bluuebunny/crossref_metadata_2025_split huggingface dataset:
E-Cadherin/β-Catenin and CD10
Authors: Burford Holly , Baloch Zubair , Liu Xiuli , Jhala Darshana , Siegal Gene P. , Jhala Nirag 
Published: November 2009

Abstract
Pancreatic endocrine neoplasm (PEN) and solid pseudopapillary neoplasm of the pancreas (SPN) frequently pose diagnostic challenges. We sought to determine which markers could provide the best immunophenotypic characterization of PEN and SPN, allowing separation on limited cytology samples. We retrieved 22 resected PEN (n = 12) and SPN (n = 10) tumors to serve as a training set for the performance of extensive immunohistochemical staining. Based on these results, we selected a subset of antibodies for application to 25 fine-needle aspiration (FNA) samples from PEN (n = 16) and SPN (n = 9).
Chromogranin A, synaptophysin, CD56, and progesterone receptor (PR) highlighted PEN cases in the training set; E-cadherin was noted in a membranous pattern. SPN cases were most immunoreactive for α1-antitrypsin, vimentin, CD10, and PR, with nuclear staining for β-catenin; E-cadherin did not show a membranous pattern. Among all FNA samples tested, the immunohistochemical staining of E-cadherin (P = .0003), β-catenin (P = .00004), and CD10 (P = .00006) demonstrated the greatest difference between PEN and SPN. The pattern of E-cadherin/β-catenin expression was highly specific for distinguishing PEN from SPN. On limited FNA samples, the characteristic expression of E-cadherin/β-catenin and the expression of CD10 can be used to distinguish PEN from SPN.
Tissue Microarray for Routine Analysis of Breast Biomarkers in the Clinical Laboratory
Authors: Thomson Thomas A. , Zhou Chen , Chu Christina , Knight Bryan 
Published: November 2009

Abstract
Tissue microarray analysis (TMA) allows multiple analyses on multiple patients on sections from a single paraffin block. Although it is widely used in research and in quality assurance settings, there are few references to its use in clinical practice. This study evaluated TMA assessment of breast biomarkers using immunohistochemical analysis in a clinical histopathology laboratory. Performance parameters, interobserver variability, and concordance between TMA and whole section results were assessed. The arrays had few lost or noninformative cores. A loss of stain intensity occurred in the arrays compared with the whole sections with some but not all antibodies, highlighting the need to validate the staining protocol for each antibody used on TMA sections. With recommended guidelines for specimen selection and reporting, TMA was found to be an economical replacement for whole section analysis for breast biomarkers.
Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma to Interdigitating Dendritic Cell Sarcoma
Authors: Fraser Cory R. , Wang Wei , Gomez Mario , Zhang Taotao , Mathew Susan , Furman Richard R. , Knowles Daniel M. , Orazi Attilio , Tam Wayne 
Published: November 2009

Abstract
Interdigitating dendritic cell sarcoma (IDCS) is a rare tumor derived from interdigitating dendritic cells. Three cases of IDCS associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have been described, but no clonal relationship between the 2 neoplasms was demonstrated. We present a detailed case analysis of a CLL/SLL with metachronous IDCS and demonstrate that these 2 neoplasms are clonally related. The IDCS and CLL cells had trisomy 12 and identical monoclonal immunoglobulin heavy chain gene rearrangements. Analysis of transcription factors with a role in myeloid differentiation demonstrated PU.1 up-regulation and C/EBPα down-regulation in IDCS compared with CLL. High-density array comparative genomic hybridization also identified gains in part of chromosome 16q in IDCS. Our study demonstrates for the first time clonal transformation of CLL/SLL into IDCS. This phenomenon may be triggered by alterations in lineage-determining transcription programs, which result in transdifferentiation, coupled with additional oncogenic stimuli caused by chromosomal imbalances.
Bright-Field Microscopy Visualization of Proteins and Protein Complexes by In Situ Proximity Ligation with Peroxidase Detection
Authors: Zieba Agata , Wählby Carolina , Hjelm Fredrik , Jordan Lee , Berg Jonathan , Landegren Ulf , Pardali Katerina 
Published: November 2009

