ResearchPad - necrosis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The <i>Caenorhabditis elegans</i> CUB-like-domain containing protein RBT-1 functions as a receptor for <i>Bacillus thuringiensis</i> Cry6Aa toxin]]> https://www.researchpad.co/article/elastic_article_14753 Bacillus thuringiensis (Bt) crystal proteins belong to pore-forming toxins (PFTs), which display virulence against target hosts by forming holes in the cell membrane. Cry6A is a nematicidal PFT, which exhibits unique protein structure and different mode of action than Cry5B, another nematicidal PFT. However, little is known about the mode of action of Cry6A. Although an intracellular nematicidal necrosis pathway of Cry6A was reported, its extracellular mode of action remains unknown. We here demonstrate that the CUB-like-domain containing protein RBT-1 acts as a functional receptor of Cry6A, which mediates the intestinal cell interaction and nematicidal activity of this toxin. RBT-1 represents a new class of crystal protein receptors. RBT-1 is dispensable for Cry5B toxicity against nematodes, consistent with that Cry6A and Cry5B have different nematicidal mechanisms. We also find that Cry6A kills nematodes by complex mechanism since rbt-1 mutation did not affect Cry6A-mediated necrosis signaling pathway. This work not only enhances the understanding of Bt crystal protein-nematode mechanism, but is also in favor for the application of Cry6A in nematode control.

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<![CDATA[DLX1008 (brolucizumab), a single-chain anti-VEGF-A antibody fragment with low picomolar affinity, leads to tumor involution in an <i>in vivo</i> model of Kaposi Sarcoma]]> https://www.researchpad.co/article/elastic_article_14618 Kaposi Sarcoma (KS) is among the most angiogenic cancers in humans and an AIDS-defining condition. KS-associated herpesvirus (KSHV) is necessary for KS development, as is vascular endothelial growth factor (VEGF-A). DLX1008 is a novel anti-VEGF-A antibody single-chain variable fragment (scFv) with low picomolar affinity for VEGF-A. In vivo imaging techniques were used to establish the efficacy of DLX1008 and to establish the mechanism of action; this included non-invasive imaging by ultrasound and optical fluorescence, verified by post-mortem histochemistry. The results showed that DLX1008 was efficacious in a KS mouse model. The NSG mouse xenografts suffered massive internal necrosis or involution, consistent with a lack of blood supply. We found that imaging by ultrasound was superior to external caliper measurements in the validation of the angiogenesis inhibitor DLX1008. Further development of DLX1008 against VEGF-dependent sarcomas is warranted.

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<![CDATA[Joint-preserving procedures for osteonecrosis of the femoral head]]> https://www.researchpad.co/article/Nf10044a5-1589-4d09-978d-292378db52cb

  • Osteonecrosis of the femoral head is a poorly understood condition that may lead to progressive destruction of the hip joint. Its incidence is common between the third and fifth decades of life and it is the diagnosis behind 5–18% of annually performed total hip arthroplasties (THAs) in the USA.

  • Regarding the high rate of complications of THA in that age group, authors have agreed on the importance of joint-preservation techniques for this disease but techniques vary to establish a generally accepted algorithmic approach.

  • Surgical head-preserving procedures, core decompression with or without graft, stem cell augmentation, or biologic adjuncts, vascularized bone grafting, and proximal femoral osteotomies have all been published on with heterogeneous results and with limited evidence to date.

  • Consensus states that the prognosis of patients with osteonecrosis of the femoral head can be significantly improved with early diagnosis and timely intervention.

