônica foram incluídos no estudo. Por meio de tomografia dos seios paranasais e, de acordo a escala de Lund-Mackay, foram determinados os graus da rinossinusite crônica. Os casos foram divididos em dois grupos: Grupo 1 (grupo com rinossinusite crônica grave) e Grupo 2 (rinossinusite crônica leve).
Resultados
No Grupo 2 não houve diferença estatisticamente significante, segundo a escala de Lund-Mackay, no resultado da comparação dos seios paranasais nos quais foram realizadas a sinuplastia com balão e por cirurgia endoscópica convencional. No entanto, no Grupo 1, os resultados da comparação dos escores pós-operatórios de Lund-Mackay mostraram-se estatisticamente e significativamente melhores naqueles submetidos à cirurgia endoscópica funcional dos seios paranasais.
Conclusão
O sucesso da sinuplastia com balão em pacientes com rinossinusite leve é o mesmo da cirurgia endoscópica funcional dos seios da face tradicional. No entanto, à medida que a gravidade da rinossinusite aumenta, a eficácia da sinuplastia com balão diminui.
https://ift.tt/2CXV6iP
A Review of the Use and Effectiveness of Digital Health Technologies in Asthma Patients
Publication date: Available online 22 October 2018
Source: Annals of Allergy, Asthma & Immunology
Author(s): Elizabeth Unni, Susan Gabriel, Rinat Ariely
https://ift.tt/2S8Mhr6
Salivary gland cell aggregates are derived from self-organization of acinar lineage cells
Publication date: Available online 22 October 2018
Source: Archives of Oral Biology
Author(s): Jomy J. Varghese, M. Eva Hansen, Azmeer Sharipol, Matthew H. Ingalls, Martha A. Ormanoski, Shawn D. Newlands, Catherine E. Ovitt, Danielle S.W. Benoit
Abstract
Objective
The objective of this study was to characterize the mechanism by which salivary gland cells (SGC) aggregate in vitro.
Design
Timelapse microscopy was utilized to analyze the process of salivary gland aggregate formation using both primary murine and human salivary gland cells. The role of cell density, proliferation, extracellular calcium, and secretory acinar cells in aggregate formation was investigated. Finally, the ability of cells isolated from irradiated glands to form aggregates was also evaluated.
Results
Salivary gland cell self-organization rather than proliferation was the predominant mechanism of aggregate formation in both primary mouse and human salivary gland cultures (SGC). Aggregation was found to require extracellular calcium while acinar lineage cells account for ~80% of the total aggregate cell population. Finally, aggregation was not impaired by irradiation.
Conclusions
The data reveal that aggregation occurs as a result of heterogeneous salivary gland cell self-organization rather than from stem cell proliferation and differentiation, contradicting previous dogma. These results suggest a re-evaluation of aggregate formation as a criterion defining salivary gland stem cells.
https://ift.tt/2Rc8aVd
Delineating metabolic dysfunction in cellular metabolism of oral submucous fibrosis using 1H nuclear magnetic resonance spectroscopy
Publication date: Available online 21 October 2018
Source: Archives of Oral Biology
Author(s): Vertika Rai, Surajit Bose, Satadal Saha, Virendra Kumar, Chandan Chakraborty
Abstract
Objective
To delineate the metabolism involved in oral submucous fibrosis progression towards carcinogenesis by 1H nuclear magnetic resonance spectroscopy.
Methods
The proposed study was designed using 1H-NMR by comparing the metabolites in the serum sample of oral submucous fibrosis (n = 20) compared to the normal group (n = 20) using 1H nuclear magnetic resonance spectroscopy. Various statistical analysis like multivariate statistical analysis, Principle component analysis, Partial least squares Discriminant Analysis, Hierarchical cluster analysis was applied to analyze potential serum metabolites.
Results
The results generated from the principle component analysis, partial least squares discriminant analysis and hierarchical cluster analysis are sufficient to distinguish between oral submucous fibrosis group and normal group. A total of 15 significant metabolites associated with main pathways were identified, which correlated with the progression of cancer. Up-regulation of glucose metabolism-related metabolites indicated the high energy demand due to enhanced cell division rate in the oral submucous fibrosis group. A significant increase in lipid metabolism-related metabolites revealed the reprogramming of the fatty acids metabolic pathway to fulfilling the need for cell membrane formation in cancer cells. On the other hand, metabolites related to choline phosphocholine, the metabolic pathway was also altered.
