tbuckley/cabot-search huggingface dataset:
Generation of the neutrophil-activating peptide NAP-2 from platelet basic protein or connective tissue-activating peptide III through monocyte proteases.
Authors: A Walz, M Baggiolini
Journal: The Journal of Experimental Medicine (1990)

We studied the origin of the neutrophil-activating peptide NAP-2, a presumed 70 amino acid cleavage product of platelet basic protein (PBP) and connective tissue-activating peptide III (CTAP-III). Purified human blood monocytes or lymphocytes were cultured with or without stimuli (LPS or PHA) in the presence or absence of platelet-release supernatant, and the formation of NAP-2 and other neutrophil-activating peptides was monitored. NAP-2 was generated whenever monocytes and platelet release supernatant were present. When a monocyte stimulus was added, NAF/NAP-1 was also formed, and in the presence of LPS a third, less potent neutrophil-stimulating fraction, consisting of NAP-2 variants with 73, 74, and 75 residues, also appeared. Monocytes alone did not yield NAP-2 and no neutrophil-activating peptide was generated by lymphocytes. The monocyte-conditioned medium was found to cleave purified CTAP-III into NAP-2 through proteinases that were highly sensitive to PMSF, moderately sensitive to leupeptin and insensitive to EDTA.
Brian V Payne
Authors: M. P. N. A. Green
Journal: BMJ (2013)

From Dulwich School Brian V Payne entered Gonville and Caius on an open scholarship, switching to medicine after studying physiology and zoology in the first year. After qualifying he embarked on a career in pathology at Addenbrooke’s Hospital, Cambridge, as one of the last junior assistant pathologists, and then moved to St Thomas’ Hospital in London. When he …
Prognostic Value of<i>KIT</i>Mutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors
Authors: Samuel Singer, Brian P. Rubin, Marcia L. Lux, Chang-Jie Chen, George D. Demetri, Christopher D.M. Fletcher, Jonathan A. Fletcher
Journal: Journal of Clinical Oncology (2002)

Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.The overall 5-year recurrence-free survival was 41% +/- 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to <or= 15 mitoses per 30 HPF, and more than 15 mitoses per 30 HPF were 89% +/- 7%, 49% +/- 12%, and 16% +/- 6%, respectively (P =.0001). The 32 patients with spindle-cell histology had a 49% +/- 7% 5-year recurrence-free survival; in contrast, the 16 patients with epithelioid or mixed histology had a 23% +/- 11% 5-year recurrence-free survival (P =.01). Five-year recurrence-free survival for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 82% +/- 12%, 45% +/- 9%, and 27% +/- 8%, respectively (P =.03). Prognostic associations were found with particular KIT mutation types, and patients with missense exon 11 mutations had a 5-year recurrence-free survival of 89% +/- 11% compared with 40% +/- 8% for GISTs with other mutation types (P =.03). The independent predictors for disease-free survival were the presence of deletion/insertion exon 11 mutations (hazard ratio [HR] = 4; P =.006), more than 15 mitoses per 30 HPF (HR = 18; P =.0001), mixed histology (HR = 21; P =.0001), and male sex (HR = 3; P =.05).In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.
Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions
Authors: Roelandt F. J. Schop, W. Michael Kuehl, Scott A. Van Wier, Gregory J. Ahmann, Tammy Price-Troska, Richard J. Bailey, Syed M. Jalal, Ying Qi, Robert A. Kyle, Philip R. Greipp, Rafael Fonseca
Journal: Blood (2002)
Inflammation, Immunity, and Hypertensive End-Organ Damage
Authors: William G. McMaster, Annet Kirabo, Meena S. Madhur, David G. Harrison
Journal: Circulation Research (2015)

