Exploiting CD22 on Antigen-Specific B-Cells to Prevent Allergy to the Major Peanut Allergen Ara h 2

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Kelly A. Orgel, Shiteng Duan, Benjamin L. Wright, Soheila J. Maleki, John C. Wolf, Brian P. Vickery, A. Wesley Burks, James C. Paulson, Mike D. Kulis, Matthew S. Macauley

Teaser

Methods for inducing antigen-specific immune tolerance are needed for the treatment and prevention of food allergies. We demonstrate that mice can be tolerized to the major peanut allergen through engaging CD22, an inhibitory B-cell co-receptor.


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An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Amy S. Paller, Yael Renert-Yuval, Maria Suprun, Hitokazu Esaki, Margeaux Oliva, Thy Nhat Huynh, Benjamin Ungar, Norma Kunjravia, Rivka Friedland, Xiangyu Peng, Xiuzhong Zheng, Yeriel D. Estrada, James G. Krueger, Keith A. Choate, Mayte Suárez-Fariñas, Emma Guttman-Yassky
BackgroundThe ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking, since the underlying molecular basis is poorly understood.ObjectiveTo characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics.MethodsWe analyzed biopsies from 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma (n=6), lamellar ichthyosis (n=7), epidermolytic ichthyosis, (n=5) and Netherton syndrome (n=3)) by immunohistochemistry and RT-PCR and compared them with healthy controls, and atopic dermatitis (AD) and psoriasis patients. Clinical measures included an ichthyosis severity score (IASI) which integrates erythema (IASI-E) and scaling (IASI-S), transepidermal water loss (TEWL), and pruritus.ResultsIchthyosis samples showed increased epidermal hyperplasia (increased thickness and K16 expression) and T-cell and dendritic-cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some Th1/IFN (IFNγ) markers in ichthyosis were comparable to psoriasis or AD. TNFα levels in ichthyosis were elevated only in Netherton syndrome, but were much lower than in psoriasis and AD. Expression of Th2 cytokines (IL-13, IL-31) was similar to controls. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNFα (IL-17A/C, IL-19, CXCL1, PI3, CCL20, IL36G; p<0.05) in ichthyosis was similar to psoriasis. IASI and IASI-E strongly correlated with IL-17A (r=0.74, p<0.001) and IL-17/TNF-synergistic/additive genes. These markers also significantly correlated with TEWL, suggesting a link between the barrier defect and inflammation in ichthyosis.ConclusionOur data associates a shared Th17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raises the possibility of IL-17-targeting strategies.Clinical ImplicationsThe link between increased expression of Th17 pathway cytokines and clinical disease severity raises the possibility of a new therapeutic paradigm of targeted IL-17/IL-23 intervention for ichthyosis patients.

Teaser

CIE, LI, EI and NS subtypes of ichthyosis are Th17-skewed. IL-17/TNF-synergistic/additive genes are predominantly increased and significantly correlated with disease severity scores and functional barrier abnormalities (TEWL).


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Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Otavio Cabral-Marques, Rodrigo Nalio Ramos, Lena F. Schimke, Taj Ali Khan, Eduardo Pinheiro Amaral, Caio César Barbosa Bomfim, Osvaldo Reis Junior, Tabata Takahashi França, Christina Arslanian, Joanna Darck Carola Correia Lima, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Jing Sun, Maria Regina D´Imperio Lima, Marília Seelaender, Vera Lucia Garcia Calich, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Gabriela Riemekasten, Gisela Seminario, Liliana Bezrodnik, Luigi Notarangelo, Troy R. Torgerson, Hans D. Ochs, Antonio Condino-Neto
BackgroundCD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T-, B-, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated.ObjectivesTo determine the impact of CD40L absence on monocytes-derived macrophage (MDMs) responses.MethodsAfter observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed killing activity, oxidative burst, cytokine production, and in vitro effects that rhIFN-γ and soluble CD40L (sCD40L) treatment had on macrophages. In addition, the impact of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied.ResultsMacrophages from CD40L-deficient patient exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of M. tuberculosis proliferation by patient macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors such as TLR1 and TLR2, dectin 1 and DC-SIGN in both controls' and patients' macrophages.ConclusionAbsence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.Clinical ImplicationsThe absence of CD40L impairs macrophage differentiation and function, and its lack contributes to increased susceptibility of CD40L-deficient patients to life threatening infections. Furthermore, rhIFN-γ improves the function of macrophages from CD40L-deficient patients, indicating this cytokine as a potential new adjuvant therapy.

Teaser

Human CD40L deficiency dysregulates the macrophage transcriptome causing functional defects, including defective microbicidal activity, reduced oxidative burst, and impaired production of inflammatory cytokines that are improved by exogenous IFN-γ.


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Allergy-Related Disease in Relation to Early Life Exposures – The Aladdin Birth Cohort

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Helena Marell Hesla, Fredrik Stenius, Hans Järnbert-Pettersson, Johan Alm

Teaser

An anthroposophic lifestyle is associated with reduced risk of parent-reported food hypersensitivity and recurrent wheeze up to two years of age. Mediating factors for the risk reduction appear to be different for the two outcomes.


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Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma

Opinion statement

While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

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The health capability paradigm and the right to health care in the United States

Abstract

Against a backdrop of non-ideal political and legal conditions, this article examines the health capability paradigm and how its principles can help determine what aspects of health care might legitimately constitute positive health care rights—and if indeed human rights are even the best approach to equitable health care provision. This article addresses the long American preoccupation with negative rights rather than positive rights in health care. Positive health care rights are an exception to the overall moral range and general thrust of U.S. legal doctrine. Some positive rights to health care have arisen from U.S. Constitutional Eighth Amendment cases and federal and state laws like Medicare, Medicaid, the State Children's Health Insurance Program, the Emergency Medical Treatment and Active Labor Act, and the Patient Protection and Affordable Care Act. Finally, this article discusses some of the difficulties inherent in implementing a positive right to health care in the U.S.

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Surgical strategy for aortic prosthetic graft infection with 18 F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

A 30-year-old man with Marfan syndrome who underwent Crawford type II extension aneurysm repair about 9 years ago was referred to our hospital with persistent fever. Computed tomography (CT) showed air around the mid-descending aortic prosthetic graft. Because the air did not disappear in spite of intravenous antibiotics, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was performed. FDG-PET/CT revealed four high-uptake lesions. After dissecting the aortic graft particularly focusing on the high-uptake lesions, this patient underwent in situ graft re-replacement of descending aortic graft with a rifampicin-bonded gelatin-impregnated Dacron graft and omentopexy. The patient remains well without recurrent infection at 3 months after surgery.

