bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B78: Histamine dihydrochloride in the treatment of mesothelioma
Authors: Newick Kheng , O'Brien Shaun , Kapoor Veena , Wang Liang-chuan , Moon Edmund , Haas Andrew , Alley Evan , Sterman Daniel , Albelda Steven
Published: October 2015

Our recent adoptive T cell transfer trial for mesothelioma revealed a striking anti-tumor response in a patient which was accompanied by anaphylaxis, suggesting endogenous histamine release. In animal models, histamine has direct and immune-based anti-tumor effects. In fact, histamine dihydrochloride is approved in Europe in combination with interleukin-2 (IL2) for leukemia treatment. We thus explored the anti-tumor role of histamine in mesothelioma. An in vitro MTT assay was used to measure cell proliferation. Daily doses of histamine (1 mg/kg) – alone, or in combination with other immunotherapies – was used to treat four subcutaneous flank tumor models in three different mouse strains. Flow cytometric analyses were subsequently performed on tumors. Histamine had in vitro anti-tumor activity against all five cell lines tested with an IC50 of 1.8 mM. Histamine also significantly reduced tumor volume in all four in vivo models without toxic side effects. Immunodepletion studies revealed that the effect was partially due to T cells. When combined with two immunotherapy approaches (adenovirally-delivered interferon-α or a tumor antigen), anti-tumor efficacy was augmented. Histamine resulted in more interferon-γ and IL2 production by tumor-infiltrating lymphocytes (TIL), downregulation of CD206 expression on tumor-infiltrating macrophages, and reduced numbers of T regulatory cells (Tregs). Histamine has direct anti-tumor effects and immune-stimulatory effects within the tumor microenvironment (as seen with macrophage polarization, increase in cytokine production, and reduction in Tregs). This pre-clinical data suggests that histamine alone, or in combination with immunotherapy, should be explored in the treatment of mesothelioma.

Citation Format: Kheng Newick, Shaun O'Brien, Veena Kapoor, Liang-chuan Wang, Edmund Moon, Andrew Haas, Evan Alley, Daniel Sterman, Steven Albelda. Histamine dihydrochloride in the treatment of mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B78.
Abstract B79: CXCR4 inhibition facilitates anti-PD-1 immunotherapy by reprogramming the tumor microenvironment during sorafenib treatment in hepatocellular carcinoma
Authors: Chen Yunching , Reiberger Thomas , Ramjiawan Rakesh , Ng Mei Rosa , Hato Tai , Unan Elizabeth C. , Reddy Tejaswini P. , Ochiai Hiroki , Huang Peigen , Zhu Andrew X. , Jain Rakesh K. , Duda Dan G.
Published: October 2015

Although the tyrosine kinase inhibitor sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC), treatment response is often transient. Using orthotopic HCC models, we showed that resistance to sorafenib is linked to hypoxia and an associated increase in SDF1alpha and CXCR4 expression levels in tumors, which resulted in tumor desmoplasia and an increase in the infiltration of Gr1+ myeloid-derived suppressive cells, regulatory T cells and M2-type macrophages. Treatment with the CXCR4 inhibitor AMD3100 in combination with sorafenib prevented these effects. Addition of the immune checkpoint blocking antibody anti-PD1 further synergized with sorafenib and AMD3100 in delaying tumor growth and reducing metastasis. Anti-PD1 treatment significantly increased intratumoral infiltration of cytotoxic CD8+ T cells and their activity. Modulation and activation of immune responses by combining AMD3100 and anti-PD1 may be a novel approach to prevent tumor evasion from sorafenib treatment in HCC.

Citation Format: Yunching Chen, Thomas Reiberger, Rakesh Ramjiawan, Mei Rosa Ng, Tai Hato, Elizabeth C. Unan, Tejaswini P. Reddy, Hiroki Ochiai, Peigen Huang, Andrew X. Zhu, Rakesh K. Jain, Dan G. Duda. CXCR4 inhibition facilitates anti-PD-1 immunotherapy by reprogramming the tumor microenvironment during sorafenib treatment in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B79.
Abstract B80: Patients treated with oncolytic adenovirus Ad5/3-hTERT-E2F-Δ24-GMCSF induce immunological antitumor responses
Authors: Hemminki Otto , Parviainen Suvi , Hemminki Akseli
Published: October 2015

Background: Gene therapy with oncolytic viruses is a promising novel treatment modality for cancer due to their selective replication and lytic effect on cancer cells. Although the clinical safety profiles of individual agents are encouraging, the efficacy of oncolytic viruses as monotherapy has been limited. Arming the virus with an immune stimulatory molecule is an appealing strategy and may increase overall antitumor potency. Granulocyte-macrophage colony-stimulating factor (GMCSF) is one of the most potent inducers of antitumor immunity. GMCSF is associated with recruitment and maturation of antigen presenting cells (APCs), mainly dendritic cells, as well as activating the innate immunity by recruiting natural killer cells and neutrophils. Local GMCSF expression could ensure sufficient local concentration for induction of an anti-tumor immune response circumventing the problems with toxic systemic exposure and side effects.