For &gt;50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell–derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
Clinical and Mutational Spectrum of Neurofibromatosis Type 1–like Syndrome
Authors: Ludwine Messiaen, Suxia Yao, Hilde Brems, Tom Callens, Achara Sathienkijkanchai, Ellen Denayer, Emily Spencer, Pamela Arn, Dusica Babovic-Vuksanovic, Carolyn Bay, Gary Bobele, Bruce H Cohen, Luis Escobar, Deborah Eunpu, Theresa Grebe, Robert Greenstein, Rachel Hachen, Mira Irons, David Kronn, Edmond Lemire, Kathleen Leppig, Cynthia Lim, Marie McDonald, Vinodh Narayanan, Amy Pearn, Robert Pedersen, Berkley Powell, Lawrence R Shapiro, David Skidmore, David Tegay, Heidi Thiese, Elaine H Zackai, Raymon Vijzelaar, Koji Taniguchi, Toranoshin Ayada, Fuyuki Okamoto, Akihiko Yoshimura, Annabel Parret, Bruce Korf, Eric Legius
Journal: JAMA (2009)

Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation.To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients.In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations.Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS.A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.
The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner
Authors: Meritxell Alberich Jordà, Nazik Rayman, Marjolein Tas, Sandra E. Verbakel, Natalia Battista, Kirsten van Lom, Bob Löwenberg, Mauro Maccarrone, Ruud Delwel
Journal: Blood (2004)
I<scp>RON</scp> R<scp>EGULATORY</scp> P<scp>ROTEINS AND THE</scp> M<scp>OLECULAR</scp> C<scp>ONTROL OF</scp> M<scp>AMMALIAN</scp> I<scp>RON</scp> M<scp>ETABOLISM</scp>
Authors: Richard S. Eisenstein
Journal: Annual Review of Nutrition (2000)

▪ Abstract Mammalian iron homeostasis is maintained through the concerted action of sensory and regulatory networks that modulate the expression of proteins of iron metabolism at the transcriptional and/or post-transcriptional levels. Regulation of gene transcription provides critical developmental, cell cycle, and cell-type-specific controls on iron metabolism. Post-transcriptional control through the action of iron regulatory protein 1 (IRP1) and IRP2 coordinate the use of messenger RNA-encoding proteins that are involved in the uptake, storage, and use of iron in all cells of the body. IRPs may also provide a link between iron availability and cellular citrate use. Multiple factors, including iron, nitric oxide, oxidative stress, phosphorylation, and hypoxia/reoxygenation, influence IRP function. Recent evidence indicates that there is diversity in the function of the IRP system with respect to the response of specific IRPs to the same effector, as well as the selectivity with which IRPs modulate the use of specific messenger RNA.
Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.
Authors: K F Lindahl, F H Bach
Journal: The Journal of Experimental Medicine (1976)

The nature of the antigens stimulating xenogeneic lymphocytes was studied using "primed LD typing". Human lymphocytes were sensitized in vitro against mouse spleen cells and restimulated with spleen cells of mouse strains sharing non-H-2 antigens or various regions of H-2 with the initial stimulating strain. The largest thymidine uptake was caused by restimulation with cells from the specific primary stimulator or an H-2-identical strain. Species-specific antigens or strain-specific antigens carried in the C57BL/10 background account for less than 15% of the total stimulation; a non-H-2 antigen associated with the Mlsalpha genotype caused moderate restimulation, amounting to 25% of the average H-2 response. Within H-2, the strongest restimulation was caused by antigens controlled by the I-A subregion; the K and D regions caused moderate, the I-C and S regions very weak, and the I-B subregion no restimulation. Thus, the genetic control of antigens stimulating xenogeneic and allogeneic MLC responses requires T cells and adherent cells, but in the human-mouse MLC, both cell types must come from the human responder; the majority of the proliferating cells are T cells. It is suggested that allograft and xenograft reactions are fundamentally identical processes, and that the relative vigor of alloaggression may be explained by secondary potentiating mechanisms depending on species-specific interactions between aggressor and target cells.
Construction and Characterization of a Bispecific Anti-CD20 Antibody with Potent Antitumor Activity against B-Cell Lymphoma
Authors: Bohua Li, Xunming Zhang, Shu Shi, Lei Zhao, Dapeng Zhang, Weizhu Qian, Lei Zheng, Jie Gao, Hao Wang, Yajun Guo
Journal: Cancer Research (2010)