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The impact of covering the bulla with an absorbable polyglycolic acid (PGA) sheet during pneumothorax surgery

Abstract

We herein present the pathological findings of a bulla covered using an absorbable polyglycolic acid sheet applied with fibrin glue. These findings indicated that the membrane of the bulla was reinforced. Covering the bulla with an absorbable polyglycolic acid sheet (Neoveil, Gunze Ltd, Kyoto, Japan) and applying fibrin glue was effective to prevent the recurrence of the pneumothorax. Moreover, this report is the first case report showing the pathological findings of a bulla which was covered with an absorbable polyglycolic acid sheet and fibrin glue.

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Endovascular repair of thoracic aortic aneurysm associated with right-sided aortic arch: report of two cases

Abstract

Right-sided aortic arch (RAA) is a rare congenital disorder. We describe herein two cases of thoracic aortic aneurysm with a right aortic arch and right-sided descending aorta treated with thoracic endovascular aortic repair (TEVAR). In one case, a 70-year-old man with Edwards type 1 RAA underwent TEVAR using a Relay stent-graft (Bolton Medical, Barcelona, Spain). In another case, a 72-year-old woman with Edwards type 3 RAA underwent TEVAR using a Kawasumi Najuta stent-graft (Kawasumi Laboratories, Inc., Tokyo, Japan) with the "buffalo horn chimney technique", our original method for left subclavian artery flow preservation. The postoperative courses were uneventful. Postoperative computed tomography showed complete exclusion of the aneurysm without endoleakage. Compared to conventional open surgical repair, TEVAR is challenging in patients with a RAA and right-sided descending aorta. However, our results showed that TEVAR might be feasible and a treatment option even in a patient with a RAA and right-sided descending aorta.

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Use of a titanium alloy (Chest Way) in the surgical stabilization of flail chest

Abstract

To avoid the complications of internal pneumatic stabilization for flail chest, we performed stabilization of the chest wall with a metal bar using the Nuss procedure. Here, we used a highly elastic lightweight biocompatible titanium alloy Chest Way (Solve Corporation, Kanagawa, Japan), enabling magnetic resonance imaging. The patient was a 37-year-old man who sustained injuries in a car crash. Gradually increasing subcutaneous emphysema was present. Bilateral pleural drainage and tracheal intubation were conducted on the scene, and a peripheral venous line was established. The patient was then transferred to our hospital by helicopter. A titanium alloy Chest Way was inserted to manage his flail chest accompanied by multiple rib fractures on the left side. Two days later, artificial respiration was no longer required.

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Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

Abstract

Background

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPARα and δ activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPARα and δ agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells.

Results

We found that PPARα and PPARδ agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPARδ induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPARα failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPARδ, but not PPARα agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPARα and PPARδ agonists increased ICAM-1 mRNA stability.

Conclusion

Therefore, our data provide the first evidence that PPARα and PPARδ agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.

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Nonlinear behaviour of interacting mid-latitude atmospheric vortices

Abstract

Nonlinear behaviour of interacting large-scale atmospheric vortices is considered. These vortices are approximately fifteen kilometres high and can have diameters of hundreds if not thousands of kilometres, and so they can be thought of as large flat structures. The air is weakly compressible, and the fluid motion is subject to the Coriolis pseudo-force, due to the Earth being in a non-inertial rotating reference frame. The vortices studied are coupled binary systems. The high or low pressure in each vortex is modelled initially using an exponential function. A spectral method is presented, for obtaining accurate numerical solutions. Nonlinear results in the f-plane approximation are discussed at mid-latitudes. It is found that the vortices do or do not interact, depending on their initial radii and the location of their centres. A scaling law is found numerically for the ratio of these two quantities, which determines whether interaction does occur.

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Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer

Abstract

A principal limitation to the clinical use of cisplatin is the high incidence of chemoresistance to this drug. Combination treatments with other drugs may help to circumvent this problem. Wogonin, one of the major natural flavonoids, is known to reverse multidrug resistance in several types of cancers. We investigated the ability of wogonin to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Two cisplatin-resistant HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effects of wogonin, either alone or in combination with cisplatin, were assessed in HNC cells and normal cells using cell cycle and death assays and by measuring cell viability, reactive oxygen species (ROS) production, and protein expression, and in tumor xenograft mouse models. Wogonin selectively killed HNC cells but spared normal cells. It inhibited nuclear factor erythroid 2-related factor 2 and glutathione S-transferase P in cisplatin-resistant HNC cells, resulting in increased ROS accumulation in HNC cells, an effect that could be blocked by the antioxidant N-acetyl-l-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and activating cell death pathways involving PUMA and PARP. Hence, wogonin significantly sensitized resistant HNC cells to cisplatin both in vitro and in vivo. Wogonin is a promising anticancer candidate that induces ROS accumulation and selective cytotoxicity in HNC cells and can help to overcome cisplatin-resistance in this cancer.

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Down-regulation of neuronal L1 cell adhesion molecule expression alleviates inflammatory neuronal injury

Abstract

In multiple sclerosis (MS), the immune cell attack leads to axonal injury as a major cause for neurological disability. Here, we report a novel role of the cell adhesion molecule L1 in the crosstalk between the immune and nervous systems. L1 was found to be expressed by CNS axons of MS patients and human T cells. In MOG_35–55-induced murine experimental neuroinflammation, CD4⁺ T cells were associated with degenerating axons in the spinal cord, both expressing L1. However, neuronal L1 expression in the spinal cord was reduced, while levels of the transcriptional repressor REST (RE1-Silencing Transcription Factor) were up-regulated. In PLP_139–151-induced relapsing–remitting neuroinflammation, L1 expression was low at the peak stage of disease, reached almost normal levels in the remission stage, but decreased again during disease relapse indicating adaptive expression regulation of L1. In vitro, activated CD4⁺ T cells caused contact-dependent down-regulation of L1, up-regulation of its repressor REST and axonal injury in co-cultured neurons. T cell adhesion to neurons and axonal injury were prevented by an antibody blocking L1 suggesting that down-regulation of L1 ameliorates neuroinflammation. In support of this hypothesis, antibody-mediated blocking of L1 in C57BL/6 mice as well as neuron-specific depletion of L1 in synapsin^Cre × L1^fl/fl mice reduces disease severity and axonal pathology despite unchanged immune cell infiltration of the CNS. Our data suggest that down-regulation of neuronal L1 expression is an adaptive process of neuronal self-defense in response to pro-inflammatory T cells, thereby alleviating immune-mediated axonal injury.

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What we know about TMEM106B in neurodegeneration

Abstract

Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer's disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy.

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Glaucoma: the retina and beyond

Abstract

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain.

