tbuckley/cabot-search huggingface dataset:
Reversible and irreversible loss of Fc receptor function of human monocytes as a consequence of interaction with immunoglobulin G.
Authors: R J Kurlander
Journal: Journal of Clinical Investigation (1980)

The effects of IgG in different configurations on the Fc receptor function of human monocytes were studied. Receptor function was assessed by quantitating immune adherence and/or ingestion of human erythrocytes coated with IgG anti-D antibody. Monomeric IgGl in solution inhibited the Fc receptor function of monocytes, but this function was restored completely after washing. In contrast, monomeric IgG that was adsorbed nonspecifically to a plastic surface inhibited the Fc receptor function of monocytes even after washing away unbound IgGl. This loss of function could be blocked by sodium azide and was reversed when the IgG adsorbed to plastic was degraded by trypsin, suggesting that loss of function was the reversible consequence of localized binding of most of the monocyte's receptors at the point of contact with immobilized IgGl. Fluid-phase aggregates of IgGl also reduced the Fc receptor function of monocytes as a consequence of direct binding to the monocyte surface. High concentrations of purified aggregates rapidly reduced Fc receptor function but function was reversed by trypsin even after incubation for 18 h. Lower concentrations of aggregates reduced Fc receptor function more slowly, but after 18 h of incubation, lost function was not restored by trypsin treatment. Because the transition from reversible to irreversible loss was blocked by sodium azide, an energy-dependent process of ingestion, shedding or denaturation of receptors is responsible for this irreversible loss of Fc receptor function. Rabbit IgG anti-human IgG bound to IgG adsorbed to the surface of monocytes also mediated a loss of Fc receptor function as a result of the binding of Fc receptors to the Fc portion of the rabbit IgG molecule, a process analogous to the binding of aggregated IgG. After irreversible depletion of Fc receptor function by anti-IgG, partial recovery of function was detectable within 12-24 h of incubation in vitro, and this recovery was blocked by cycloheximide, suggesting that new receptor synthesis was required for restoration of function.
Stem cell gene<i>SALL4</i>in aggressive hepatocellular carcinoma: A cancer stem cell-specific target?
Authors: Elizabeth Yakaboski, Alexander Jares, Yupo Ma
Journal: Hepatology (2013)

Background: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. Methods: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. Results: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. Conclusions: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma.
Faculty of Public Health calls for the health bill to be withdrawn
Authors: M. Limb
Journal: BMJ (2012)

The Faculty of Public Health has called for the “complete withdrawal” of the Health and Social Care Bill after members voted overwhelmingly for their leaders to change policy.

The faculty surveyed its 3300 members after strong criticism of the board’s stance on the govenment’s health reforms surfaced at an emergency meeting in Birmingham on 25 January ( BMJ 2012;344:e690, doi:10.1136/bmj.e690).

Of those responding, 93% said that the Health and Social Care Bill, if passed, would damage the NHS and the health of people in England.

Three-quarters of members called on the faculty to demand the complete withdrawal of the bill.

The faculty said that almost …
Secondary psychoses: an update
Authors: Matcheri S. Keshavan, Yoshio Kaneko
Journal: World Psychiatry (2013)

Psychotic disorders due to a known medical illness or substance use are collectively termed secondary psychoses. In this paper, we first review the historic evolution of the concept of secondary versus primary psychosis and how this distinction supplanted the earlier misleading classification of psychoses into organic and functional. We then outline the clinical features and approach to the diagnosis of secondary psychotic disorders. Features such as atypical presentation, temporal relation to detectable medical cause, evidence of direct physiological causal relationship to the etiological agent, and the absence of evidence of a primary psychotic illness that may better explain the presentation suggest consideration of a secondary psychosis. Finally, we discuss how careful studies of secondary psychotic disorders can help elucidate the pathophysiology of primary, or idiopathic, psychotic disorders such as schizophrenia. We illustrate this issue through a discussion of three secondary psychotic disorders — psychoses associated with temporal lobe epilepsy, velocardiofacial syndrome, and N‐methyl D‐aspartate (NMDA) receptor encephalitis — that can, respectively, provide neuroanatomical, genetic, and neurochemical models of schizophrenia pathogenesis.
Single Injection of a Sustained-release Prostacyclin Analog Improves Pulmonary Hypertension in Rats
Authors: Hiroaki Obata, Yoshiki Sakai, Shunsuke Ohnishi, Satoshi Takeshita, Hidezo Mori, Makoto Kodama, Kenji Kangawa, Yoshifusa Aizawa, Noritoshi Nagaya
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres.We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS.After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle.We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A(2) level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment.We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.
Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia
Authors: Ronald W. Stam, Monique L. Den Boer, Pauline Schneider, Jasper de Boer, Jill Hagelstein, Maria G. Valsecchi, Paola de Lorenzo, Stephen E. Sallan, Hugh J. M. Brady, Scott A. Armstrong, Rob Pieters
Journal: Blood (2009)
Genetic Damage From Diagnostic Radiation
Authors: Charles E. Land
Journal: JAMA (1977)