Results: 5/3 chimeric oncolytic adenovirus selective for the p16-Rb pathway engineered to contain a tumor specific E2F promoter and carrying GMCSF (Ad5/3-hTERT-E2F-Δ24-GMCSF aka. CGTG-602) was constructed. Preclinical studies in vivo showed promising efficacy in immune competent Syrian hamster model. Encouraged by these results, 13 patients were treated with Ad5/3-hTERT-E2F-Δ24-GMCSF in Advance Therapy Access Program. Treatments were well-tolerated and overall signs of antitumor efficacy were seen in 9/12 patients (75%) when evaluated by PET-CT or tumor markers. Patient samples were analyzed for virus circulation in blood, neutralizing antibody titers, tumor- and adenovirus-specific PBMCs and antibodies against selected tumor associated antigens. Microarray analysis and immunohistochemistry were performed on available tumor biopsies and indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.

Conclusions: These findings demonstrate that Ad5/3-hTERT-E2F-Δ24-GMCSF was safe and able to show promising signs of efficacy in preclinical studies and in patients. Clinical trials are needed to confirm these preliminary findings in larger patient cohorts.

Citation Format: Otto Hemminki, Suvi Parviainen, Akseli Hemminki. Patients treated with oncolytic adenovirus Ad5/3-hTERT-E2F-Δ24-GMCSF induce immunological antitumor responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B80.
Abstract B83: Quantitative recovery of aspartyl (asparaginyl) beta hydroxylase (HAAH) from an exosomal fraction of human sera from cancer patients
Authors: Semenuk Mark A. , Ghanbari Eleanor B. , Lebowitz Michael S. , Ghanbari Hossein A.
Published: October 2015

Human Aspartyl (Asparaginyl) Beta Hydroxylase (HAAH) is an overexpressed cell surface enzyme in tumor cells that is closely associated with cancer etiologyincluding cell proliferation, motility, and invasiveness. In keeping with this correlation, we have pursued HAAH as a target for both diagnostic and therapeutic applications. Our monoclonal sandwich ELISA detecting HAAH in serum performs with a clinical specificity and sensitivity greater than 90% to distinguish the presence of cancer. However, we have encountered occasional assay interference by some samples that result in under-detection of HAAH. Trouble shooting and follow-up resulted in the discovery that detectable HAAH resides in the exosomal fraction of serum. Isolation of cancer patient serum exosomes and reconstitution into normal serum or serum-free buffer, results in quantitative recovery of HAAH compared to the original intact serum for most cancer patients. When this exosomal reconstitution is done on false negative cancer patient samples, HAAH detection is restored. The HAAH signal is lost when the exosomal fraction is reconstituted in serum that contains the interfering substance(s). The nature of the interfering substance(s) is yet to be determined but the extraction of HAAH signal producing exosomes from serum improves assay performance. Since exosomes are produced by cells and released into the tumor microenvironment, studying this association with HAAH will help in the understanding of exosomal role in elimination, distribution and other functions in the body. This, in turn, is expected to greatly enhance and expand our development of diagnostic and therapeutic programs targeting HAAH.

Citation Format: Mark A. Semenuk, Eleanor B. Ghanbari, Michael S. Lebowitz, Hossein A. Ghanbari. Quantitative recovery of aspartyl (asparaginyl) beta hydroxylase (HAAH) from an exosomal fraction of human sera from cancer patients. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B83.
Abstract IA06: Designing immunostimulatory antibodies for cancer treatment
Authors: Glennie Martin J. , Al-Shamkhani Aymen , Beers Stephen A. , White Ann L. , Johnson Peter W. , French Ruth R. , Cragg Mark S.
Published: October 2015

Immunomodulatory mAb, led by the checkpoint blockers against CTLA-4 and PD-1/PD-L1, are changing the outlook for a number of difficult to manage cancers, such as melanoma and non-small cell lung cancer, and look set to become blockbuster drugs in the near future. While there is still some uncertainty concerning how these reagents work, it is generally agreed that they target exhausted effector T cells and Tregs within the tumour tissue. An alternative way to regulate anti-cancer T cells is using immunostimulatory mAb which trigger activatory T-cell co-receptors, often of the TNF receptor superfamily. Interestingly, most preclinical models show that immunostimulatory mAb are as good if not better than checkpoint blockers in terms of therapeutic potency. However, other than some limited success with anti-CD40 mAb in pancreatic cancer, immunostimulatory mAb have yet to display the level of clinical success seen with the checkpoint blockers. In this lecture we will discuss the mechanisms of action of these two groups of reagents and explore how differences in the rodent and human antibody effector functions might explain why immunostimulatory mAb have not performed as well in patients. We will show how the mouse inhibitory Fc gamma Receptor (FcγR), FcγRIIB, plays a critical role in hyper-crosslinking agonistic anti-TNFR mAb, yet in humans the equivalent receptor is less available to perform this function. We will also discuss how this knowledge is being used to engineer new immunostimulatory mAb which can exploit human FcγR effectively, or even mAb which can operate independently of FcγR with the opportunity of potent agonistic function regardless of bio-availability of FcγR.