Abstract
Background: The in situ proximity ligation assay (PLA) allows a protein or protein complex to be represented as an amplifiable DNA molecule. Recognition is mediated by proximity probes consisting of antibodies coupled with oligonucleotides. Upon dual binding of the proximity probes, the oligonucleotides direct the formation of a circular DNA molecule, which is then amplified by rolling-circle replication. The localized concatemeric product is then detected with fluorescent probes. The in situ PLA enables localized detection of individual native proteins or interacting protein pairs in fixed cells or tissue sections, thus providing an important tool for basic and clinical research.
Methods: We used horseradish peroxidase (HRP)-conjugated oligonucleotides to couple in situ PLA with enzymatic visualization of the localized detection event.
Results: We demonstrate the detection of protein complexes, both in cells and in tissue sections, and show that we can quantify the complexes with image-analysis software specially developed for recognizing HRP signals in bright-field microscopy images. We show that fluorescence and HRP signals produce equivalent results, both in cultured cells and in tissue samples.
Conclusions: The combination of in situ PLA with bright-field detection and automated image analysis allows the signals present to be counted in an automated fashion and thus provides a sensitive and specific method for quantification of proteins and protein complexes with bright-field microscopy. With this approach, in situ PLA can be used without the requirement for expensive fluorescence microscopes, thereby avoiding problems with nonspecific fluorescence while maintaining compatibility with conventional histologic staining.
The Birth of an Idea
Authors: Walshe John 
Published: November 2009

The story began in 1912, but my involvement only began in 1951. In 1912 Dr Kinnier Wilson, working at the National Hospital for Nervous Diseases in London described a new illness affecting youngsters, the principal symptoms being loss of control of movement and contractures of the limbs. This was always associated with scarring of the liver. All these patients died with in a few months of diagnosis.
Dr Wilson's life long ambition was to find a cure for this disease which became known as Wilson's disease, technically hepatolenticular degeneration.. In 1948 Professor John Cumings, working at the same hospital, showed that patients dying of Wilson's disease all had large abnormal amounts of copper deposited in the brain and in the liver. He suggested that the new metal binding drug, British Antilewisite (BAL) might be used to arrest the course of the disease.
In 1951, working in the Metabolic Unit at University College Hospital in London I discovered that patients treated with the antibiotic penicillin excreted in their urine, a breakdown product of the drug, penicillamine. Later, when studying as a Fulbright Fellow in the Liver Unit at the Boston City Hospital, I saw a patient with Wilson's disease being treated, with little, benefit, with BAL. I suggested that penicillamine had the right structural formula to bind copper and promote its excretion and this would be a more effective treatment than BAL and, could be given my mouth and not by painful injection, it would be easier to give over a lifetime.
Progress Despite Bureaucracy
Authors: Walshe John 
Published: November 2009

Although the hospital pharmacy had taken over the production of trientine this drug needed to be put on an official basis with production by a pharmaceutical company. None, however, were interested. A letter to the British Medical Journal aroused some interest but no positive result. In 1976 I convened a conference in Cambridge to which all interested groups were invited to discuss this problem. An unexpected result was that the Department of Health agreed to take out a product license and that the Government Chemist would test the final product for purity if a manufacturer could be found. A small chemical firm Cambrian Chemicals undertook the manufacturer and Rupert Purchase, their principal chemist worked out a large scale method for production. However It took several more years of correspondence with the Department of Health to overcome the bureaucratic baffles and to obtain the necessary product license. This was achieved successfully in 1985, shortly before a similar license was issued in the United States.
Basic work had continued during this time. This included studies with radiolabelled penicillamine to determine its rate of absorption from the gut, distribution in the body and rate of excretion in the urine. Later similar studies were conducted with radiolabellesd trientine. One problem remained, and still remains unsolved. Why does a small percentage of patients fail to respond to any of the currently available lines of treatment. Can it be due to a particularly unfavourable gene mutation?
Going International and yet more Problems
Authors: Walshe John 
Published: November 2009