Cite this article: EFORT Open Rev 2019;4:647-658. DOI: 10.1302/2058-5241.4.180073

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<![CDATA[Prognostic value of uPAR expression and angiogenesis in primary and metastatic melanoma]]> https://www.researchpad.co/article/5c466554d5eed0c484518a14

Angiogenesis is important for the progression of cutaneous melanoma. Here, we analyzed the prognostic impact of the angiogenic factor urokinase plasminogen activator resecptor (uPAR), vascular proliferation index (VPI) and tumor necrosis as a measure of hypoxia in a patient series of nodular melanomas (n = 255) and matched loco-regional metastases (n = 78). Expression of uPAR was determined by immunohistochemistry and VPI was assessed by dual immunohistochemistry using Factor-VIII/Ki67 staining. Necrosis was recorded based on HE-slides. As novel findings, high uPAR expression and high VPI were associated with each other, and with increased tumor thickness, presence of tumor necrosis, tumor ulceration, increased mitotic count and reduced cancer specific survival in primary melanoma. In matched cases, VPI was decreased in metastases, whereas the frequency of necrosis was increased. Our findings demonstrate for the first time the impact on melanoma specific survival of uPAR expression and VPI in primary tumors, and of increased necrosis as an indicator of tumor hypoxia in loco-regional metastases. These findings support the importance of tumor angiogenesis in melanoma aggressiveness, and suggest uPAR as an indicator of vascular proliferation and a potential biomarker in melanoma.

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<![CDATA[Pulp response of rats submitted to bleaching and the use of different anti-inflammatory drugs]]> https://www.researchpad.co/article/5c3e503ad5eed0c484d7f09c

This study aimed to evaluate neuropeptide expression after bleaching treatment using histopathological and immunohistochemical analyses and the effects of hydrocortisone and acetaminophen on pulp inflammation, sine dental bleaching and inflammation first occur, and only then, the treatmentt. Sixty-three rats were divided into three groups (n = 21) according to the pain-relieving therapy used: I-control; II-topical application of Otosporin for 10 min after the bleaching treatment; III-oral administration of paracetamol 30 min before whitening and then every 12h. In all the study groups, placebo gel was applied to the left upper jaw (control) and a 35% H2O2-based whitening gel was applied to the right upper jaw for 45 min. Seven animals from each group were euthanized at different time points: 0h after treatment, 24h, and 48h. After euthanasia, the first molar on each side was analyzed by histology and immunohistochemistry to assess the degree of inflammation and verify the presence of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP). The data were analyzed using the statistical nonparametric Kruskal-Wallis test followed by Dunn's test for individual comparisons. Extensive areas of necrosis were observed in the groups that received bleaching treatment only, whereas reduced damage were obtained in the group treated with Otosporin. The immunohistochemical analysis showed positive immunolabeling in all groups, including the control, but this was stronger in the groups that received bleaching treatment. The best results were obtained in the group that received treatment with Otosporin. The use of Otosporin after dental bleaching minimized the side effects of this treatment.

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<![CDATA[Continuous and bolus intraventricular topotecan prolong survival in a mouse model of leptomeningeal medulloblastoma]]> https://www.researchpad.co/article/5c390badd5eed0c48491dcce

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 μM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 μg/day), daily bolus IVT topotecan injections with a similar daily dose (6 μg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 μg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.

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<![CDATA[Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain: A computer modeling study]]> https://www.researchpad.co/article/5989db5eab0ee8fa60be0a82

Background

Tumor treating fields (TTFields) are increasingly used in the treatment of glioblastoma. TTFields inhibit cancer growth through induction of alternating electrical fields. To optimize TTFields efficacy, it is necessary to understand the factors determining the strength and distribution of TTFields. In this study, we provide simple guiding principles for clinicians to assess the distribution and the local efficacy of TTFields in various clinical scenarios.

Methods

We calculated the TTFields distribution using finite element methods applied to a realistic head model. Dielectric property estimates were taken from the literature. Twentyfour tumors were virtually introduced at locations systematically varied relative to the applied field. In addition, we investigated the impact of central tumor necrosis on the induced field.

Results

Local field “hot spots” occurred at the sulcal fundi and in deep tumors embedded in white matter. The field strength was not higher for tumors close to the active electrode. Left/right field directions were generally superior to anterior/posterior directions. Central necrosis focally enhanced the field near tumor boundaries perpendicular to the applied field and introduced significant field non-uniformity within the tumor.