Citation Format: Martin J. Glennie, Aymen Al-Shamkhani, Stephen A. Beers, Ann L. White, Peter W. Johnson, Ruth R. French, Mark S. Cragg. Designing immunostimulatory antibodies for cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA06.
Abstract IA18: Fighting fire with fire: Developing a personalized neoantigen cancer vaccine
Authors: Wu Catherine J.
Published: October 2015

One of the critical steps to developing curative and tumor-specific immunotherapy is the identification and selection of antigens with tumor-restricted expression in order to avoid undesirable immune responses against normal tissues. Tumor neoantigens are analogous to non-self foreign proteins, therefore bypassing central tolerance and are also exquisitely tumor-specific. Seminal studies have provided compelling evidence suggesting their immunogenicity. However, the comprehensive identification of such neoantigens has only become feasible recently using next-generation massively-parallel sequencing technologies, providing unprecedented genetic information about cancer cells. In addition, refinements in class I HLA prediction algorithms, particularly NetMHCpan, have enabled the reliable prediction of peptide binding for a broad range of class I HLA alleles. Recent studies by us and others in humans and mice have leveraged these tools to demonstrate evidence of protective immunity when targeting tumor neoantigens. We have developed pipelines that leverage WES to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in a multi-epitope personalized therapeutic vaccine. We are pioneering this approach in a first-in-man clinical trial in melanoma.

Citation Format: Catherine J. Wu. Fighting fire with fire: Developing a personalized neoantigen cancer vaccine. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA18.
Abstract PR08: Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma
Authors: Stromnes Ingunn M. , Brockenbrough Scott J. , Schmitt Thomas M. , Hingorani Sunil R. , Greenberg Philip D.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that employs numerous mechanisms of immune suppression. Here we demonstrate the therapeutic activity and safety of an affinity-enhanced T cell receptor (TCR)-based therapy targeting a naturally overexpressed self/tumor antigen in an autochthonous, genetically engineered mouse model of PDA (KPC). T cells engineered to recognize Mesothelin infiltrated the desmoplastic tumor, induced tumor cell lysis and remodeled the extracellular matrix without apparent toxicities to normal tissues. However, this anti-tumor activity was transient despite T cell persistence in PDA. Donor T cells progressively upregulated inhibitory receptors and became dysfunctional specifically in the tumor microenvironment, indicating selective immunosuppression at the tumor site. However, the T cell dysfunction in PDA also was, in part, independent of antigen specificity and the observed upregulation of inhibitory receptors. Nevertheless, a second infusion of engineered T cells still preferentially accumulated in PDA and increased tumor epithelial cell death indicating that PDA remains susceptible to the effects of serial T cell infusions. Finally, we demonstrate that serial T cell infusions significantly increased survival in KPC mice enrolled with invasive PDA indicating that the observed anti-tumor activity can be associated with therapeutic benefits to the host. These results support the clinical advancement of TCR-based therapies for treatment of PDA.

This abstract is also presented as Poster B20.

Citation Format: Ingunn M. Stromnes, Scott J. Brockenbrough, Thomas M. Schmitt, Sunil R. Hingorani, Philip D. Greenberg. Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR08.
Integrin β1 Gene Therapy Enhances in Vitro Creation of Tissue-Engineered Cartilage Under Periodic Mechanical Stress
Authors: Liang Wenwei , Zhu Chunhui , Liu Feng , Cui Weiding , Wang Qing , Chen Zhefeng , Zhou Qijia , Xu Shun , Zhai Chenjun , Fan Weimin
Published: October 2015

Background/Aims: Periodic mechanical stress activates integrin β1-initiated signal pathways to promote chondrocyte proliferation and matrix synthesis. Integrin β1 overexpression has been demonstrated to play important roles in improving the activities and functions of several non-chondrocytic cell types. Therefore, in the current study, we evaluated the effects of integrin β1 up-regulation on periodic mechanical stress-induced chondrocyte proliferation, matrix synthesis and ERK1/2 phosphorylation in chondrocyte monolayer culture, and evaluated the quality of tissue-engineered cartilage constructed in vitro under periodic mechanical stress combined with integrin β1 up-regulation. Methods and Results: Our results revealed that under periodic mechanical stress, pre-treatment with integrin β1-wild type vector significantly enhanced chondrocyte proliferation and matrix synthesis and promoted ERK1/2 phosphorylation in comparison to mock transfectants. Furthermore, when chondrocytes were seeded in PLGA scaffolds, more accumulated GAG and type II collagen tissue were detected after Lv-integrin β1 transfection compared with sham controls exposed to periodic mechanical stress. In contrast, in the Lv-shRNA-integrin β1 group, the opposite results were observed. Conclusion: Our findings collectively suggest that in addition to periodic mechanical stress, integrin β1 up-regulation in chondrocytes could further improve the quality of tissue-engineered cartilage.
SIRT2 Expression Is Higher in Uveal Melanoma than In Ocular Melanocytes
Authors: Halfed Danielle G. , Zoroquiain Pablo , Wood Henry A. , Blanco Paula , Al-Saati Nouf , Aldrees Sultan , Bravo-Filho Vasco , Burnier Miguel N.
Published: October 2015