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Neuroimaging as a Selection Tool and Endpoint in Clinical and Pre-clinical Trials

Abstract

Standard imaging in acute stroke enables the exclusion of non-stroke structural CNS lesions and cerebral haemorrhage from clinical and pre-clinical ischaemic stroke trials. In this review, the potential benefit of imaging (e.g., angiography and penumbral imaging) as a translational tool for trial recruitment and the use of imaging endpoints are discussed for both clinical and pre-clinical stroke research. The addition of advanced imaging to identify a "responder" population leads to reduced sample size for any given effect size in phase 2 trials and is a potentially cost-efficient means of testing interventions. In pre-clinical studies, technical failures (failed or incomplete vessel occlusion, cerebral haemorrhage) can be excluded early and continuous multimodal imaging of the animal from stroke onset is feasible. Pre- and post-intervention repeat scans provide real time assessment of the intervention over the first 4–6 h. Negative aspects of advanced imaging in animal studies include increased time under general anaesthesia, and, as in clinical studies, a delay in starting the intervention. In clinical phase 3 trial designs, the negative aspects of advanced imaging in patient selection include higher exclusion rates, slower recruitment, overestimated effect size and longer acquisition times. Imaging may identify biological effects with smaller sample size and at earlier time points, compared to standard clinical assessments, and can be adjusted for baseline parameters. Mechanistic insights can be obtained. Pre-clinically, multimodal imaging can non-invasively generate data on a range of parameters, allowing the animal to be recovered for subsequent behavioural testing and/or the brain taken for further molecular or histological analysis.

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Resting heart rate as a prognostic factor for mortality in patients with breast cancer

Abstract

Although elevated resting heart rate (RHR) has been shown to be associated with mortality in the general population and patients with certain diseases, no study has examined this association in patients with breast cancer. A total of 4786 patients with stage I–III breast cancer were retrospectively selected from the Severance hospital breast cancer registry in Seoul, Korea. RHR was measured at baseline and the mean follow-up time for all patients was 5.0 ± 2.5 years. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated using Cox regression models. After adjustment for prognostic factors, patients in the highest quintile of RHR (≥85 beat per minute (bpm)) had a significantly higher risk of all-cause mortality (HR: 1.57; 95 %CI 1.05–2.35), breast cancer-specific mortality (HR: 1.69; 95 %CI 1.07–2.68), and cancer recurrence (HR: 1.49; 95 %CI 0.99–2.25), compared to those in the lowest quintile (≤67 bpm). Moreover, every 10 bpm increase in RHR was associated with 15, 22, and 6 % increased risk of all-cause mortality, breast cancer-specific mortality, and cancer recurrence, respectively. However, the association between RHR and cancer recurrence was not statistically significant (p = 0.26). Elevated RHR was associated with an increased risk of mortality in patients with breast cancer. The findings from this study suggest that RHR may be used as a prognostic factor for patients with breast cancer in clinical settings.

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Reevaluation of RINT1 as a breast cancer predisposition gene

Abstract

Rad50 interactor 1 (RINT1) has recently been reported as an intermediate-penetrance (odds ratio 3.24) breast cancer susceptibility gene, as well as a risk factor for Lynch syndrome. The coding regions and exon–intron boundaries of RINT1 were sequenced in 2024 familial breast cancer cases previously tested negative for BRCA1, BRCA2, and PALB2 mutations and 1886 population-matched cancer-free controls using HaloPlex Targeted Enrichment Assays. Only one RINT1 protein-truncating variant was detected in a control. No excess was observed in the total number of rare variants (truncating and missense) (28, 1.38 %, vs. 27, 1.43 %. P > 0.999) or in the number of variants predicted to be pathogenic by various in silico tools (Condel, Polyphen2, SIFT, and CADD) in the cases compared to the controls. In addition, there was no difference in the incidence of classic Lynch syndrome cancers in RINT1 rare variant-carrying families compared to RINT1 wild-type families. This study had 90 % power to detect an odds ratio of at least 2.06, and the results do not provide any support for RINT1 being a moderate-penetrance breast cancer susceptibility gene, although larger studies will be required to exclude more modest effects. This study emphasizes the need for caution before designating a cancer predisposition role for any gene based on very rare truncating variants and in silico-predicted missense variants.

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UK Breast Cancer Research Symposium 2016: Submitted Abstracts

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Toxins, Vol. 8, Pages 223: Interaction between TNF and BmooMP-Alpha-I, a Zinc Metalloprotease Derived from Bothrops moojeni Snake Venom, Promotes Direct Proteolysis of This Cytokine: Molecular Modeling and Docking at a Glance

Tumor necrosis factor (TNF) is a major cytokine in inflammatory processes and its deregulation plays a pivotal role in several diseases. Here, we report that a zinc metalloprotease extracted from Bothrops moojeni venom (BmooMP-alpha-I) inhibits TNF directly by promoting its degradation. This inhibition was demonstrated by both in vitro and in vivo assays, using known TLR ligands. These findings are supported by molecular docking results, which reveal interaction between BmooMP-alpha-I and TNF. The major cluster of interaction between BmooMP-alpha-I and TNF was confirmed by the structural alignment presenting Ligand Root Mean Square Deviation LRMS = 1.05 Å and Interactive Root Mean Square Deviation IRMS = 1.01 Å, this r

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Visual Cortex Plasticity Following Peripheral Damage To The Visual System: fMRI Evidence

Abstract

Over the last two decades, functional magnetic resonance imaging (fMRI) has become a powerful research method to investigate cortical visual plasticity. Abnormal fMRI response patterns have been occasionally detected in the visually deprived cortex of patients with bilateral retinal diseases. Controversy remains whether these observations indicate structural reorganization of the visual cortex or unmasking of previously silent cortico-cortical connections. In optic nerve diseases, there is weak evidence showing that early visual cortex seems to lack reorganization, while higher-order visual areas undergo plastic changes which may contribute to optimise visual function. There is however accumulating imaging evidence demonstrating trans-synaptic degeneration of the visual cortex in patients with disease of the anterior visual pathways. This may preclude the use of restorative treatments in these patients. Here, we review and update the body of fMRI evidence on visual cortical plasticity.