Conclusion
Our findings could identify the differentiating metabolites in the oral submucous fibrosis group. Significant alteration in metabolites in the oral submucous fibrosis group exhibited deregulation in metabolic events. The findings reported in the study can be beneficial to further explain the molecular aspects that lead to the progression of oral submucous fibrosis towards carcinogenesis
Graphical abstract
https://ift.tt/2q2W9pc
Prenatal 25-hydroxyvitamin D deficiency affects development of atopic dermatitis via DNA methylation
Publication date: Available online 22 October 2018
Source: Journal of Allergy and Clinical Immunology
Author(s): Hyun-Ju Cho, Youn Ho Sheen, Mi-Jin Kang, Seung-Hwa Lee, So-Yeon Lee, Jisun Yoon, Sungsu Jung, Si Hyeon Lee, Young-Ho Kim, Song-I. Yang, Eun Lee, Ju-Hee Seo, Kangmo Ahn, Kyung Won Kim, Dong In Suh, Hye-Sung Won, Mi-Young Lee, Soo Hyun Kim, Suk-Joo Choi, Ja-Young Kwon
https://ift.tt/2CZrBgR
Identification of biomarkers for predicting the response to cyclosporine A therapy in patients with chronic spontaneous urticaria
Publication date: Available online 22 October 2018
Source: Allergology International
Author(s): Takahiro Endo, Shota Toyoshima, Kazuko Kanegae, Satoshi Izaki, Nobuyuki Nishimori, Mana Ito, Kazuko Sugai, Koremasa Hayama, Tadashi Terui, Yoshimichi Okayama
https://ift.tt/2R50XGg
Cumulative incidence of neck recurrence with increasing depth of invasion
Publication date: December 2018
Source: Oral Oncology, Volume 87
Author(s): Justin R. Shinn, C. Burton Wood, Juan M. Colazo, Frank E. Harrell, Sarah L. Rohde, Kyle Mannion
Abstract
Objective
To determine if there is a critical depth of invasion that predicts micrometastasis in early oral tongue cancer.
Methods
Retrospective series identifying patients undergoing primary surgical resection of T1 or T2 oral tongue cancer who elected against neck treatment between 2000 and 2015. Cox proportional-hazard model compared the relative hazard and cumulative incidence of recurrence to depth of invasion. The model used a 2 parameter quadratic effect for depth that was chosen based on Akaike's information criterion.
Results
Ninety-three patients were identified with T1 or T2 oral tongue squamous cell carcinoma and clinically N0 neck undergoing glossectomy without elective neck treatment. 61% were male and median age was 60 years. Median follow up was 45 months, and 76 patients had at least two years of follow up. Thirty-six of 76 patients recurred (47.4%), with 15 recurring in the oral cavity (19.7%) and 21 developing nodal metastasis (27.6%). Cox proportional-hazards quadratic polynomial showed increasing hazard of recurrence with depth of invasion and the cumulative incidence increased sharply within the range of data from 2 to 6 mm depth of invasion.
Conclusions
Depth of invasion is significantly associated with nodal metastasis and has been added to the 8th AJCC staging guidelines. Variable depths of invasion have been associated with regional metastasis; however, there is likely not a critical depth that predicts neck recurrence due to progressive hazards and cumulative risk of occult metastasis. The risk of regional metastasis is likely much greater than previously believed and increases progressively with increasing depth.
https://ift.tt/2S8mejO
Biophysical properties of striae rubra and striae alba in human skin: Comparison with normal skin
Skin Research and Technology, EarlyView.
https://ift.tt/2OGWEnR
The role of in vivo reflectance confocal microscopy in assessing the stability of vitiligo vulgaris prior to cellular grafting
Skin Research and Technology, EarlyView.
https://ift.tt/2NXuWxK
Micro‐relief analysis with skin capacitive imaging
Skin Research and Technology, EarlyView.
https://ift.tt/2OCNDfs
Water adsorption with relative humidity changes for keratin and collagen as studied by infrared (IR) micro‐spectroscopy
Skin Research and Technology, EarlyView.
https://ift.tt/2NW9064
Cerebral venous sinus thrombosis in a young female misdiagnosed as migraine ending in a permanent vegetative state: a case report and review of the literature
Cerebral venous thrombosis refers to acute thrombosis or blood clots that can lead to strokes. This illness can be misdiagnosed as a migraine, resulting in a delay in management and catastrophic outcomes. We p...
https://ift.tt/2PcdE4H
An unusual presentation of anomalous left coronary artery from the pulmonary artery (ALCAPA) syndrome in a 70-year-old man: a case report
We present a rare case of anomalous origin of the left coronary artery from the pulmonary artery syndrome in an elderly man, and we describe coronary computed tomographic angiographic imaging findings to impro...
https://ift.tt/2Ezdpgc
Breastfeeding and weaning in ancient populations: Challenges and future directions
International Journal of Osteoarchaeology, Volume 28, Issue 5, Page 477-478, September/October 2018.
https://ift.tt/2AlvpGt
Issue Information ‐ TOC
International Journal of Osteoarchaeology, Volume 28, Issue 5, Page 475-476, September/October 2018.
https://ift.tt/2CvmSCy
Therapeutic approaches to pyogenic granuloma: an updated review
International Journal of Dermatology, EarlyView.
https://ift.tt/2OH56Dm
Pyoderma gangrenosum associated with dulaglutide therapy
International Journal of Dermatology, EarlyView.
https://ift.tt/2NW1cBC
Diffuse palmoplantar keratotic papules and melanosis
International Journal of Dermatology, EarlyView.
https://ift.tt/2OBWazc
Mid borderline leprosy in type Bα Blaschko linear pattern: a rare phenomenon
International Journal of Dermatology, EarlyView.
https://ift.tt/2NVXcRF
The law of food allergy and accommodation in Canadian schools
There is ongoing controversy surrounding the appropriate standards and limits of accommodation of children with food allergies in schools. We identify and explain how relevant Canadian common law, legislation,...
https://ift.tt/2OH4XQk
Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency
Daclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell prolife...
https://ift.tt/2NQFWNz
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