Purpose: Sirtuins (SIRTs) are the family of proteins associated with the cell cycle and that correlate with cancer development and progression. SIRTs have never been studied in uveal melanocytes. The aim of this study is to characterize the expression of SIRT2 in uveal melanoma (UM) cases and compare it with the expression of SIRT2 in melanocytes of the uveal tract of normal human eyes (NHE). Methods: Twenty-one formalin-fixed, paraffin-embedded human UM cases were immunostained for SIRT2, along with 15 NHE obtained from the Eye Bank of Canada. Results: SIRT2 expression was higher in melanomas than in normal melanocytes of both tumor and donor eyes (p < 0.0001). No significant difference in SIRT2 expression was found when comparing normal melanocytes in UM and NHE cases. Conclusions: SIRT2 expression is significantly stronger in UM cells than in normal ocular melanocytes. This finding may indicate an important role of SIRT2 as a prognostic marker in UM progression. SIRT2 should also be investigated as a possible therapeutic target.
Laparoscopic Pylorus- and Spleen-Preserving Duodenopancreatectomy for a Multifocal Neuroendocrine Tumor
Authors: Schlöricke Erik , Hoffmann Martin , Kujath Peter , Shetty Ganesh M. , Scheer Fabian , Liedke Marc O. , Zimmermann Markus
Published: October 2015

Background: In contrast to laparoscopic left pancreatic resection, laparoscopic total duodenopancreatectomy is a procedure that has not been standardized until now. It is not only the complexity that limits such a procedure but also its rare indication. The following article demonstrates the technical aspects of laparoscopic pylorus- and spleen-preserving duodenopancreatectomy. Case Report: The indication for intervention in the underlying case was a patient diagnosed with a multiple endocrine neoplasia (MEN) I syndrome and a multifocal neuroendocrine tumor (NET) infiltrating the duodenum and the pancreas. The patient was post median laparotomy which was necessary after jejunal perforation due to a peptic ulcer. The resection was carried out entirely laparoscopically, and the reconstruction, which included a biliodigestive anastomosis and a gastroenterostomy, was carried out by means of a median upper abdomen laparotomy of 7 cm in length through which the resected specimen was also removed. The total operative time was 391 min. The blood loss accounted for 250 ml. The postoperative course was uneventful, and the patient was discharged on the eighth postoperative day. Conclusion: Laparoscopic pancreatectomy is a treatment option in carefully selected indications. The complexity of the operation demands a high level of expertise in the surgical team.
Extracorporeal Membrane Oxygenation and the Kidney
Authors: Villa Gianluca , Katz Nevin , Ronco Claudio
Published: October 2015

Background: Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with reversible cardiac and/or respiratory failure. Acute kidney injury (AKI) often occurs in patients supported with ECMO; it frequently evolves into chronic kidney damage or end-stage renal disease and is associated with a reported 4-fold increase in mortality rate. Although AKI is generally due to the hemodynamic alterations associated with the baseline disease, ECMO itself may contribute to maintaining kidney dysfunction through several mechanisms. Summary: AKI may be related to conditions derived from or associated with extracorporeal therapy, leading to a reduction in renal oxygen delivery and/or to inflammatory damage. In particular, during pathological conditions requiring ECMO, the biological defense mechanisms maintaining central perfusion by a reduction of perfusion to peripheral organs (such as the kidney) have been identified as pretreatment and patient-related risk factors for AKI. Hormonal pathways are also impaired in patients supported with ECMO, leading to failures in mechanisms of renal homeostasis and worsening fluid overload. Finally, inflammatory damage, due to the primary disease, heart and lung crosstalk with the kidney or associated with extracorporeal therapy itself, may further increase the susceptibility to AKI. Renal replacement therapy can be integrated into the main extracorporeal circuit during ECMO to provide for optimal fluid management and removal of inflammatory mediators. Key Messages: AKI is frequently observed in patients supported with ECMO. The pathophysiology of the associated AKI is chiefly related to a reduction in renal oxygen delivery and/or to inflammatory damage. Risk factors for AKI are associated with a patient's underlying disease and ECMO-related conditions.
Pregnancy and Neonatal Outcomes in Gestational Diabetes Treated with Regular Insulin or Fast-Acting Insulin Analogues
Authors: You Ji Yeon , Choi Suk-Joo , Roh Cheong-Rae , Kim Jong-Hwa , Oh Soo-young
Published: October 2015