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Trace element contamination differentiates the natural population of Scots pine: evidence from DNA microsatellites and needle morphology

Abstract

The Scots pine is often used in the biomonitoring of forests. Studies on the chemical composition plus variability of its needles morphological structure allow for an assessment of the state of environmental pollution. However, in their natural populations, the response of individual trees to stress differs. This study reports on the influence of long-term soil contamination with trace elements on the morphology of the needles, its possible relation to the differentiation of the genetic pool, and their implications for biomonitoring. In the natural and self-renewable pine stand growing near the point polluter (zinc smelter, Upper Silesia, Poland), two categories of trees are observed with respect to their health status: pollution-tolerant (T) and pollution-sensitive (S). A detailed analysis of the trace element content of the needles reveals that the concentration of Cd, Zn, Pb, and Cu in the needles is significantly higher in S as compared to T individuals. The metal accumulation pattern decidedly follows the sequence Pb > Cd > Cu > Zn. An analysis of the fluctuating asymmetry (FA) of the needles reveals that sensitive trees showed an FA index ten times higher in comparison to tolerant ones. Moreover, the high differences between these S and T tree groups are also observed in the basic genetic diversity parameters investigated by an analysis of DNA simple sequence repeats (SSR). The concentration of trace elements in pine needles, distinct in sensitive and tolerant trees and in connection with their morphological and genetic characteristics, may reflect an adaptation process. The level of Mg and Fe content in the needles could be a physiological-toxicological index for evaluating trace element "lethality" expressed as Mg and Fe mineral-survival strategies. The example of differences described in this Scots pine population should be taken into consideration in ecotoxicological research to better interpret the obtained results.

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Photoproduction of dissolved organic carbon and inorganic nutrients from resuspended lake sediments

Abstract

Sediments exposed to simulated solar radiation can serve as an important source of dissolved organic carbon (DOC) to surrounding waters. However, it is still unclear if dissolved nutrients can be photoproduced from lake sedimentary organic matter. In this study, a series of laboratory-based experiments was conducted to address the photoproduction of dissolved inorganic nutrients and DOC from resuspended Taihu Lake sediments. Dissolved inorganic nutrients and DOC were photoproduced after 8-h irradiation. The released NH₄⁺, NO_x⁻, and DOC levels ranged from 3.57 to 12.14, 1.43 to 6.43, and 24.17 to 69.17 μmol L⁻¹, respectively. The variation in the amount released indicated that sediment source had an effect on DOC and nutrient photorelease. More DOC and nutrients were released from higher concentration suspensions. However, due to the light absorption by suspended sediment, less DOC and nutrients were released from per gram of suspended sediment in high concentration suspensions. The decrease in DOC and increase in dissolved inorganic nitrogen during the last 2-h irradiation indicated that the photoproduction of inorganic nutrients proceeded via direct photodissolution of suspended sediments and subsequent photodegradation of the produced dissolved organic matter. Our results demonstrated that the photoproduction flux of NH₄⁺ and NO_x⁻ accounts for 12.3 and 6.5 % of wet deposition, respectively, which suggest that the photodissolution of suspended sediment could be a potential source of DOC and dissolved nutrients in shallow water ecosystems.

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Antimicrobial susceptibility of Vibrio alginolyticus isolated from oyster in Korea

Abstract

Pathogenic Vibrio alginolyticus, a cause of severe infection in shellfish, as well as in humans, has been found at high frequency around all coastal areas of Korea. The aim of this study was to determine the occurrence of V. alginolyticus, to identify the strains isolated from oysters in West Sea, and to investigate their antimicrobial resistance profiles. Biochemical analyses of the 90 initially recovered presumptive V. alginolyticus colonies indicated that 16 isolates were V. alginolyticus. PCR analysis to detect the presence of the gyrB gene confirmed that 15 (93.8 %) of the 16 isolates were V. alginolyticus. These 15 isolates had the following profiles of resistance against 16 antibiotics: all isolates were resistant to ampicillin and vancomycin, and 26.7 % of the isolates exhibited resistance to cephalothin. A large number of isolates showed intermediate resistance to erythromycin (100 %) and rifampin (73.3 %). Five (33.3 %) of the V. alginolyticus isolates demonstrated multiple resistance to at least three antimicrobials.

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Effects of triclosan on aquatic invertebrates in tropics and the influence of pH on its toxicity on microalgae

Abstract

The antimicrobial triclosan (TCS) has been detected in household wastewaters (untreated and treated) and receiving environments across the globe. The toxic effects of TCS on temperate standard aquatic test organisms have been widely reported with microalgae being the most sensitive. However, environmental differences between tropical and temperate regions may have selected different trait compositions between these two regions, which in turn may lead to a difference in species sensitivity. Therefore, additional information is required to better characterize risks to organisms in tropics and ensure biodiversity in these regions is not adversely impacted. This study aims to supplement existing TCS toxicity data with five aquatic invertebrates found in tropics and to compare the sensitivity between aquatic invertebrate species from tropical and temperate regions. In addition, the effect of pH on the toxicity of neutral and ionized forms of TCS to microalgae (Chlorella ellipsoidea) was investigated. The reported 96-h LC50 values for the studied invertebrate species ranged from 72 to 962 μg/L. There was no significant difference between the sensitivity of aquatic invertebrate species from tropical and temperate regions. EC50 values for C. ellipsoidea, with and without pH buffer, were significantly different. The findings of this study can be used to support site-specific water quality criteria and environmental risk assessment for TCS in tropical regions. However, further chronic and semi-field experiments with TCS could potentially enable a refined assessment of direct and indirect effects on tropical aquatic communities and further explore functional endpoints of tropical ecosystems.

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Laser-induced breakdown spectroscopy for elemental characterization of calcitic alterations on cave walls

Abstract

Cave walls are affected by different kinds of alterations involving preservative issues in the case of ornate caves, in particular regarding the rock art covering the walls. In this context, coralloids correspond to a facies with popcorn-like aspect belonging to the speleothem family, mostly composed of calcium carbonate. The elemental characterization indicates the presence of elements that might be linked to the diagenesis and the expansion of the alterations as demonstrated by prior analyses on stalagmites. In this study, we report the use of laser-induced breakdown spectroscopy (LIBS) to characterize the elemental composition of one coralloid sample with a portable instrument allowing punctual measurements and a laboratory mapping setup delivering elemental images with spatial resolution at the micrometric scale, being particularly attentive to Mg, Sr, and Si identified as elements of interest. The complementarity of both instruments allows the determination of the internal structure of the coralloid. Although a validation based on a reference technique is necessary, LIBS data reveal that the external layer of the coralloid is composed of laminations correlated to variations of the LIBS signal of Si. In addition, an interstitial layer showing high LIBS signals for Fe, Al, and Si is interpreted to be a detrital clay interface between the external and the internal part of the coralloid. These preliminary results sustain a possible formation scenario of the coralloid by migration of the elements from the bedrock.

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Response of three biofilm-forming benthic microorganisms to Ag nanoparticles and Ag + : the diatom Nitzschia palea , the green alga Uronema confervicolum and the cyanobacteria Leptolyngbya sp.