Conclusions

The TTFields distribution is largely determined by local conductivity differences. The well conducting tumor tissue creates a preferred pathway for current flow, which increases the field intensity in the tumor boundaries and surrounding regions perpendicular to the applied field. The cerebrospinal fluid plays a significant role in shaping the current pathways and funnels currents through the ventricles and sulci towards deeper regions, which thereby experience higher fields. Clinicians may apply these principles to better understand how TTFields will affect individual patients and possibly predict where local recurrence may occur. Accurate predictions should, however, be based on patient specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

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<![CDATA[Exposure to maternal obesogenic diet worsens some but not all pre-cancer phenotypes in a murine genetic model of prostate cancer]]> https://www.researchpad.co/article/5989db5aab0ee8fa60bdf69f

Prostate cancer research has been predominantly focused on adult exposures and risk factors. However, because the prostate develops during gestation and early life, exposure to external factors, such as obesity, during development could affect the prostate cancer progression in adults. Our previous work demonstrated that exposure to a high fat/high sugar (HF/HS) diet during gestation and until weaning stimulated prostate hyperplasia and altered the Pten/Akt pathway in adult mice fed a normal diet after weaning. Here, we asked whether maternal exposure to HF/HS would worsen prostate phenotypes in mice lacking Pten, a widely accepted driver of prostate cancer. We found that, at six weeks of age, both Chow (control)—and HF/HS-exposed Pten knockout mice showed evidence of murine PIN that included ducts with central comedo necrosis but that the HF/HS exposure did not influence murine PIN progression. The Pten knockout mice exposed to HF/HS in utero had significantly more mitotic cells than Pten knockouts exposed to Chow diet. In the Pten null background, the maternal HF/HS diet enhanced proliferation but did not have an additive effect on Akt activation. We observed neuroendocrine differentiation in Pten knockout mice, a phenotype that had not been previously described in this model.

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<![CDATA[Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy]]> https://www.researchpad.co/article/5989da13ab0ee8fa60b7a2e2

Objective

The aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.

Methods

CT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (Ktrans) and volume fractions of the extravascular extracellular space (ve) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.

Results

The therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.

Conclusion

DCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.

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<![CDATA[Preliminary Study of MR Diffusion Tensor Imaging of Pancreas for the Diagnosis of Acute Pancreatitis]]> https://www.researchpad.co/article/5989daeeab0ee8fa60bc0265

Objectives

To evaluate the feasibility of differentiating between acute pancreatitis (AP) and healthy pancreas using diffusion tensor imaging (DTI) and correlate apparent diffusion coefficient (ADC) /fractional anisotropy (FA) values with the severity of AP.

Material and Methods

66 patients diagnosed with AP and 20 normal controls (NC) underwent DTI sequences and routine pancreatic MR sequences on a 3.0T MRI scanner. Average ADC and FA values of the pancreatic were measured. Differences of FA and ADC values between the AP group and the NC group with AP and healthy pancreas were compared by two-sample independent t-test. The severity of AP on MRI was classified into subgroups using MR severity index (MRSI), where the mean FA and ADC values were calculated. Relationship among the FA values, ADC values and MRSI were analyzed using Spearman's rank correlation coefficients.

Results

The pancreatic mean ADC value in the AP group (1.68 ± 0.45×10−3mm2/s) was significantly lower than in the NC group (2.09 ± 0.55×10−3mm2/s) (P = 0.02); the same as mean FA value (0.39 ± 0.23 vs 0.54 ± 0.12, P = 0.00). In the subgroup analysis, the pancreatic ADC and FA value of edema AP patients was significantly higher than necrosis AP patients with P = 0.000 and P = 0.001respectively. In addition, as severity of pancreatitis increased according to MRSI, lower pancreatic ADC (r = -0.635) and FA value (r = -0.654) were noted.

Conclusion

Both FA and ADC value from DTI can be used to differentiate AP patients from NC. Both ADC and FA value of pancreas have a negative correlation with the severity of AP.