Background/Aims: Fast-acting insulin analogues (FAIAs) are being used more frequently during pregnancy. Previous studies comparing regular insulin (RI) and FAIA consist primarily of women enrolled with pre-existing diabetes; therefore, we compared pregnancy and neonatal outcomes in women with gestational diabetes. Methods: We retrospectively investigated 197 pregnant women with gestational diabetes mellitus (GDM) requiring insulin treatment for glycemic control. Individuals were divided into 2 groups: RI (n = 55) and FAIA (aspart or lispro; n = 142). Pregnancy outcomes, including caesarean section rate, and neonatal outcomes, including macrosomia and ponderal index, were compared between groups. Results: There were no significant differences in maternal baseline characteristics (age, parity, body mass index and weight gain) between groups or in haemoglobinA1c before delivery. The frequency of emergency caesarean section (caesarean section after trial of labor) was not significantly different between groups (RI 16.7%, FAIA 24.7%; p = 0.452). There were no differences in frequencies of macrosomia (RI 3.4%, FAIA 6.5%; p = 0.518), ponderal index (RI 2.65 ± 0.5, FAIA 2.71 ± 0.5; p = 0.322), cranial-thoracic circumference ratio (RI 1.07 ± 0.06, FAIA 1.07 ± 0.06; p = 0.386) or neonatal hypoglycemia (RI 5.1%, FAIA 5.8%; p = 1.000). Conclusion: Our data indicate that FAIA achieves similar pregnancy and neonatal outcomes in GDM compared with RI. Considering patient convenience, FAIA may be better to use during pregnancy.
Decreased VEGF Level Is Associated with Elevated Ferritin Concentration in Bronchoalveolar Lavage Fluid of Children with Interstitial Lung Diseases
Authors: Papp Ágnes , Bene Zsolt , Gáspár Imre , Nagy Jr. Béla , Kádár László , Márialigeti Tivadar , Bánfi Andrea , Baktai György , Balla György , Nagy Béla
Published: October 2015

Background: A decreased level of vascular endothelial growth factor (VEGF) was previously described in bronchoalveolar lavage fluid (BALF) of adults with interstitial lung diseases (ILD) due to bronchial epithelial cell apoptosis and its proteolytic degradation. Elevated intrapulmonary ferritin was produced by alveolar cells that promoted oxidative injury in such patients. Objectives: In this study, we analyzed the concentrations of VEGF and ferritin in BALF samples of ILD children and studied the relationship between their levels and the degree of inflammation. Methods: BALF and serum concentration of VEGF as well as ferritin and albumin in BALF samples were measured using enzyme-linked immunosorbent assay in children with idiopathic interstitial pneumonia (n = 16), hypersensitivity pneumonitis (n = 11) and idiopathic pulmonary hemosiderosis (n = 3). Twenty-four age- and gender-matched subjects with suspicious foreign body aspiration served as a control group. Results: VEGF per albumin levels in BALF were significantly decreased in ILD children compared to controls (1,075 [784-1,415] pg/mg albumin vs. 2,741 [1,131-4,660] pg/mg albumin, p = 0.0008). These values showed a significant negative correlation with inflammatory markers of total immune cell count in BALF (r = -0.411, p = 0.002) and serum C-reactive protein (r = -0.367, p = 0.006). Although serum VEGF was augmented in ILD children versus controls, no difference was observed among the ILD groups. In addition, BALF ferritin/albumin level (688 [188-1,571] ng/mg albumin vs. 256 [178-350] ng/mg albumin, p = 0.022) was significantly higher than normal in ILD individuals, especially in idiopathic pulmonary hemosiderosis. Conclusion: Depressed VEGF and increased ferritin in BALF may reflect the severity of chronic pulmonary inflammation in altered respiratory epithelium of childhood ILD.
Expanded Disability Status Scale-Based Disability and Dental-Periodontal Conditions in Patients with Multiple Sclerosis
Authors: Hatipoglu Hasan , Canbaz Kabay Sibel , Gungor Hatipoglu Mujgan , Ozden Hilmi
Published: October 2015

Objective: The aim of this study was to evaluate the association between different disability states in patients with multiple sclerosis (MS) as determined by the expanded disability status scale (EDSS) and dental-periodontal measures. Subjects and Methods: Eighty patients with MS (64 females and 16 males) were included in this study. Data on MS types, attack frequency, disease duration, EDSS scores and orofacial complaints prior to an MS attack were obtained from medical records. The plaque index (PI), probing depth (PD), clinical attachment level (CAL), gingival index (GI), decayed-missing-filled teeth (DMFT) index and number of present teeth were measured during one dental examination for each subject. The MS patients were divided into the following 2 groups based on their EDSS scores: low physical disability (L-DS) and high physical disability (H-DS). Differences in dental parameters between groups of low and high disability were investigated. p < 0.05 was considered statistically significant. Results: The mean age of the participants was 38.06 ± 10.11 years. Age and disease duration were higher in the H-DS MS group than in the L-DS MS group (p < 0.05). The PI, PD and GI were higher and the number of filled teeth was lower in the H-DS MS group than in the L-DS MS group (p < 0.05). The EDSS scores of the H-DS MS group presented a significant correlation with the number of decayed teeth (r = -0.548, p = 0.005). Orofacial complaints prior to an MS attack were reported by 18 (22.5%) patients. Conclusion: Oral measurements revealed various differences between groups of low and high disability in MS patients. In addition, some maxillofacial-oral complaints prior to an MS attack were observed.
Palliative Endoscopic Therapy of Esophageal Cancer
Authors: Rabenstein Thomas
Published: October 2015

Background: This is a review of endoscopic therapy in the setting of palliative management of patients suffering from esophageal cancer (EC). Unfortunately, many cases of EC present in a stage of disease in which curative therapy is not possible. The maintenance of quality of life includes the ability to swallow and of oral feeding, pain control, and the prevention of bleeding. Methods: A review of the current literature was performed. Results: Many endoscopic methods are available for the management of dysphagia, of which dilation, endoluminal tumor destruction, stenting, and brachytherapy are the most common. Conclusion: Surgical palliation should be avoided as much as possible since the alternatives show at least the same efficacy and have fewer complications.
Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis
Authors: Gupta Nilaksh , Li Wei , McIntyre Thomas M.
Published: October 2015

Objective—

Platelets express a functional ubiquitin–proteasome system. Mass spectrometry shows that platelets contain several deubiquitinases, but whether these are functional, modulate the proteome, or affect platelet reactivity are unknown.