Abstract

Although the industrial use of nanoparticles has increased over the past decade, the knowledge about their interaction with benthic phototrophic microorganisms in the environment is still limited. This study aims to characterize the toxic effect of ionic Ag⁺ and Ag nanoparticles (citrate-coated silver nanoparticles, AgNPs) in a wide concentration range (from 1 to 1000 μg L⁻¹) and duration of exposure (2, 5 and 14 days) on three biofilm-forming benthic microorganisms: diatom Nitzschia palea, green algae Uronema confervicolum and cyanobacteria Leptolyngbya sp. Ag⁺ has a significant effect on the growth of all three species at low concentrations (1–10 μg L⁻¹), whereas the inhibitory effect of AgNPs was only observed at 1000 μg L⁻¹ and solely after 2 days of exposure. The inhibitory effect of both Ag⁺ and AgNPs decreased in the course of the experiments from 2 to 14 days, which can be explained by the progressive excretion of the exopolysaccharides and dissolved organic carbon by the microorganisms, thus allowing them to alleviate the toxic effects of aqueous silver. The lower impact of AgNPs on cells compared to Ag⁺ can be explained in terms of availability, internalization, reactive oxygen species production, dissolved silver concentration and agglomeration of AgNPs. The duration of exposure to Ag⁺ and AgNPs stress is a fundamental parameter controlling the bioaccumulation and detoxification in benthic phototrophic microorganisms.

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Harvesting of microalgae biomass from the phycoremediation process of greywater

Abstract

The wide application of microalgae in the field of wastewater treatment and bioenergy source has improved research studies in the past years. Microalgae represent a good source of biomass and bio-products which are used in different medical and industrial activities, among them the production of high-valued products and biofuels. The present review focused on greywater treatment through the application of phycoremediation technique with microalgae and presented recent advances in technologies used for harvesting the microalgae biomass. The advantages and disadvantages of each method are discussed. The microbiological aspects of production, harvesting and utilization of microalgae biomass are viewed.

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Levels of five metals in male hair from urban and rural areas of Chongqing, China

Abstract

Heavy metals were measured by flame atomic absorption in male hair from residents in urban and rural areas in Chongqing. The median values of the Cd, Cu, Ni, Pb and Zn were 2.90, 23.9, 9.31, 39.3 and 203 μg/g in urban areas and 0.84, 13.4, 5.56, 14.5 and 169 μg/g in rural area, respectively. The levels of Cd, Ni and Pb both in urban and rural areas lie at the high end of the worldwide figures. The differences in heavy metal distribution pattern indicated that there were more sources of Cd and Pb in urban areas. The levels of Cd were increasing along with the growth of age except for the aged people in urban areas, and no significant relationship was observed between the levels of the heavy metal and the age. It is noticed that the hair of smokers exhibited more heavy metal levels than that of non-smokers both in urban and rural areas. In addition, the hair metal levels of the smokers and non-smokers in urban areas were significantly higher than those in rural area, respectively. Significant pairwise correlations (p < 0.01) were observed among Cd, Cu, Ni and Pb in rural area and only between Cu and Ni and between Pb and Ni in urban areas, indicating the elements in these two areas might originate from different sources. The elevated levels of Cd, Pb and Ni implied that the residents both in urban and rural areas might be at high risk of toxic metal exposure, especially for the children.

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Impacts of CuO nanoparticles on nitrogen removal in sequencing batch biofilm reactors after short-term and long-term exposure and the functions of natural organic matter

Abstract

The impacts of CuO nanoparticle (NP) exposure on total nitrogen (TN) removal in a sequencing batch biofilm reactor (SBBR) as well as the effects of natural organic matter (NOM) in wastewater were studied. Short-term exposure (8 h) to 1 and 50 mg/L CuO NPs induced negligible influence on the nitrogen removal efficiency, and biofilms could recover from the slight damage caused by the prolonged exposure (45 days) to 1 mg/L CuO NPs. On the other hand, long-term exposure to 50 mg/L CuO NPs notably decreased the nitrogen removal efficiencies to 47.74 and 59.04 % in the absence and presence of bovine serum albumin (BSA), much lower than those in the control (75.43 %), mainly as the suppressed denitrification process. Analysis of key enzyme activities showed that the activities of nitrite reductase and nitrate reductase were obviously reduced with 50 mg/L CuO NP exposure. Further studies revealed that the inhibited nitrite/nitrate reductase was related to the variations of microenvironment pH and decrease of nirS and nirK by microelectrode and fluorescent quantitative polymerase chain reaction (PCR) analysis. In addition, the presence of BSA mitigated the toxicity of CuO NPs due to the enhanced particle size and Cu²⁺ release, electrostatic repulsion, and surface coating of CuO NPs, which indicated that lower inhibition effects of CuO NPs in NOM-rich wastewater is of importance when evaluating the environmental risk of NPs to wastewater treatment plants.

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INGs are potential drug targets for cancer

Abstract

Purpose

The inhibitor of growth (ING) family consists of ING1, ING2, ING3, ING4 and ING5, which function as the type II tumor suppressors. INGs regulate cell proliferation, senescence, apoptosis, differentiation, angiogenesis, DNA repair, metastasis, and invasion by multiple pathways. In addition, INGs increase cancer cell sensitivity for chemotherapy and radiotherapy, while clinical observations show that INGs are frequently lost in some types of cancers. The aim of the study was to summarize the recent progress regarding INGs regulating tumor progression.

Methods

The literatures of INGs regulating tumor progression were searched and assayed.

Results

The regulating signaling pathways of ING1, ING2, ING3 or ING4 on tumor progression were shown. The mechanisms of INGs on tumor suppression were also assayed.

Conclusions

This review better summarized the signaling mechanism of INGs on tumor suppression, which provides a candidate therapy strategy for cancers.

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Differential somatostatin and CXCR4 chemokine receptor expression in MALT-type lymphoma of gastric and extragastric origin

Abstract

Purpose

Whereas the different somatostatin receptor (SSTR) subtypes and the chemokine receptor CXCR4 are known to be expressed in a wide variety of human malignancies, comprehensive data are still lacking for MALT-type lymphomas.

Methods

Overall, 55 cases of MALT-type lymphoma of both gastric and extragastric origin were evaluated for the SSTR subtype and CXCR4 expression by means of immunohistochemistry using novel monoclonal rabbit antibodies. The stainings were rated by means of the immunoreactive score and correlated with clinical data.

Results

While the CXCR4 was detected in 92 % of the cases investigated, the SSTR subtypes were much less frequently present. The SSTR5 was expressed in about 50 % of the cases, followed by the SSTR3, the SSTR2A, the SSTR4 and the SSTR1, which were present in 35, 27, 18 or 2 %, respectively, of the tumors only. Gastric lymphomas displayed a significantly higher SSTR3, SSTR4 and SSTR5 expression than extragastric tumors. A correlation between CXCR4 and Ki-67 expression was seen in gastric lymphomas, whereas primarily in extragastric tumors SSTR5 negativity was associated with poor patient outcome.

Conclusions

The CXCR4 may serve as a promising target for diagnostics and therapy of MALT-type lymphomas, while the SSTRs appear not suitable in this respect.