To the Editor.—  Bross and Natarajan, using the data from the Tri-State Leukemia Survey and a mathematical model, argue that low doses of diagnostic radiation given during pregnancy result in severe genetic damage to a small (about 1%) proportion of fetuses. For those affected, this damage is later expressed as greatly increased risk of childhood leukemia (by 50-fold) and of a group of other childhood diseases called  diseases (by fivefold).  The authors do not indicate the precision of their estimated parameters but present estimated numbers of irradiated children with and without leukemia and with and without indicator disease in three age ranges; these numbers agree well with the corresponding frequencies observed in the Tri-State Survey. The object of the exercise appears to be to circumvent the problems of demonstrating an exposure effect that may increase disease rates only slightly in the exposed population and of impressing on others, who
Pleural effusion arising from a rare pancreatic neoplasm
Authors: Breda Cushen, Aoife McKeating, John F. Garvey, Jonathan D. Dodd, Hugh Mulcahy, Justin Geoghegan, Edward F. McKone, Charles G. Gallagher
Journal: European Respiratory Journal (2012)

candidates.Our patient had already recovered from septic shock and was no longer in a hypotensive and hyperdynamic circulatory state, which was probably a prerequisite for the high efficacy of ECMO support.Her prompt improvement and rapid recovery after ECMO insertion were remarkable and the course of ARDS in patients receiving ECMO support without invasive ventilation warrants further study.In patients with more severe lung injury one might also consider the use of ECMO in awake patients receiving noninvasive ventilation.
Integrated Molecular Analysis Indicates Undetectable Change in DNA Damage in Mice after Continuous Irradiation at ~ 400-fold Natural Background Radiation
Authors: Werner Olipitz, Dominika Wiktor-Brown, Joe Shuga, Bo Pang, Jose McFaline, Pallavi Lonkar, Aline Thomas, James T Mutamba, Joel S Greenberger, Leona D Samson, Peter C Dedon, Jacquelyn C Yanch, Bevin P Engelward
Journal: Environmental Health Perspectives (2012)

In the event of a nuclear accident, people are exposed to elevated levels of continuous low dose-rate radiation. Nevertheless, most of the literature describes the biological effects of acute radiation.DNA damage and mutations are well established for their carcinogenic effects. We assessed several key markers of DNA damage and DNA damage responses in mice exposed to low dose-rate radiation to reveal potential genotoxic effects associated with low dose-rate radiation.We studied low dose-rate radiation using a variable low dose-rate irradiator consisting of flood phantoms filled with 125Iodine-containing buffer. Mice were exposed to 0.0002 cGy/min (~ 400-fold background radiation) continuously over 5 weeks. We assessed base lesions, micronuclei, homologous recombination (HR; using fluorescent yellow direct repeat mice), and transcript levels for several radiation-sensitive genes.We did not observe any changes in the levels of the DNA nucleobase damage products hypoxanthine, 8-oxo-7,8-dihydroguanine, 1,N6-ethenoadenine, or 3,N4-ethenocytosine above background levels under low dose-rate conditions. The micronucleus assay revealed no evidence that low dose-rate radiation induced DNA fragmentation, and there was no evidence of double strand break-induced HR. Furthermore, low dose-rate radiation did not induce Cdkn1a, Gadd45a, Mdm2, Atm, or Dbd2. Importantly, the same total dose, when delivered acutely, induced micronuclei and transcriptional responses.These results demonstrate in an in vivo animal model that lowering the dose-rate suppresses the potentially deleterious impact of radiation and calls attention to the need for a deeper understanding of the biological impact of low dose-rate radiation.
The IgE‐binding epitopes of rPar j 2, a major allergen of <i>Parietaria judaica</i> pollen, are heterogeneously recognized among allergic subjects
Authors: M. Assunta Costa, G. Duro, V. Izzo, P. Colombo, M. G. Mirisola, G. Locorotondo, R. Cocchiara, D. Geraci
Journal: Allergy (2000)