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<![CDATA[Characterization and Predictive Value of Near Infrared 2-Deoxyglucose Optical Imaging in Severe Acute Pancreatitis]]> https://www.researchpad.co/article/5989da35ab0ee8fa60b85e79

Background

Studying the uptake of 2-deoxy glucose (2-DG) analogs such as 2-Deoxy-2-[18F] fluoroglucose (FDG) is a common approach to identify and monitor malignancies and more recently chronic inflammation. While pancreatitis is a common cause for false positive results in human studies on pancreatic cancer using FDG, the relevance of these findings to acute pancreatitis (AP) is unknown. FDG has a short half-life. Thus, with an aim to accurately characterize the metabolic demand of the pancreas during AP in real-time, we studied the uptake of the non-radioactive, near infrared fluorescence labelled 2-deoxyglucose analog, IRDye® 800CW 2-DG probe (NIR 2-DG; Li-Cor) during mild and severe biliary AP.

Methods

Wistar rats (300 g; 8–12/group) were administered NIR 2-DG (10 nM; I.V.). Mild and severe biliary AP were respectively induced by biliopancreatic duct ligation (DL) alone or along with infusing glyceryl trilinoleate (GTL; 50 μL/100 g) within 10 minutes of giving NIR 2-DG. Controls (CON) only received NIR 2-DG. Imaging was done every 5–10 minutes over 3 hrs. Average Radiant Efficiency [p/s/cm²/sr]/[μW/cm²] was measured over the pancreas using the IVIS 200 in-vivo imaging system (PerkinElmer) using the Living Image® software and verified in ex vivo pancreata. Blood amylase, lipase and pancreatic edema, necrosis were measured over the course of AP.

Results

NIR 2-DG uptake over the first hour was not influenced by AP induction. However, while the signal declined in controls and rats with mild AP, there was significantly higher retention of NIR 2-DG in the pancreas after 1 hour in those with GTL pancreatitis. The increase was > 3 fold over controls in the GTL group and was verified to be in the pancreas ex vivo. In vitro, pancreatic acini exposed to GTL had a similar increase in NIR 2-DG uptake which was followed by progressively worse acinar necrosis. Greater retention of NIR 2-DG in vivo was associated with worse pancreatic necrosis, reduced ATP concentrations and mortality, which were not predicted by the blood parameters.

Conclusion

In-vivo fluorescent imaging of a non-radioactive near infrared 2-DG optical probe can predict the AP severity early during the disease.

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<![CDATA[Evaluation of potential changes in liver and lung tissue of rats in an ischemia-reperfusion injury model (modified pringle maneuver)]]> https://www.researchpad.co/article/5989db5eab0ee8fa60be0acf

In surgical procedures involving the liver, such as transplantation, resection, and trauma, a temporary occlusion of hepatic vessels may be required. This study was designed to analyze the lesions promoted by ischemia and reperfusion injury of the hepatic pedicle, in the liver and lung, using histopathological and immunohistochemical techniques. In total, 39 Wistar rats were divided into four groups: control group (C n = 3) and ischemia groups subjected to 10, 20, and 30 minutes of hepatic pedicle clamping (I10, n = 12; I20, n = 12; I30, n = 12). Each ischemia group was subdivided into four subgroups of reperfusion (R15, n = 3; R30, n = 3; R60, n = 3; R120, n = 3), after 15, 30, 60, and 120 minutes of reperfusion, respectively. Significant differences were observed in the liver parenchyma (P < 0.05) between the values of microvesicles and hydropic degeneration at different times of ischemia and reperfusion. However, the values of vascular congestion, necrosis, and pyknotic nuclei showed no significant differences (P > 0.05). In the lung parenchyma, a significant difference was observed (P < 0.05) between the values of alveolar septal wall thickening and inflammatory infiltration at different times of ischemia and reperfusion. However, there was no significant difference (P < 0.05) between the values of vascular congestion, bronchial epithelial degeneration, interstitial edema, and hemorrhage. The positive immunoreactivity of caspase-3 protein in the liver parenchyma (indication of ongoing apoptosis), showed no significant differences (P > 0.05) at different times of ischemia and reperfusion. In the pulmonary parenchyma, the immunoreactivity was not specific, and was not quantified. This study demonstrated that the longer the duration of ischemia and reperfusion, the greater are the morphological lesions found in the hepatic and pulmonary parenchyma.