Approach and Results—

Platelet lysates contained ubiquitin–protein deubiquitinase activity hydrolyzing both Lys
48
and Lys
63
polyubiquitin conjugates that was suppressed by the chemically unrelated deubiquitinase inhibitors PYR41 and PR619. These inhibitors acutely and markedly increased monoubiquitination and polyubiquitination of the proteome of resting platelets. PYR41 (intravenous, 15 minutes) significantly impaired occlusive thrombosis in FeCl
3
-damaged carotid arteries, and deubiquitinase inhibition reduced platelet adhesion and retention during high shear flow of whole blood through microfluidic chambers coated with collagen. Total internal reflection microscopy showed that adhesion and spreading in the absence of flow were strongly curtailed by these inhibitors with failure of stable process extension and reduced the retraction of formed clots. Deubiquitinase inhibition also sharply reduced homotypic platelet aggregation in response to not only the incomplete agonists ADP and collagen acting through glycoprotein VI but also to the complete agonist thrombin. Suppressed aggregation was accompanied by curtailed procaspase activating compound-1 binding to activated IIb/IIIa and inhibition of P-selectin translocation to the platelet surface. Deubiquitinase inhibition abolished the agonist-induced spike in intracellular calcium, suppressed Akt phosphorylation, and reduced agonist-stimulated phosphatase and tensin homolog phosphatase phosphorylation. Platelets express the proteasome-associated deubiquitinases USP14 and UCHL5, and selective inhibition of these enzymes by b-AP15 reproduced the inhibitory effect of the general deubiquitinase inhibitors on ex vivo platelet function.

Conclusions—

Remodeling of the ubiquitinated platelet proteome by deubiquitinases promotes agonist-stimulated intracellular signal transduction and platelet responsiveness.
Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity
Authors: Mastenbroek Tom G. , Feijge Marion A.H. , Kremers Romy M.W. , van den Bosch Marion T.J. , Swieringa Frauke , De Groef Lies , Moons Lieve , Bennett Cavan , Ghevaert Cedric , Johnson Jason L. , van der Meijden Paola E.J. , Cosemans Judith M.E.M.
Published: October 2015

Objective—

Platelets are increasingly implicated in processes beyond hemostasis and thrombosis, such as vascular remodeling. Members of the matrix metalloproteinase (MMP) family not only remodel the extracellular matrix but also modulate platelet function. Here, we made a systematic comparison of the roles of MMP family members in acute thrombus formation under flow conditions and assessed platelet-dependent collagenolytic activity over time.

Approach and Results—

Pharmacological inhibition of MMP-1 or MMP-2 (human) or deficiency in MMP-2 (mouse) suppressed collagen-dependent platelet activation and thrombus formation under flow, whereas MMP-9 inhibition/deficiency stimulated these processes. The absence of MMP-3 was without effect. Interestingly, MMP-14 inhibition led to the formation of larger thrombi, which occurred independently of its capacity to activate MMP-2. Platelet thrombi exerted local collagenolytic activity capable of cleaving immobilized dye-quenched collagen and fibrillar collagen fibers within hours, with loss of the majority of the platelet adhesive properties of collagen as a consequence. This collagenolytic activity was redundantly mediated by platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 but occurred independently of platelet α-granule release (
Nbeal2
−/−
mice). The latter was in line with subcellular localization experiments, which indicated a granular distribution of MMP-1 and MMP-2 in platelets, distinct from α-granules. Whereas MMP-9 protein could not be detected inside platelets, activated platelets did bind plasma-derived MMP-9 to their plasma membrane. Overall, platelet MMP activity was predominantly membrane-associated and influenced by platelet activation status.

Conclusions—

Platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 differentially modulate acute thrombus formation and at later time points limit thrombus formation by exerting collagenolytic activity.
VEGF-Induced Expression of miR-17–92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis
Authors: Chamorro-Jorganes Aránzazu , Lee Monica Y. , Araldi Elisa , Landskroner-Eiger Shira , Fernández-Fuertes Marta , Sahraei Mahnaz , Quiles del Rey Maria , van Solingen Coen , Yu Jun , Fernández-Hernando Carlos , Sessa William C. , Suárez Yajaira
Published: October 2015

Rationale:

Several lines of evidence indicate that the regulation of microRNA (miRNA) levels by different stimuli may contribute to the modulation of stimulus-induced responses. The miR-17–92 cluster has been linked to tumor development and angiogenesis, but its role in vascular endothelial growth factor–induced endothelial cell (EC) functions is unclear and its regulation is unknown.

Objective:

The purpose of this study was to elucidate the mechanism by which VEGF regulates the expression of miR-17–92 cluster in ECs and determine its contribution to the regulation of endothelial angiogenic functions, both in vitro and in vivo. This was done by analyzing the effect of postnatal inactivation of miR-17–92 cluster in the endothelium (miR-17–92 iEC-KO mice) on developmental retinal angiogenesis, VEGF-induced ear angiogenesis, and tumor angiogenesis.