Pollen allergens are multivalent proteins that cross‐link IgE antibodies on mast or basophil cells, inducing secretion of biologic mediators, and resulting in various allergic symptoms. The IgE‐binding regions of the Parietaria judaica ( Pj ) pollen major allergen rPar j 2 were investigated. Twenty‐nine single sera from Pj ‐allergic subjects were tested by Western blot against five recombinant peptides. At least four putative IgE‐binding epitopes were identified. The analysis of their diffusion suggested a heterogeneous IgE‐binding response. In fact, 75% of the sera reacted with peptide 1–54, 48% with peptide 48–101, 24% with peptide 1–30, 7% with peptide 29–54, and none with peptide 48–76. These five peptides were analyzed with the histamine‐release assay. Only peptide 48–101 was capable of inducing degranulation and release of histamine. These results suggest that the recombinant rPar j 2 allergen contains IgE epitopes that are heterogeneously recognized by sensitive patients, and that therefore the therapeutic approach based on the use of haptenic peptides needs a careful evaluation.
A malarial cysteine protease is necessary for <i>Plasmodium</i> sporozoite egress from oocysts
Authors: Ahmed S.I. Aly, Kai Matuschewski
Journal: The Journal of Experimental Medicine (2005)

The Plasmodium life cycle is a sequence of alternating invasive and replicative stages within the vertebrate and invertebrate hosts. How malarial parasites exit their host cells after completion of reproduction remains largely unsolved. Inhibitor studies indicated a role of Plasmodium cysteine proteases in merozoite release from host erythrocytes. To validate a vital function of malarial cysteine proteases in active parasite egress, we searched for target genes that can be analyzed functionally by reverse genetics. Herein, we describe a complete arrest of Plasmodium sporozoite egress from Anopheles midgut oocysts by targeted disruption of a stage-specific cysteine protease. Our findings show that sporozoites exit oocysts by parasite-dependent proteolysis rather than by passive oocyst rupture resulting from parasite growth. We provide genetic proof that malarial cysteine proteases are necessary for egress of invasive stages from their intracellular compartment and propose that similar cysteine protease–dependent mechanisms occur during egress from liver-stage and blood-stage schizonts.
Abstract 5188: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs
Authors: Eiso Hiyama, Sho Kurihara, Yoshiyuki Onitake, Nagisa Morihara, Kyoko Ikeda, Keiko Hiyama
Journal: Cancer Research (2014)

Abstract Background: Hepatobastoma (HBL) accounts for more than 80% of childhood hepatic malignant tumors. The outcome of the HBL cases mainly depends on the biological characteristics and disease stagings, but the candidate genes correlated with HBL progression have not been identified. Sequence capture enrichment strategies and massively parallel next generation sequencing (NGS) were used for such gene discovery.Methods: Out of approximately 300 HBL case treated according to the JPLT (Japanese study group for Pediatric Liver Tumor)-2 protocol, 48 samples cases were analyzed by a method for whole-exome sequencing coupling Ilumina Nextera whole-exome capture to the Illumina DNA-sequencing platform. In these cases, 10 had lung metastatic cases and 13 of the remaining 38 cases had vascular invasion or multifocal lesions at admission. Consequently, 14 cases had a relapse and 10 cases died of disease. Using conventional technology, we investigated CNNB1 point-mutations and deletions in these cases.Results: Among these 48 HBL cases, mutation and deletion in CNNB1 exon 3 was identified in 40 cases, which had been already detected by conventional techniques. The remaining 8 cases showed the mutation of Wnt signal genes including AXIN1 and FAP genes. Among the cases with metastatic lesion and/or consequently dead cases, stemness-associated and cancer-associated genes showed homozygous deletion (e. g. CDKN2A), a homozygous inversion in the genes including NF1, and an unbalanced translocation. The response rates in the 35 cases that underwent neo-adjuvant chemotherapy revealed that existence of the mutations in several genes associated with proliferation was significantly correlated with chemo-resistance. Therefore, we are now constructing next clinical trial for HBL based on the whole-exome era.Conclusions: Whole-exome sequencing using NGS in hepatoblastoma revealed several candidates mutated or deleted genes except for CNNB1 in Wnt-signaling pathway. NGS can be also used in research and diagnostic settings to screen for mutations and deletion/insertion of the genes associated with malignant grade and chemo-resistance. Further NGS analysis provided important candidates of indicators for diagnostic and therapeutic targets for HBL clinical trials. Note: This abstract was not presented at the meeting. Citation Format: Eiso Hiyama, Sho Kurihara, Yoshiyuki Onitake, Nagisa Morihara, Kyoko Ikeda, Keiko Hiyama. Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5188. doi:10.1158/1538-7445.AM2014-5188
Abstract 1965: Evaluating the use of Fe3O4@TiO2 nanoparticles and nanoconjugates with a HPV 18 E2 peptide as a potential therapy for HPV containing cancer cells
Authors: Caroline B. Doty, Ye Yuan, Aiguo Wu, Tatjana Paunesku, Gayle E. Woloschak
Journal: Cancer Research (2012)