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<![CDATA[Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity]]> https://www.researchpad.co/article/5989db02ab0ee8fa60bc723d

Introduction

Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis.

Aim

To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions.

Methods

HepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1–50 μM) of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h), menadione (50 μM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed.

Results

Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA-preconditioning.

Conclusions

Sub-toxic concentrations of bile acids in the range that occur under normal physiological conditions protect HepG2.rNtcp cells against GCDCA-induced apoptosis, which is independent of FXR-controlled changes in bile acid transport.

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<![CDATA[Effect of a computer-aided diagnosis system on radiologists' performance in grading gliomas with MRI]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdb891

The effects of a computer-aided diagnosis (CAD) system based on quantitative intensity features with magnetic resonance (MR) imaging (MRI) were evaluated by examining radiologists' performance in grading gliomas. The acquired MRI database included 71 lower-grade gliomas and 34 glioblastomas. Quantitative image features were extracted from the tumor area and combined in a CAD system to generate a prediction model. The effect of the CAD system was evaluated in a two-stage procedure. First, a radiologist performed a conventional reading. A sequential second reading was determined with a malignancy estimation by the CAD system. Each MR image was regularly read by one radiologist out of a group of three radiologists. The CAD system achieved an accuracy of 87% (91/105), a sensitivity of 79% (27/34), a specificity of 90% (64/71), and an area under the receiver operating characteristic curve (Az) of 0.89. In the evaluation, the radiologists’ Az values significantly improved from 0.81, 0.87, and 0.84 to 0.90, 0.90, and 0.88 with p = 0.0011, 0.0076, and 0.0167, respectively. Based on the MR image features, the proposed CAD system not only performed well in distinguishing glioblastomas from lower-grade gliomas but also provided suggestions about glioma grading to reinforce radiologists’ confidence rating.

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<![CDATA[Effects of the Commercial Flame Retardant Mixture DE-71 on Cytokine Production by Human Immune Cells]]> https://www.researchpad.co/article/5989daa1ab0ee8fa60ba5b83

Introduction

Although production of polybrominated diphenyl ethers (PBDEs) is now banned, release from existing products will continue for many years. The PBDEs are assumed to be neurotoxic and toxic to endocrine organs at low concentrations. Their effect on the immune system has not been investigated thoroughly. We aimed to investigate the influence of DE-71 on cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with Escherichia Coli lipopolysaccharide (LPS) or phytohaemagglutinin-L (PHA-L).

Material and Methods

PBMCs isolated from healthy donors were pre-incubated with DE-71 at various concentrations and subsequently incubated with the monocyte stimulator LPS, or the T-cell activator PHA-L. Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, IL-17A, and IL-17F were quantified in the supernatants by Luminex kits.

Results

At non-cytotoxic concentrations (0.01–10 μg/mL), DE-71 significantly enhanced secretion of IL-1β, IL-6, CXCL8, IL-10, and TNF-α (p<0.001–0.019; n = 6) from LPS-stimulated PBMCs. IFN-γ, TNF-α, IL-17A, and IL-17F (p = <0.001–0.043; n = 6) secretion were enhanced from PHA-L-stimulated PBMCs as well. Secretion of IL-1β, IL-2, IL-10, IL-8 and IL-6 was not significantly affected by DE-71.

Conclusions

We demonstrate an enhancing effect of DE-71 on cytokine production by normal human PBMCs stimulated with LPS or PHA-L ex vivo.

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<![CDATA[Prognostic significance of chemotherapy-induced necrosis in osteosarcoma patients receiving pasteurized autografts]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcaf8

Background

Among various reconstruction methods after wide excision for osteosarcoma, pasteurized autograft is often preferred. While the whole area of the tumor can be assessed for chemotherapy-induced necrosis, one of the important prognostic factors, in other reconstructive techniques, only a portion removed from a wide-resection specimen is available when using pasteurized autograft method. The assessment, therefore, may be unreliable. We analyzed the prognostic significance of the chemotherapy-induced necrosis in osteosarcoma patients who underwent reconstruction with pasteurized autografts.