Abstract To develop more effective anti-CD20 reagents for B-cell lymphoma, we designed and constructed a bispecific tetravalent anti-CD20 antibody, 11B8/2F2(ScFvHL)4-Fc, derived from two fully human monoclonal antibodies (mAb), 2F2 and 11B8. 2F2 is a type I CD20 mAb, which is potent in complement-dependent cytotoxicity (CDC) assays but poor at inducing apoptosis, whereas 11B8 is a type II CD20 mAb, which is effective in induction of apoptosis but ineffective in CDC. Our results showed that 11B8/2F2(ScFvHL)4-Fc possessed apoptosis-inducing activity markedly superior to that of 2F2, and even 11B8, 11B8 plus 2F2, and 2F2(ScFvHL)4-Fc, a 2F2-derived monospecific tetravalent antibody developed previously. Interestingly, 11B8/2F2(ScFvHL)4-Fc displayed a similar ability to mediate CDC as 2F2(ScFvHL)4-Fc, although two of its four antigen-binding arms originated from 11B8. To explore why 11B8/2F2(ScFvHL)4-Fc was so potent in both CDC and apoptotic activity, a bispecific divalent antibody composed of 2F2 and 11B8, denoted as 11B8/2F2-ScFvFc, was constructed and characterized. Our results partially explained the reason for the potent CDC and apoptosis-inducing activity of 11B8/2F2(ScFvHL)4-Fc. Further in vivo therapy studies showed that 11B8/2F2(ScFvHL)4-Fc had a significantly more potent antitumor activity compared with 2F2, 11B8, 2F2 plus 11B8, and 2F2(ScFvHL)4-Fc. These data suggest that 11B8/2F2(ScFvHL)4-Fc may serve as a potential therapeutic agent for B-cell lymphoma. Cancer Res; 70(15); 6293–302. ©2010 AACR.
Effects of Arsenic on Maternal and Fetal Health
Authors: Marie Vahter
Journal: Annual Review of Nutrition (2009)

Arsenic, which is commonly found in drinking water, is a potent toxicant, but little is known about its effects on maternal health. Arsenic's modes of action include enzyme inhibition and oxidative stress as well as immune, endocrine, and epigenetic effects. A couple of studies reported increased blood pressure and anemia during pregnancy. Susceptibility to arsenic is dependent on the biomethylation, which occurs via one-carbon metabolism. Methylarsonic acid and dimethylarsinic acid are main metabolites in urine, and elevated methylarsonic acid is considered a general risk factor. Arsenic easily passes the placenta, and a few human studies indicate a moderately increased risk of impaired fetal growth and increased fetal and infant mortality. The fetus and infant are probably partly protected by the increased methylation of arsenic during pregnancy and lactation; the infant is also protected by low arsenic excretion in breast milk. Early-life exposure may induce changes that will become apparent much later in life.
Two cases of Whipple's disease showing clinical and morphological similarity
Authors: H. Oliva, C. G. Campos, V. Navarro, H. H. Mogena
Journal: Gut (1972)