Abstract Over half a million women world wide are affected by cervical cancer each year. HPV, human papillomavirus, is currently seen as the causative agent of this form of cancer. There are multiple mechanisms by which HPV can cause cervical cancer, the primary mechanisms being the integration of HPV viral DNA into human DNA and the production of the viral oncoproteins E6 and E7. The mechanism of action of these oncoproteins lies in the deregulation of tumor suppressor proteins p53 and Rb. Current cervical cancer therapies, such as radiation, surgical removal, and chemotherapy target the cancerous cells but not the causative agent, HPV. The purpose of this investigation is to find the optimal formulation for, and evaluate the ability of, titanium dioxide (TiO2) shell - iron oxide (Fe3O4) core nanoconjugates (Fe3O4@TiO2) to target HPV genome as a method of therapy. Fe3O4@TiO2, which act the same as pure TiO2 nanoparticles, produce reactive oxygen species (ROS) in solution and have the ability to cleave DNA upon the induction of photon energies above 3.2 eV (e.g. white light), as was shown as a part of these studies. In this study, 6nm Fe3O4@TiO2 nanoconjugates were covalently linked, via a dopamine linker, to a truncated HPV 18 E2 peptide. The peptide linked to the nanoparticle is a 22 amino acid sequence that contains a nuclear localization sequence as well as a DNA binding motif. We hypothesized that (1) the Fe3O4@TiO2-PNA nanoconjugates would localize to the nucleus of cells; (2) presence of nanoconjugates in cells would lead to the production of reactive oxygen species (ROS) upon induction with white light; (3) presence of light activated nanoconjugates in cells would lead to double strand breaks in DNA. The nanoconjugate was tested in HeLa cells which contain multiple copies of HPV genome. To evaluate the effectiveness of this nanoconjugate therapy, we have used DCFDA staining to determine levels of ROS in cells upon the induction of light. As a method to determine double strand DNA damage, we have used immunofluorescence techniques to reveal changes in 53BP1 foci. Upon the introduction and induction of Fe3O4@TiO2-HPV 18 E2 peptide nanoconjugates in HeLa cells we have found increases in ROS levels and increases 53BP1 foci suggesting the presence of double strand DNA damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1965. doi:1538-7445.AM2012-1965
Abstract A47: Inhibition of Rho kinase signaling in angiosarcomas leads to decreased tumor growth and invasiveness, but enhanced resistance to standard chemotherapeutics
Authors: Dianne Courtenay Mitchell, Brad Allen Bryan
Journal: Clinical Cancer Research (2012)

Abstract The Rho-associated coiled-coil protein kinases (ROCK 1 &amp; 2) are serine/threonine kinases serving as key modulators of processes involving cytoskeletal rearrangement, focal adhesion formation, cell motility, and tumor cell invasion. Deregulation of ROCK signaling has been reported across diverse tumors types and overexpression of ROCK proteins in metastatic tumors directly contributes to their aggressive behavior through stimulating cell migration and epithelial-to-mesenchymal transition. Indeed, a number of published reports from our lab and others indicate that inhibiting ROCK signaling effectively disrupts solid tumor formation, progression, and metastasis. Interestingly, over the past decade more than 20 publications from different groups have reported diverse and often conflicting roles for the ROCK proteins in cell survival in differing tumor types, bringing into question what the overall response would be of a cancer patient who is taking standard chemotherapy combined with ROCK inhibitors. Despite the widespread interest in targeting ROCK signaling for cancer therapy, the molecular mechanisms explaining these conflicting pleiotropic roles for ROCK signaling in cell fate decisions is almost exclusively unknown. In this study, we examined the effects of ROCK inhibition combined with standard chemotherapy regimens on angiosarcoma tumor progression. Pharmacological inhibition of ROCK's kinase activity or shRNA knockdown of ROCK1 or 2 gene expression resulted in decreased angiosarcoma tumor formation and invasion, however led to significantly increased tumor cell survival following cisplatin or busulfan treatment. To determine the molecular mechanisms controlling the pro-survival response of inhibiting ROCK signaling following cytotoxic injury, we performed whole genome microarray analysis revealing that pharmacological inhibition or gene expression knockdown of ROCK proteins led to a statistically significant ablation in the expression of a number of cisplatin and busulfan responsive genes known to be downstream targets of p53 induction, DNA damage response and repair, and cell cycle control. This study provides one of the most detailed explanations at the molecular level as to how ROCK signaling modulates cell survival by regulating gene expression at a global level—a paradox that must be solved before inhibition of ROCK activity can be clinically used as an effective anticancer therapeutic, lest we develop an excellent antimetastatic drug that unfortunately (for some tumor types) enhances tumor resistance to chemotherapies.