Methods and Results:

Here, we show that Erk/Elk1 activation on VEGF stimulation of ECs is responsible for Elk-1-mediated transcription activation (chromatin immunoprecipitation analysis) of the miR-17–92 cluster. Furthermore, we demonstrate that VEGF-mediated upregulation of the miR-17–92 cluster in vitro is necessary for EC proliferation and angiogenic sprouting. Finally, we provide genetic evidence that miR-17–92 iEC-KO mice have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis. Computational analysis and rescue experiments show that PTEN (phosphatase and tensin homolog) is a target of the miR-17–92 cluster and is a crucial mediator of miR-17-92–induced EC proliferation. However, the angiogenic transcriptional program is reduced when miR-17–92 is inhibited.

Conclusions:

Taken together, our results indicate that VEGF-induced miR-17–92 cluster expression contributes to the angiogenic switch of ECs and participates in the regulation of angiogenesis.
Knowledge of Thrombolytic Therapy Amongst Hospital Staff
Authors: Mellon Lisa , Hasan Husain , Lee Stuart , Williams David , Hickey Anne
Published: October 2015

Background and Purpose—

In-hospital stroke is associated with slower access to thrombolysis than community-occurring stroke. It has been suggested that lack of knowledge regarding appropriate stroke response among hospital staff may contribute to delays in referral, assessment, and treatment of in-hospital stroke.

Method—

A survey was conducted among hospital ward staff members using the Stroke Awareness Questionnaire, which was adapted for use among hospital staff to assess their knowledge of stroke symptoms, acute treatments, and hospital protocols for treatment of stroke.

Results—

Ninety-six staff members were interviewed, 81% of whom were clinical staff (medical, nursing, allied health professionals). Ninety-two percent of staff could name ≥3 stroke symptoms. Only 49% of staff were aware of thrombolysis treatment, and only 48% could identify the time window for thrombolysis administration, with staff from stroke-related specialties likely to name thrombolysis as an acute treatment for stroke (71%; odds ratio =3.36, 95% confidence interval 1.17–9.61) and identify the correct treatment window (71%; odds ratio =3.55, 95% confidence interval 1.24–10.16). Only 52% of staff on general wards were aware of an in-hospital stroke protocol.

Conclusions—

Hospital staff had adequate knowledge of stroke signs and symptoms; however, there was low awareness of thrombolysis therapy and its correct treatment time window among hospital staff. Targeted educational programmes among hospital staff regarding stroke are required to optimize acute stroke care.
Montreal Cognitive Assessment
Authors: Wong Adrian , Law Lorraine S.N. , Liu Wenyan , Wang Zhaolu , Lo Eugene S.K. , Lau Alexander , Wong Lawrence K.S. , Mok Vincent C.T.
Published: October 2015

Background and Purpose—

The objective of this study is to examine the discrepancy between single versus age and education corrected cutoff scores in classifying performance on the Montreal Cognitive Assessment (MoCA) in patients with stroke or transient ischemic attack.

Methods—

MoCA norms were collected from 794 functionally independent and stroke- and dementia-free persons aged ≥65 years. magnetic resonance imaging was used to exclude healthy controls with significant brain pathology and medial temporal lobe atrophy. Cutoff scores at 16th, 7th, and 2nd percentiles by age and education were derived for the MoCA and MoCA 5-minute Protocol. MoCA performance in 919 patients with stroke or transient ischemic attack was classified using the single and norm-derived cutoff scores.

Results—

The norms for the Hong Kong version of the MoCA total and domain scores and the total score of the MoCA 5-minute protocol are described. Only 65.1% and 25.7% healthy controls and 45.2% and 19.0% patients scored above the conventional cutoff scores of 21/22 and 25/26 on the MoCA. Using classification with norm-derived cutoff scores as reference, locally derived cutoff score of 21/22 yielded a classification discrepancy of ≤42.4%. Discrepancy increased with higher age and lower education level, with the majority being false positives by single cutoffs. With the 25/26 cutoff of the original MoCA, discrepancy further increased to ≤74.3%.

Conclusions—

Conventional single cutoff scores are associated with substantially high rates of misclassification especially in older and less-educated patients with stroke. These results caution against the use of one-size-fits-all cutoffs on the MoCA.
Reduction of Global Plant Production due to Droughts from 2001 to 2010: An Analysis with a Process-Based Global Terrestrial Ecosystem Model
Authors: Liao Chang , Zhuang Qianlai
Published: October 2015