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Decreased cruzipain and gp85/trans-sialidase family protein expression contributes to loss of Trypanosoma cruzi trypomastigote virulence

Publication date: Available online 20 August 2016
Source:Microbes and Infection
Author(s): Juan San Francisco, Iván Barría, Bessy Gutiérrez, Ivan Neira, Christian Muñoz, Hernán Sagua, Jorge Araya, Juan Carlos Andrade, Anibal Zailberger, Alejandro Catalán, Francisco Remonsellez, José Luis Vega, Jorge González
Two cell lines derived from a single Trypanosoma cruzi clone by long-term passaging generated a highly virulent (C8C3hvir) and a low virulent (C8C3lvir) cell line. The C8C3hvir cell line was highly infective and lethal to Balb/c mice, and the C8C3lvir cell line was three-to five-fold less infective to mouse cardiomyocytes than C8C3hvir. The highly virulent T. cruzi cell line abundantly expressed the major cysteine proteinase cruzipain (Czp), complement regulatory protein (CRP) and trans-sialidase (TS), all of which are known to act as virulence factors in this parasite. The in vitro invasion capacity and in vivo Balb/c mouse infectiveness of the highly virulent strain was strongly reduced by pre-treatment with antisense oligonucleotides targeting TS or CRP or with E64d. Based on these results, we conclude that decreased levels of TS, CRP and Czp expression could contribute to loss of T.cruzi trypomastigote virulence.



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Margin of Error for a Frameless Image-Guided Radiosurgery System: Direct Confirmation Based On Post-Treatment MRI Scans

Publication date: Available online 20 August 2016
Source:Practical Radiation Oncology
Author(s): Guozhen Luo, Joseph S. Neimat, Anthony Cmelak, Austin N. Kirschner, Albert Attia, Manuel Morales-Paliza, George X. Ding
PurposeTo report on radiosurgery delivery positioning accuracy in the treatment of tremor patients with frameless image-guided radiosurgery using the linear accelerator (LINAC) based ExacTrac system and to describe quality assurance (QA) procedures used.MethodsBetween 2010 and 2015, twenty patients underwent radiosurgical thalamotomy targeting the ventral intermediate nucleus for the treatment of severe tremor. The median prescription dose was 140Gy (range 120–145Gy) in a single fraction. The median maximum dose was 156Gy (range 136–162Gy). All treatment planning was performed with the iPlan system using a 4-mm circular cone with multiple arcs. Before each treatment QA procedures were performed including the imaging system. As a result of the extremely high dose delivered in a single fraction, a well-defined circular mark developed on the post-treatment MRI. Eight out of these twenty patients were selected to evaluate treatment localization errors because their circular marks were available in post treatment MRI. In this study the localization error is defined as the distance between the center of the intended target and the center of the post-treatment mark.ResultsThe mean error of distance was found to be 1.1mm (range 0.4mm to 1.5mm). The mean errors for the left–right, anterior–posterior, and superior–inferior directions are 0.5mm, 0.6mm, and 0.7mm, respectively.ConclusionsThe result reported in this study includes all tremor patients treated at our institution when their post treatment MRI data were available for study. It represents a direct confirmation of target positioning accuracy in radiosurgery with a LINAC-based frameless system and its limitations. This level of accuracy is only achievable with an appropriate QA program in place for a LINAC-based frameless radiosurgery system.



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Inherent Functional Dependence Among Cochlear Dose Surrogates for Stereotactic Radiosurgery of Vestibular Schwannomas

Publication date: Available online 20 August 2016
Source:Practical Radiation Oncology
Author(s): Lijun Ma, Steve E. Braunstein, Philip V. Theodosopoulos, Michael W. McDermott, Penny K. Sneed
PurposeVarious cochlear dose surrogates have been reported as associated with hearing outcome in studies of stereotactic radiosurgery (SRS) for vestibular schwannomas. In this study, we investigated whether an inherent functional relationship exits among these reported surrogates.Methods and MaterialsA cohort of 85 serial patient cases treated with single-fraction stereotactic radiosurgery from 1997–2013 at our institution was analyzed. For all the cases, the mean prescription dose was 12.5±0.3Gy (range, 12–13Gy) and mean target volume 1.32±1.51mL (range, 0.80–8.77mL). The mean cochlea volume was 0.078±0.016mL (range, 0.048–0.131mL; median, 0.076mL). Correlation analysis among mean cochlear dose, point maximum dose and modiolus dose was performed and also parameterized with new variables such as the Effective Dose Radius (EDR) as derived from a general dose fall-off model.ResultsWeak correlation via linear regression was found between the point maximum dose and the mean cochlear dose (R²=0.719) as well as the modiolus dose (R²=0.568). However, when parameterized with EDR, a near perfect correlation (p<0.0001) via linear regression was found between the EDR for the point maximum dose and the EDR for the mean cochlear dose (R²=0.996), and with the EDR for the modiolus dose (R²=0.993). Such a result led to a functional formula relating these dose surrogates, yielding dose equivalence results such as: 12Gy point maximum dose is equivalent to mean cochlear dose of 5.6±0.1Gy (95% CL), or modiolous dose of 6.0±0.2Gy (95% CL).ConclusionsAn inherent functional relationship was found among point maximum, modiolus, and mean cochlear doses for SRS of vestibular schwannomas. As such, clinical hearing outcome can be interchangeably analyzed or reported via any of these dose surrogates.



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Concussion May Increase the Risk of Subsequent Lower Extremity Musculoskeletal Injury in Collegiate Athletes

Abstract

Background

Laboratory-based studies on neuromuscular control after concussion and epidemiological studies suggest that concussion may increase the risk of subsequent musculoskeletal injury.

Objective

The purpose of this study was to determine if athletes have an increased risk of lower extremity musculoskeletal injury after return to play from a concussion.

Methods

Injury data were collected from 2006 to 2013 for men's football and for women's basketball, soccer and lacrosse at a National Collegiate Athletic Association Division I university. Ninety cases of in-season concussion in 73 athletes (52 male, 21 female) with return to play at least 30 days prior to the end of the season were identified. A period of up to 90 days of in-season competition following return to play was reviewed for time-loss injury. The same period was studied in up to two control athletes who had no concussion within the prior year and were matched for sport, starting status and position.

Results

Lower extremity musculoskeletal injuries occurred at a higher rate in the concussed athletes (45/90 or 50 %) than in the non-concussed athletes (30/148 or 20 %; P < 0.01). The odds of sustaining a musculoskeletal injury were 3.39 times higher in the concussed athletes (95 % confidence interval 1.90–6.05; P < 0.01). Overall, the number of days lost because of injury was similar between concussed and non-concussed athletes (median 9 versus 15; P = 0.41).