Patients and methods

We reviewed the records of osteosarcoma patients who underwent treatment in our institution from 1998 to 2013. Cases of reconstruction with pasteurized autografts were defined as the patient group, and the same number of patients who underwent other reconstruction methods served as controls. Chemotherapy-induced necrosis was evaluated for removed extra-osseous and curetted intramedullary tumor tissues.

Results

A total of 22 patients were identified; the median age was 15.5 years, and there were 12 males. The most common tumor location was the distal femur. The most common histological subtype was osteoblastic. Median size was 8.1 cm. Disease status was stage IIB in 13 patients and IIA in 9. Median follow-up was 76 months. No differences between the patient and control groups were observed in potential prognostic factors, overall survival, metastasis-free survival, or recurrence-free survival. Univariate analyses demonstrated that histological response was a significant prognostic factor for metastasis-free survival and also significant for recurrence-free survival.

Conclusion

Chemotherapy-induced necrosis grading, using only available tumor tissues, could be a prognostic factor for osteosarcoma patients receiving pasteurized autografts for reconstructive surgery.

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<![CDATA[A Five-Year, In Situ Growth Study on Shallow-Water Populations of the Gorgonian Octocoral Calcigorgia spiculifera in the Gulf of Alaska]]> https://www.researchpad.co/article/5989daa5ab0ee8fa60ba7648

Gorgonian octocorals are the most abundant corals in Alaska where they provide important structural habitat for managed species of demersal fish and invertebrates. Fifty-nine gorgonian species have been reported from Alaska waters but little is known about their life history characteristics to help us gauge their ability to recover from seafloor disturbance. Colonies of the holaxonian Calcigorgia spiculifera were tagged beginning in 1999 at three sites in Chatham Strait, Southeast Alaska, using scuba and their growth measured annually for up to 5 years. Colonies were video recorded, and computer image analysis tools provided calibration of video images for measuring the length of several branches. Growth data indicate that C. spiculifera grows much slower (6.0 mm yr-1) than other gorgonians in Alaska for which there are data and that intraspecific growth is highly variable. We fit a Bayesian linear mixed-effects model that showed that average colony growth was significantly reduced with warmer temperature and presence of necrosis. The model further indicated that growth may slow among larger (older) colonies. Based on these results and previous studies, we propose that gorgonian growth rates are taxonomically constrained at the Suborder level and that holaxonians grow the slowest followed by scleraxonians and calcaxonians (2–3 times as fast). Findings of this study indicate that it would take approximately 60 years for C. spiculifera to grow to its maximum size and depending on the location and size of the parental standing stock, at least one and possibly 10 additional years for recruitment to occur. Our results further indicate that colonies that are injured, perhaps chronically in areas of frequent disturbance, grow at slower rates and if the current trend of ocean warming continues then we can expect these corals to grow more slowly, and the habitats they form will require more time to recover from disturbance.

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<![CDATA[Monitoring Radiofrequency Ablation Using Ultrasound Envelope Statistics and Shear Wave Elastography in the Periablation Period: An In Vitro Feasibility Study]]> https://www.researchpad.co/article/5989da26ab0ee8fa60b80a1f

Radiofrequency ablation (RFA) is a minimally invasive method for treating tumors. Shear wave elastography (SWE) has been widely applied in evaluating tissue stiffness and final ablation size after RFA. However, the usefulness of periablation SWE imaging in assessing RFA remains unclear. Therefore, this study investigated the correlation between periablation SWE imaging and final ablation size. An in vitro porcine liver model was used for experimental validation (n = 36). During RFA with a power of 50 W, SWE images were collected using a clinical ultrasound system. To evaluate the effects of tissue temperature and gas bubbles during RFA, changes in the ablation temperature were recorded, and image echo patterns were measured using B-mode and ultrasound statistical parametric images. After RFA, the gross pathology of each tissue sample was compared with the region of change in the corresponding periablation SWE image. The experimental results showed that the tissue temperature at the ablation site varied between 70°C and 100°C. Hyperechoic regions and changes were observed in the echo amplitude distribution induced by gas bubbles. Under this condition, the confounding effects (including the temperature increase, tissue stiffness increase, and presence of gas bubbles) resulted in artifacts in the periablation SWE images, and the corresponding region correlated with the estimated final ablation size obtained from the gross pathology (r = 0.8). The findings confirm the feasibility of using periablation SWE imaging in assessing RFA.