Two cases of Whipple9s disease are reported in which a parallel course is confirmed between the clinical and ultrastructural findings. This is not so with light microscopy since it takes much longer for these findings to return to normal. In case 1, the presence of bacilli circulating freely in the sinusoid of a lymph node is described. Case 2 demonstrates the existence of special granulomata formed by atypical macrophage histiocytes which appear in coagulative necrosis together with a closely adherent crown of lymphocytes. Furthermore, these histiocytes have moved towards the deepest part of the lamina propria, and have become dissociated from the muscularis mucosae causing a diverticulosis of the small intestine.
Identification of a Novel Cancer-Testis Antigen CRT2 Frequently Expressed in Various Cancers Using Representational Differential Analysis
Authors: Emiko Hayashi, Yuriko Matsuzaki, Go Hasegawa, Tomonori Yaguchi, Sachiko Kurihara, Tomonobu Fujita, Toshiro Kageshita, Makoto Sano, Yutaka Kawakami
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Cancer-testis antigens are promising targets for cancer immunotherapy. Identification of additional cancer-testis antigens with frequent expression in various cancers was attempted using representational differential analysis (RDA) and immunogenicity evaluation. Experimental Design: cDNAs preferentially expressed in testis were enriched using RDA by subtraction between testis and normal tissues. Thirty clones showing cancer-testis–like expression based on EST database analysis were evaluated by reverse transcription-PCR. A potential antigen, CRT2, was identified and its expression was analyzed with a newly generated anti-CRT2 antibody. The immunogenicity of CRT2 was examined based on reactivity with serum immunoglobulin G (IgG) from cancer patients, using Western blot and ELISA analysis, and on in vitro induction of tumor-reactive CTLs from HLA-A24 transgenic mice and human peripheral blood lymphocytes. Results: CRT2 was expressed in elongated spermatids of testis among normal tissues and in various cancer cell lines and tissues. The recombinant CRT2 protein was recognized by serum IgG from patients with various cancers in Western blot and ELISA analyses. A CRT2-derived peptide was identified as an HLA-A24–restricted T-cell epitope that induced tumor-reactive CTLs. Conclusion: CRT2 was identified as a new cancer-testis antigen expressed in elongated spermatids of testis and in cancer tissues (particularly melanoma) that is recognized by serum IgG from cancer patients. An HLA-A24–restricted T-cell epitope capable of inducing tumor-reactive CTLs was identified, suggesting that CRT2 may be useful for cancer diagnosis and immunotherapy.
Tpre, a new alloantigen encoded in the IgT-C region of chromosome 12, is expressed on bone marrow of nude mice, fetal T cell hybrids, and fetal thymus.
Authors: F L Owen
Journal: The Journal of Experimental Medicine (1983)

A new T cell alloantigen, Tpre, has been identified by monoclonal F.6.9.1 antibody. This antigen is encoded by a gene linked to the cluster of T cell antigens in the IgT-C region of chromosome 12 (Tthy, Tind, and Tsu). Tpre is distinct from Tthy, Tind, or Tsu because it is expressed on bone marrow cells of the AKR nustr/nustr, the thymus repopulating precursor cell in normal adult marrow, and normal fetal thymocytes. Several fetal and adult T cell hybrids express these antigens independently. Tpre and Tthy are expressed on largely overlapping cell populations in adult thymus.
HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells
Authors: Nadire Duru, Ming Fan, Demet Candas, Cheikh Menaa, Hsin-Chen Liu, Danupon Nantajit, Yunfei Wen, Kai Xiao, Angela Eldridge, Brett A. Chromy, Shiyong Li, Douglas R. Spitz, Kit S. Lam, Max S. Wicha, Jian Jian Li
Journal: Clinical Cancer Research (2012)

To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2(-/low) breast cancers.HER2-expressing BCSCs (HER2(+)/CD44(+)/CD24(-/low)) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program.Compared with HER2-negative BCSCs, HER2(+)/CD44(+)/CD24(-/low) cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2(+)/CD44(+)/CD24(-/low) cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified.This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2(-/low) breast cancer.
Heterogeneity of Neoplastic Stem Cells: Theoretical, Functional, and Clinical Implications
Authors: Peter Valent, Dominique Bonnet, Stefan Wöhrer, Michael Andreeff, Mhairi Copland, Christine Chomienne, Connie Eaves
Journal: Cancer Research (2013)

Accumulating evidence suggests that human cancers develop through a step-wise, but nonlinear process of cellular diversification and evolution. Recent mutational analyses indicate that this process is more complex and diverse than anticipated before whole-genome sequencing methods were readily available. Examples are also emerging now of genetically abnormal clones of cells that have acquired mutations with known oncogenic potential but, nevertheless, may show no manifestations of malignant change for many years. To accommodate these diverse realities, we suggest the term neoplastic refer to clones of cells that have any type of somatic aberrancy associated with an increased propensity to become malignant, and the derivative term neoplastic stem cell be adopted to identify the cells responsible for the long-term maintenance of such clones. Neoplastic clones would thus include those that never evolve further, as well as those that eventually give rise to fully malignant populations, and all stages in between. The term cancer stem cells would then be more appropriately restricted to cells generating subclones that have established malignant properties. More precise molecular understanding of the different stem cell states thus distinguished should contribute to the development of more effective prognostic and therapeutic tools for cancer diagnosis and treatment.