Conclusions

The results of this study demonstrate a relationship between concussion and an increased risk of lower extremity musculoskeletal injury after return to play, and may have implications for current medical practice standards regarding evaluation and management of concussion injuries.

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Pediatric patients on ketogenic diet undergoing general anesthesia—a medical record review

To identify guidelines for anesthesia management and determine whether general anesthesia is safe for pediatric patients on ketogenic diet (KD).

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Bilateral hypoglossal nerve paralysis following elongated styloid process resection: case report

Abstract

We report a case of anesthetic management of a 43-year-old patient with Eagle's syndrome (ES) in whom post-extubation acute airway obstruction occurred due to bilateral hypoglossal nerve paralysis. After an accurate examination, elongated bilateral stylohyoid ligament was observed and surgical resection was planned. After completion of the surgery following extubation, significant dysfunction in swallowing, speech function, and tongue motion was observed. The clinical situation was evaluated as bilateral hypoglossal nerve paralysis related to the procedure. The patient was closely observed over 48 h in the intensive care unit. After 2 days, the patient was discharged to a surgical ward. Following clinical assessment, the patient was discharged from hospital for monthly return. At the 6-month follow-up, there were no further episodes of paresthesia and other symptoms. In conclusion, patients with ES represent a real challenge for physicians from diagnosis to treatment, especially regarding perioperative complications, and close collaboration between surgeons and anesthesiologists is of crucial importance.

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43th ISOBM Annual Congress of International Society of Oncology and BioMarkers, September 1-6, 2016 Chicago, USA

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MiR-384 regulated IRS1 expression and suppressed cell proliferation of human hepatocellular carcinoma

Abstract

Acquired evidence indicated that microRNAs (miRNAs) played essential roles in cancer development, including hepatocellular carcinoma (HCC). Functions and mechanisms of miRNAs involved in HCC remain largely unknown. Here, we found that miR-384 was significantly downregulated in HCC cells and tissues by RT-PCR. Gain and loss of function studies revealed that miR-384 significantly suppressed HCC cell proliferation. Insulin receptor substrate 1(IRS1) was identified as a direct and functional target of miR-384. Moreover, miR-384 decreased IRS1 expression, subsequently downregulating cyclin D1 and upregulating p21 and p-Rb expression. In addition, promotion of cell proliferation caused by miR-384-in was counteracted by silencing IRS1 expression with siRNAs. Taken together, our data provided convincing evidence that miR-384 exerted suppressive effect on HCC cell proliferation through the direct inhibition of IRS1 expression, suggesting miR-384 may serve as a potential therapeutic target for HCC.

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Depletion of STYK1 inhibits intrahepatic cholangiocarcinoma development both in vitro and in vivo

Abstract

Intrahepatic cholangiocarcinoma (ICC) has been reported to be the second most common primary hepatic carcinoma worldwide, and very limited therapies are currently available. Serine threonine tyrosine kinase (STYK1), a member of the receptor tyrosine kinase family, exhibits tumorigenicity in many types of cancers and is a potential therapeutic target for ICC. In this study, STYK1 was knocked down in the ICC cell lines HCCC-9810 and RBE via a lentivirus-mediated system using short hairpin RNA (shRNA). Next, cell proliferation, colony formation, cell cycle progression, tumor formation in nude mice, migration and invasion, and the expression levels of cell cycle proteins in Lv-sh STYK1- or Lv-sh Con-infected cells were analyzed by CCK-8 assay, colony formation evaluation, flow cytometry, tumor formation evaluation, wound scratch assay, transwell assay, and western blotting. The results indicated that depletion of STYK1 inhibits ICC development both in vitro and in vivo.

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SPARC expression in patients with high-risk localized soft tissue sarcoma treated on a randomized phase II trial of neo/adjuvant chemotherapy

Abstract

Background

Treatment for localized soft tissue sarcoma includes surgery and radiation, while the role of chemotherapy is controversial. Biomarkers that could predict therapeutic response or prognosticate overall survival (OS) are needed to define patients most likely to benefit from systemic treatment. Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling.

Methods

Using primary biopsy and resection specimens from patients with high-risk localized, soft tissue sarcoma treated on a neo/adjuvant chemotherapy study, SPARC expression was assessed and compared to patient and tumor characteristics, treatment, and outcomes. Survival functions were estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox model was used for multivariate analysis.

Results

Fifty patients had primary tumor specimens available. High, low, and no SPARC expression was found in 22, 13, and 15 patients, respectively. There was no significant difference in time to recurrence or OS between patients in these three groups. Comparing lack of SPARC expression with any SPARC expression, there was no significant difference in time to recurrence in patients without SPARC expression (n = 15) compared to patients with SPARC expression (n = 35). Likewise, there was no statistically significant difference in OS in patients without SPARC expression versus patients whose tumors expressed SPARC.

Conclusions

Although we did not find a statistically significant difference in time to recurrence and OS in patients with high-risk soft tissue sarcoma, we did identify a trend toward improved time to recurrence and OS in patients whose tumors lacked SPARC expression. However, SPARC did not demonstrate the ability to discern which high-risk patients may have a worse prognosis or greater benefit from chemotherapy.

Trial registration

The trial was registered on September 13, 2005 with ClinicalTrials.gov, number http://ift.tt/2b6Ig4z.

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Environmental, maternal, and reproductive risk factors for childhood acute lymphoblastic leukemia in Egypt: a case-control study

Abstract

Background

Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into risk factors in this developing country. Methods: We conducted a case-control design from May 2009 to February 2012. Cases were recruited from Children's Cancer Hospital, Egypt (CCHE). Healthy controls were randomly selected from the general population to frequency-match the cumulative group of cases by sex, age groups (<1; 1 – 5; >5 – 10; >10 years) and region of residence (Cairo metropolitan region, Nile Delta region (North), and Upper Egypt (South)). Mothers provided answers to an administered questionnaire about their environmental exposures and health history including those of the father. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated using logistic regression with adjustment for covariates.

Results

Two hundred ninety nine ALL cases and 351 population-based controls frequency-matched for age group, gender and location were recruited. The risk of ALL was increased with the mother's use of medications for ovulation induction (OR_adj = 2.5, 95 % CI =1.2 –5.1) and to a lesser extend with her age (OR_adj = 1.8, 95 % CI = 1.1 – 2.8, for mothers ≥ 30 years old). Delivering the child by Cesarean section, was also associated with increased risk (OR_adj = 2.01, 95 % CI =1.24–2.81).

Conclusions

In Egypt, the risk for childhood ALL appears to be associated with older maternal age, and certain maternal reproductive factors.

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Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study

Abstract

Background

The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors).

Methods

In this case-control study, we report the NSAID – breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women's characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics.

Results

In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers.

Conclusion

Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers.

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Is there any role of intravenous iron for the treatment of anemia in cancer?