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<![CDATA[A secondary wave of neutrophil infiltration causes necrosis and ulceration in lesions of experimental American cutaneous leishmaniasis]]> https://www.researchpad.co/article/5989db5dab0ee8fa60be0406

We evaluated the importance of neutrophils in the development of chronic lesions caused by L. Viannia spp. using the hamster as experimental model of American Cutaneous Leishmaniasis (ACL). Neutrophils infiltrated the lesion within the first six hours post-infection. Inhibition of this early infiltration using a polyclonal antibody or cyclophosphamide was associated with transient parasite control but the protective effect vanished when lesions became clinically apparent. At lesion onset (approximately 10 days p.i.), there was an increased proportion of both uninfected and infected macrophages, and subsequently a second wave of neutrophils infiltrated the lesion (after 19 days p.i.) This second neutrophil infiltration was associated with lesion necrosis and ulceration (R2 = 0.75) and maximum parasite burden. Intradermal delivery of N-formylmethionyl-leucyl-phenylalanine (fMLP), aimed to increase neutrophil infiltration, resulted in larger lesions with marked necrosis and higher parasite burden than in mock treated groups (p<0.001 each). In contrast, reduced neutrophil infiltration via cyclophosphamide-mediated depletion led to more benign lesions and lower parasite loads compared to controls (p<0.001 each). Neutrophils of the second wave expressed significantly lower GM-CSF, reactive oxygen species and nitric oxide than those of the first wave, suggesting that they had less efficient anti-leishmania activity. However, there was increased inflammatory cytokines and expression of neutrophil proteases (myeloperoxidase, cathepsin G and elastase) in lesions during the second wave of neutrophil infiltration compared with the levels reached during the first wave (6h p.i.). This suggests that augmented neutrophil proteases and inflammatory cytokines during the secondary wave of neutrophils could contribute to skin inflammation, ulceration and necrosis in ACL. The overall results indicate that neutrophils were unable to clear the infection in this model, and that the second wave of neutrophils played an important role in the severity of ACL.

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<![CDATA[Disentangling of Malignancy from Benign Pheochromocytomas/Paragangliomas]]> https://www.researchpad.co/article/5989da1aab0ee8fa60b7c6e3

Objective

Many malignant tumors initially appear benign but subsequently exhibit extensive metastases. Early identification of malignant pheochromocytomas and paragangliomas (PPGLs) before metastasis is important for improved prognosis. However, there are no robust prognostic indices of recurrence and malignancy. The aim of this study was to identify the clinical and histopathological factors that predict malignant PPGLs.

Design

Retrospective follow-up study.

Methods

In this study, we included 223 patients with pathologically confirmed PPGLs who were treated between 2000 and 2015 at the Seoul National University Hospital in South Korea.

Results

Of these patients, 29 were diagnosed with malignancy, 12 of whom presented with metastatic lesions at the initial diagnosis while 17 developed metastases during follow-up. Nineteen patients with recurrent PPGLs consisted of ones with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations. The mean age at presentation for malignant PPGLs was significantly younger than that for benign PPGLs (43.0 vs. 49.0 years, respectively; p = 0.023). Tumor size was not a distinguishing factor between malignant and benign PPGLs (5.0 vs. 4.5 cm, respectively; p = 0.316) nor did it predict recurrence. Of 119 patients with available pheochromocytoma of adrenal gland scaled score (PASS) data, those with malignant PPGLs presented PASS values ≥4. Of 12 parameters of PASS, necrosis, capsular invasion, vascular invasion, cellular monotony, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were significant predictors of malignancy.

Conclusions

Tumor size did not predict malignancy or recurrence of PPGLs. PPGL patients with characteristic pathologic findings and PASS ≥4 or germline mutations require close follow-up.

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