Droughts dramatically affect plant production of global terrestrial ecosystems. To date, quantification of this impact remains a challenge because of the complex plant physiological and biochemical processes associated with drought. Here, this study incorporates a drought index into an existing process-based terrestrial ecosystem model to estimate the drought impact on global plant production for the period 2001–10. Global Moderate Resolution Imaging Spectroradiometer (MODIS) gross primary production (GPP) data products are used to constrain model parameters and verify the model algorithms. The verified model is then applied to evaluate the drought impact. The study indicates that droughts will reduce GPP by 9.8 g C m−2 month−1 during the study period. On average, drought reduces GPP by 10% globally. As a result, the global GPP decreased from 106.4 to 95.9 Pg C yr−1 while the global net primary production (NPP) decreased from 54.9 to 49.9 Pg C yr−1. This study revises the estimation of the global NPP and suggests that the future quantification of the global carbon budget of terrestrial ecosystems should take the drought impact into account.
Atmospheric Predictors for Annual Maximum Precipitation in North Africa
Authors: Nasri Bouchra , Tramblay Yves , El Adlouni Salaheddine , Hertig Elke , Ouarda Taha B. M. J.
Published: October 2015

The high precipitation variability over North Africa presents a major challenge for the population and the infrastructure in the region. The last decades have seen many flood events caused by extreme precipitation in this area. There is a strong need to identify the most relevant atmospheric predictors to model these extreme events. In the present work, the effect of 14 different predictors calculated from NCEP–NCAR reanalysis, with daily to seasonal time steps, on the maximum annual precipitation (MAP) is evaluated at six coastal stations located in North Africa (Larache, Tangier, Melilla, Algiers, Tunis, and Gabès). The generalized extreme value (GEV) B-spline model was used to detect this influence. This model considers all continuous dependence forms (linear, quadratic, etc.) between the covariates and the variable of interest, thus providing a very flexible framework to evaluate the covariate effects on the GEV model parameters. Results show that no single set of covariates is valid for all stations. Overall, a strong dependence between the NCEP–NCAR predictors and MAP is detected, particularly with predictors describing large-scale circulation (geopotential height) or moisture (humidity). This study can therefore provide insights for developing extreme precipitation downscaling models that are tailored for North African conditions.
Raindrop Size Distribution in a Midlatitude Continental Squall Line Measured by Thies Optical Disdrometers over East China
Authors: Chen Baojun , Wang Jun , Gong Dianli
Published: October 2015

Disdrometer data measured by ground-based optical disdrometers during a midlatitude continental squall line event on 18 August 2012 in Shandong Province, eastern China, are analyzed to study characteristics of raindrop size distribution (DSD). Four disdrometers simultaneously performed continuous measurements during the passage of the convective line. The convective line was partitioned into three regions: the convective center, leading edge, and trailing edge. Results show distinct differences in DSDs and integral rainfall parameters between the convective-center and the edge regions. The convective center has higher drop concentrations, larger mean diameters, and wider size distributions when compared with the edge regions. The leading and trailing edges have similar drop concentrations, but the latter has larger mean diameters and wider size distributions. The shape of DSD for the convective center is convex down, whereas it is convex upward in tropical continental squall lines, as reported in the literature. There is also spatial variability of the DSD and its integral rainfall parameters in the along-convective-line direction.
The Formation of Small-Scale Atmospheric Vortices via Horizontal Shearing Instability
Authors: Buban Michael S. , Ziegler Conrad L.
Published: October 2015

Motivated by high-resolution observations of small-scale atmospheric vortices along near-surface boundaries, this study presents a series of idealized simulations that attempt to replicate shear zones typical of drylines and other near-surface boundaries. The series of dry, constant potential temperature simulations are initialized with a north–south-oriented constant-vorticity shear zone and north–south periodic boundary conditions.

In all simulations, the shear zones develop wavelike perturbations that eventually roll up into discrete vortices. These vortices have features resembling those observed in many laboratory and numerical studies (i.e., instabilities developed into elliptical cores connected by vorticity braids that precess and contain pressure minima in their centers). To assess the instability mechanism, the results are compared to linear theory. Excellent agreement is found between predictions from linear theory for the wavenumber of maximum growth as a function of shear zone width and growth rate as a function of shear zone vorticity, suggesting to a very good first approximation, horizontal shearing instability (HSI) is responsible for the growth of initial small perturbations. It is also found that predictions of linear theory tend to extend well into the nonlinear regime.

Finally, preferred regions of cumulus formation are assessed by including moisture in four simulations. Maximum updrafts and simulated cumuli tend to form along the periphery of cores and/or along the braided regions adjacent to the cores. Because of the important modulating effect of misocyclone development via HSI and subsequent moisture transport, cumulus spacing and size/depth are also dependent on the shear zone width and vorticity.
Intraseasonal Teleconnections between South America and South Africa
Authors: Grimm Alice M. , Reason C. J. C.
Published: October 2015

Teleconnection of climate anomalies between various parts of the tropics and extratropics is a well-established feature of the climate system. Building on previous work showing that a teleconnection exists between the South American monsoon system and interannual summer rainfall variability over southern Africa, this study considers intraseasonal variability over these landmasses. It is shown that strong teleconnections exist between South African daily rainfall and that over various areas of South America, with the latter leading by 4–5 days, for both winter and summer, involving regions with strong rainfall in these seasons. During the summer, the mechanisms involve both a modulation of the local Walker cell as well as extratropical Rossby wave trains. For winter, the latter mechanism is more important. While in summer tropical convective anomalies over South America play an important role, in winter the subtropics become more important. In both cases, these modulations lead to regional changes in circulation over southern Africa that are favorable for the dominant synoptic rainfall-producing weather systems such as cutoff lows and tropical extratropical cloud bands.