Abstract

Background

Anemia is a major cause of morbidity in patients with cancer resulting in poor physical performance, prognosis and therapy outcome. The aim of this study is to assess the efficacy of intravenous (iv) iron administration for the correction of anemia, for the prevention of exacerbation of anemia, for decreasing blood transfusion rates, and for the survival of cancer patients.

Methods

Patients with different solid tumor diagnosis who received iv iron during their cancer treatment were evaluated retrospectively. Sixty-three patients with hemoglobin (Hgb) levels between ≥ 9 g/dL, and ≤ 10 g/dL, and no urgent need for red blood cell transfusion were included in this retrospective analysis. The aim of cancer treatment was palliative for metastatic patients (36 out of 63), or adjuvant or curative for patients with localized disease (27 out of 63). All the patients received 100 mg of iron sucrose which was delivered intravenously in 100 mL of saline solution, infused within 30 min, 5 infusions every other day. Complete blood count, serum iron, and ferritin levels before and at every 1 to 3 months subsequently after iv iron administration were followed regularly.

Results

Initial mean serum Hgb, serum ferritin and serum iron levels were 9.33 g/dL, 156 ng/mL, and 35.9 μg/dL respectively. Mean Hgb, ferritin, and iron levels 1 to 3 months, and 6 to 12 months after iv iron administration were 10.4 g/dL, 11.2 g/dL, 298.6 ng/mL, 296.7 ng/mL, and 71.6 μg/dL, 67.7 μg/dL respectively with a statistically significant increase in the levels (p < 0.001). Nineteen patients (30 %) however had further decrease in Hgb levels despite iv iron administration, and blood transfusion was necessary in 18 of these 19 patients (28.5 %). The 1-year overall survival rates differed in metastatic cancer patients depending on their response to iv iron; 61.1 % in responders versus 35.3 % in non-responders, (p = 0.005), furthermore response to iv iron correlated with tumor response to cancer treatment, and this relation was statistically significant, (p < 0.001).

Conclusions

Iv iron administration in cancer patients undergoing active oncologic treatment is an effective and safe measure for correction of anemia, and prevention of worsening of anemia. Amelioration of anemia and increase in Hgb levels with iv iron administration in patients with disseminated cancer is associated with increased tumor response to oncologic treatment and overall survival. Response to iv iron may be both a prognostic and a predictive factor for response to cancer treatment and survival.

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Mitochondrial disulfide relay and its substrates: mechanisms in health and disease

Abstract

Eukaryotic cells harbor membrane-enclosed compartments to spatially separate different biochemical processes. As a result, proteins that become synthesized in the cytosol but fulfill their function in another compartment require translocation machineries. In the intermembrane space (IMS) of mitochondria, the mitochondrial disulfide relay is responsible for the import of many soluble proteins in an oxidation-dependent manner. These IMS proteins carry out important tasks and therefore their import, folding and maintenance are crucial for the remainder of the cell. In this review, we first describe the machinery for oxidative protein folding in the IMS and then focus on recent developments, which especially concern the mammalian machinery, its substrates and its physiological role.

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Characterisation and vascular expression of nitric oxide synthase 3 in amphibians

Abstract

In mammals, nitric oxide (NO) produced by nitric oxide synthase 3 (NOS3) localised in vascular endothelial cells is an important vasodilator but the presence of NOS3 in the endothelium of amphibians has been concluded to be absent, based on physiological studies. In this study, a nos3 cDNA was sequenced from the toad, Rhinella marina. The open reading frame of R. marina nos3 encoded an 1170 amino acid protein that showed 81 % sequence identity to the recently cloned Xenopus tropicalis nos3. Rhinella marina nos3 mRNA was expressed in a range of tissues and in the dorsal aorta and pulmonary, mesenteric, iliac and gastrocnemius arteries. Furthermore, nos3 mRNA was expressed in the aorta of Xenopus laevis and X. tropicalis. Quantitative real-time PCR showed that removal of the endothelium of the lateral aorta of R. marina significantly reduced the expression of nos3 mRNA compared to control aorta with the endothelium intact. However, in situ hybridisation was not able to detect any nos3 mRNA in the dorsal aorta of R. marina. Immunohistochemistry using a homologous R. marina NOS3 antibody showed immunoreactivity (IR) within the basal region of many endothelial cells of the dorsal aorta and iliac artery. NOS3-IR was also observed in the proximal tubules and collecting ducts of the kidney but not within the capillaries of the glomeruli. This is the first study to demonstrate that vascular endothelial cells of an amphibian express NOS3.

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Aberrant expression of the tight junction molecules claudin-1 and zonula occludens-1 mediates cell growth and invasion in oral squamous cell carcinoma

Publication date: November 2016
Source:Human Pathology, Volume 57
Author(s): Hamzah Babkair, Manabu Yamazaki, Md. Shihab Uddin, Satoshi Maruyama, Tatsuya Abé, Ahmed Essa, Yoshimasa Sumita, Md. Shahidul Ahsan, Wael Swelam, Jun Cheng, Takashi Saku
We reported that altered cell contact mediated by E-cadherin is an initial event in the pathogenesis of oral epithelial malignancies. To assess other effects of cell adhesion, we examined the expression levels of tight junction (TJ) molecules in oral carcinoma in situ (CIS) and squamous cell carcinoma (SCC). To identify changes in the expression of TJ molecules, we conducted an analysis of the immunohistochemical profiles of claudin-1 (CLDN-1) and zonula occludens-1 (ZO-1) in surgical specimens acquired from patients with oral SCC containing foci of epithelial dysplasia or from patients with CIS. We used immunofluorescence, Western blotting, reverse-transcription polymerase chain reaction, and RNA interference to evaluate the functions of CLDN-1 and ZO-1 in cultured oral SCC cells. TJ molecules were not detected in normal oral epithelial tissues but were expressed in SCC/CIS cells. ZO-1 was localized within the nucleus of proliferating cells. When CLDN-1 expression was inhibited by transfecting cells with specific small interference RNAs, SCC cells dissociated, and their ability to proliferate and invade Matrigel was inhibited. In contrast, although RNA interference–mediated inhibition of ZO-1 expression did not affect cell morphology, it inhibited cell proliferation and invasiveness. Our findings indicated that the detection of TJ molecules in the oral epithelia may serve as a marker for the malignant phenotype of cells in which CLDN-1 regulates proliferation and invasion.



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Olfactory Behaviors Assayed by Computer Tracking Of Drosophila in a Four-quadrant Olfactometer

We describe here a behavioral setup and data analysis method for assaying olfactory responses of up to 100 vinegar flies (Drosophila melanogaster). This system may be used with single or multiple olfactory stimuli, and adaptable for optogenetic activation or silencing of neuronal subsets.

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