Inevitably the news of the success of penicillamine treatment for patients with Wilson's disease spread and calls came from abroad for help. My first overseas call for help came from Rheims, then Vienna and the last one was from Rome. Unfortunately I was not able to help any of these patients as they were already on penicillamine and had failed to respond and no other therapies were available at the time of those visits although the patient from Vienna was eventually transferred to Cambridge. However the television programme on the BBC Overseas Service did result in the opening of a flood gate of patients from Europe and then the Middle East. The first of these patients came from Hungary and this was closely followed by patients from Italy, including Sardinia, Spain, Yugoslavia (as was), Greece, Turkey, Iran, Iraq, The Yemen and Egypt. There was also one each from the USA and South Africa.
A new problem arose with a home patient who developed intolerance to penicillamine, trientne BAL and zinc treatment. A new drug had to be found for her. Earlier workers had investigated the use of molybdate on good theoretical basis but had used the wrong salt. This problem was solved by using a sulphur molybdate compound which was known to induce copper deficiency in sheep. As nothing was known of its safety in many I successfully assayed this first on myself.
Role of CX3CL1/Fractalkine in Osteoclast Differentiation and Bone Resorption
Authors: Koizumi Keiichi , Saitoh Yurika , Minami Takayuki , Takeno Nobuhiro , Tsuneyama Koichi , Miyahara Tatsuro , Nakayama Takashi , Sakurai Hiroaki , Takano Yasuo , Nishimura Miyuki , Imai Toshio , Yoshie Osamu , Saiki Ikuo 
Published: November 2009

Abstract
The recruitment of osteoclast precursors toward osteoblasts and subsequent cell-cell interactions are critical for osteoclast differentiation. Chemokines are known to regulate cell migration and adhesion. CX3CL1 (also called fractalkine) is a unique membrane-bound chemokine that has dual functions for cells expressing its receptor CX3CR1: a potent chemotactic factor in its soluble form and a type of efficient cell adhesion molecule in its membrane-bound form. In this paper, we demonstrate a novel role of CX3CL1 in osteoblast-induced osteoclast differentiation. We found that osteoclast precursors selectively expressed CX3CR1, whereas CX3CL1 is expressed by osteoblasts. We confirmed that soluble CX3CL1 induced migration of bone marrow cells containing osteoclast precursors, whereas immobilized CX3CL1 mediated firm adhesion of osteoclast precursors. Furthermore, a blocking mAb against CX3CL1 efficiently inhibited osteoclast differentiation in mouse bone marrow cells cocultured with osteoblasts. Anti-CX3CL1 also significantly suppressed bone resorption in neonatal mice by reducing the number of bone-resorbing mature osteoclasts. Collectively, CX3CL1 expressed by osteoblasts plays an important role in osteoclast differentiation, possibly through its dual functions as a chemotactic factor and adhesion molecule for osteoclast precursors expressing CX3CR1. The CX3CL1-CX3CR1 axis may be a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis, osteoporosis, and cancer bone metastasis.
Infection with Arginase-DeficientLeishmania majorReveals a Parasite Number-Dependent and Cytokine-Independent Regulation of Host Cellular Arginase Activity and Disease Pathogenesis
Authors: Muleme Helen M. , Reguera Rosa M. , Berard Alicia , Azinwi Richard , Jia Ping , Okwor Ifeoma B. , Beverley Stephen , Uzonna Jude E. 
Published: November 2009

AbstractThe balance between the products of l-arginine metabolism in macrophages regulates the outcome of Leishmania major infection. l-arginine can be oxidized by host inducible NO synthase to produce NO, which contributes to parasite killing. In contrast, l-arginine hydrolysis by host arginase blocks NO generation and provides polyamines, which can support parasite proliferation. Additionally, Leishmania encode their own arginase which has considerable potential to modulate infectivity and disease pathogenesis. In this study, we compared the infectivity and impact on host cellular immune response in vitro and in vivo of wild-type (WT) L. major with that of a parasite arginase null mutant (arg−) L. major. We found that arg− L. major are impaired in their macrophage infectivity in vitro independent of host inducible NO synthase activities. As with in vitro results, the proliferation of arg− L. major in animal infections was also significantly impaired in vivo, resulting in delayed onset of lesion development, attenuated pathology, and low parasite burden. Despite this attenuated pathology, the production of cytokines by cells from the draining lymph node of mice infected with WT and arg− L. major was similar at all times tested. Interestingly, in vitro and in vivo arginase levels were significantly lower in arg− than in WT-infected cases and were directly correlated with parasite numbers inside infected cells. These results suggest that Leishmania-encoded arginase enhances disease pathogenesis by augmenting host cellular arginase activities and that contrary to previous in vitro studies, the host cytokine response does not influence host arginase activity.
Enhanced Susceptibility toLeishmaniaInfection in Resistant Mice in the Absence of Immediate Early Response Gene X-1
Authors: Akilov Oleg E. , Ustyugova Irina V. , Zhi Liang , Hasan Tayyaba , Wu Mei X. 
Published: November 2009

AbstractImmediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both γδ T and CD4+ cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-α production in both macrophages and T cells, resulting in a high intralesional load of parasites and delayed healing of the lesion, both of which were reversed by TNF-α treatment. These findings indicate the crucial role of IL-17 and TNF-α in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses.
Signaling Crosstalk during Sequential TLR4 and TLR9 Activation Amplifies the Inflammatory Response of Mouse Macrophages
Authors: De Nardo Dominic , De Nardo Christine M. , Nguyen Thao , Hamilton John A. , Scholz Glen M. 
Published: November 2009

AbstractThe TLR family of pattern recognition receptors is largely responsible for meditating the activation of macrophages by pathogens. Because macrophages may encounter multiple TLR ligands during an infection, signaling crosstalk between TLR pathways is likely to be important for the tailoring of inflammatory reactions to pathogens. Here, we show that rather than inducing tolerance, LPS pretreatment primed the inflammatory response (e.g., TNF production) of mouse bone marrow-derived macrophages (BMM) to the TLR9 ligand, CpG DNA. The priming effects of LPS, which correlated with enhanced Erk1/2, JNK, and p38 MAPK activation, appeared to be mediated via both c-Fms-dependent and -independent mechanisms. LPS pretreatment and inhibition of the M-CSF receptor, c-Fms, with GW2580 had comparable effects on CpG DNA-induced Erk1/2 and p38 MAPK activation. However, c-Fms inhibition did not enhance CpG DNA-induced JNK activation; also, the levels of TNF produced were significantly lower than those from LPS-primed BMM. Thus, the priming effects of LPS on TLR9 responses appear to be largely mediated via the c-Fms-independent potentiation of JNK activity. Indeed, inhibition of JNK abrogated the enhanced production of TNF by LPS-pretreated BMM. The c-Fms-dependent priming effects of LPS are unlikely to be a consequence of the inhibitory constraints of M-CSF signaling on TLR9 expression being relieved by LPS; instead, LPS may exert its priming effects via signaling molecules downstream of TLR9. In summary, our findings highlight the importance of signaling crosstalk between TLRs, as well as between TLRs and c-Fms, in regulating the inflammatory reaction to pathogens.
Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia
Authors: Mizoguchi Yoshito , Monji Akira , Kato Takahiro , Seki Yoshihiro , Gotoh Leo , Horikawa Hideki , Suzuki Satoshi O. , Iwaki Toru , Yonaha Miyuki , Hashioka Sadayuki , Kanba Shigenobu 
Published: November 2009

Abstract
Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca2+]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IFN-γ-induced increase in [Ca2+]i, along with a rise in basal levels of [Ca2+]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.
CCR7 Modulates Pulmonary and Lymph Node Inflammatory Responses in Cigarette Smoke-Exposed Mice
Authors: Demoor Tine , Bracke Ken R. , Vermaelen Karim Y. , Dupont Lisa , Joos Guy F. , Brusselle Guy G. 
Published: November 2009

AbstractPeribronchial lymphoid follicles have recently been identified as one of the hallmark features of (severe) chronic obstructive pulmonary disease (COPD). However, little is known about the relative contribution of peribronchial lymphoid follicles vs mediastinal lymph nodes in inflammatory responses in COPD patients and animal models. In a murine model of COPD, we studied inflammatory responses in airways, lungs, and mediastinal lymph nodes of wild-type (WT) vs CCR7 knockout (CCR7−/−) mice upon subacute or chronic exposure to cigarette smoke (CS). Although crucial for the organization of the secondary lymphoid organs, CCR7 was not required for the development of chronic CS-induced pulmonary lymphoid follicles. Moreover, T cell numbers were significantly increased in airways and lungs of air-exposed CCR7−/− mice, and they continued to increase upon chronic CS exposure. Unexpectedly, subacute CS-induced inflammation in airways and lungs, including airway neutrophilia and the recruitment of inflammatory-type CD11b+ dendritic cells, depended greatly on CCR7. In the draining lymph nodes, chronic CS exposure induced CCR7-dependent recruitment of airway-derived dendritic cells, accompanied by increases in CD4+ and CD8+ T cells. Correspondingly, CS exposure up-regulated mRNA expression of CCR7 ligands CCL19 and CCL21-Ser in lymph nodes of WT mice, but not CCR7−/− mice. In the lungs of WT mice, chronic CS exposure significantly increased CCL19 mRNA and protein. Furthermore, double staining for CCL19 and pro-surfactant protein C showed that alveolar type II cells express high levels of CCL19. These data unveil a so far unappreciated role for CCR7 in modulating inflammatory responses in airways and lungs.
Langerin+CD8α+ Dendritic Cells Are Critical for Cross-Priming and IL-12 Production in Response to Systemic Antigens
Authors: Farrand Kathryn J. , Dickgreber Nina , Stoitzner Patrizia , Ronchese Franca , Petersen Troels R. , Hermans Ian F. 
Published: November 2009

AbstractDistinct dendritic cell (DC) subsets differ with respect to pathways of Ag uptake and intracellular routing to MHC class I or MHC class II molecules. Murine studies suggest a specialized role for CD8α+ DC in cross-presentation, where exogenous Ags are presented on MHC class I molecules to CD8+ T cells, while CD8α− DC are more likely to present extracellular Ags on MHC class II molecules to CD4+ T cells. As a proportion of CD8α+ DC have been shown to express langerin (CD207), we investigated the role of langerin+CD8α+ DC in presenting Ag and priming T cell responses to soluble Ags. When splenic DC populations were sorted from animals administered protein i.v., the ability to cross-present Ag was restricted to the langerin+ compartment of the CD8α+ DC population. The langerin+CD8α+ DC population was also susceptible to depletion following administration of cytochrome c, which is known to trigger apoptosis if diverted to the cytosol. Cross-priming of CTL in the presence of the adjuvant activity of the TLR2 ligand N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-Cys-[S]-Serl-[S]-Lys4-trihydrochloride or the invariant NKT cell ligand α-galactosylceramide was severely impaired in animals selectively depleted of langerin+ cells in vivo. The production of IL-12p40 in response to these systemic activation stimuli was restricted to langerin+CD8α+ DC, and the release of IL-12p70 into the serum following invariant NKT cell activation was ablated in the absence of langerin+ cells. These data suggest a critical role for the langerin+ compartment of the CD8α+ DC population in cross-priming and IL-12 production.