tbuckley/cabot-search huggingface dataset:
<i>In vivo</i> Expansion, Persistence, and Function of Peptide Vaccine–Induced CD8 T Cells Occur Independently of CD4 T Cells
Authors: Deepak Assudani, Hyun-Il Cho, Nicholas DeVito, Norma Bradley, Esteban Celis
Journal: Cancer Research (2008)

Abstract Significant efforts are being devoted toward the development of effective therapeutic vaccines against cancer. Specifically, well-characterized subunit vaccines, which are designed to generate antitumor cytotoxic CD8 T-cell responses. Because CD4 T cells participate at various stages of CD8 T-cell responses, it is important to study the role of CD4 T cells in the induction and persistence of antitumor CD8 T-cell responses by these vaccines. Recent evidence points to the requirement of CD4 T cells for the long-term persistence of memory CD8 T cells, which in the case of cancer immunotherapy would be critical for the prevention of tumor recurrences. The purpose of the present study was to assess whether CD4 T cells are necessary for the generation and maintenance of antigen-specific CD8 T cells induced by subunit (peptide or DNA) vaccines. We have used a vaccination strategy that combines synthetic peptides representing CD8 T-cell epitopes, a costimulatory anti-CD40 antibody and a Toll-like receptor agonist (TriVax) to generate large numbers of antigen-specific CD8 T-cell responses. Our results show that the rate of decline (clonal contraction) of the antigen-specific CD8 T cells and their functional state is not affected by the presence or absence of CD4 T cells throughout the immune response generated by TriVax. We believe that these results bear importance for the design of effective vaccination strategies against cancer. [Cancer Res 2008;68(23):9892–9]
Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism
Authors: Kulandaivelu S Vetrivel, Ping Gong, James W Bowen, Haipeng Cheng, Ying Chen, Meghan Carter, Phuong D Nguyen, Lisa Placanica, Felix T Wieland, Yue-Ming Li, Maria Z Kounnas, Gopal Thinakaran
Journal: Molecular Neurodegeneration (2007)

Abstract Background Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides. Aβ is released from ectodomain cleaved amyloid precursor protein (APP) via intramembranous proteolysis by γ-secretase, a complex consisting of presenilin and a few other proteins. p23/TMP21, a member of the p24 family type I transmembrane proteins, was recently identified as a presenilin complex component capable of modulating γ-secretase cleavage. The p24 family proteins form oligomeric complexes and regulate vesicular trafficking in the early secretory pathway, but their role in APP trafficking has not been investigated. Results Here, we report that siRNA-mediated depletion of p23 in N2a neuroblastoma and HeLa cells produces concomitant knockdown of additional p24 family proteins and increases secretion of sAPP. Furthermore, intact cell and cell-free Aβ production increases following p23 knockdown, similar to data reported earlier using HEK293 cells. However, we find that p23 is not present in mature γ-secretase complexes isolated using an active-site γ-secretase inhibitor. Depletion of p23 and expression of a familial AD-linked PS1 mutant have additive effects on Aβ 42 production. Knockdown of p23 expression confers biosynthetic stability to nascent APP, allowing its efficient maturation and surface accumulation. Moreover, immunoisolation analyses show decrease in co-residence of APP and the APP adaptor Mint3. Thus, multiple lines of evidence indicate that p23 function influences APP trafficking and sAPP release independent of its reported role in γ-secretase modulation. Conclusion These data assign significance to p24 family proteins in regulating APP trafficking in the continuum of bidirectional transport between the ER and Golgi, and ascribe new relevance to the regulation of early trafficking in AD pathogenesis.
Type I Escherichia coli pili: characterization of binding to monkey kidney cells.
Authors: I E Salit, E C Gotschlich
Journal: The Journal of Experimental Medicine (1977)

We have demonstrated binding of purified pili from a strain of Escherichia coli to Vero cell monolayers as a model of prokaryotic-eukaryotic cell adherence. Pili bound to the tissue culture in a rapid reaction that did not require enzymatic activation. Attachment occurred optimally at pH 4-5 and could be inhibited by analogues of D-mannose, anti-pili antibodies, or by preincubation of tissue cells with mannose-specific plant lectins. Binding remained after treatment of the monolayer with glycosidases, trypsin, or a protease mixture but was enhanced after neuraminidase treatment. These results indicate that bacterial binding can occur via pili which act like lectins and presumably bind to mannose-containing glycoproteins on mammalian cell surfaces.
Transplantation of Mesenchymal Cells Rejuvenated by the Overexpression of Telomerase and Myocardin Promotes Revascularization and Tissue Repair in a Murine Model of Hindlimb Ischemia
Authors: Rosalinda Madonna, Doris A. Taylor, Yong-Jian Geng, Raffaele De Caterina, Harnath Shelat, Emerson C. Perin, James T. Willerson
Journal: Circulation Research (2013)

Rationale: The number and function of stem cells decline with aging, reducing the ability of stem cells to contribute to endogenous repair processes. The repair capacity of stem cells in older individuals may be improved by genetically reprogramming the stem cells to exhibit delayed senescence and enhanced regenerative properties. Objective: We examined whether the overexpression of myocardin (MYOCD) and telomerase reverse transcriptase (TERT) enhanced the survival, growth, and myogenic differentiation of mesenchymal stromal cells (MSCs) isolated from adipose or bone marrow tissues of aged mice. We also examined the therapeutic efficacy of transplanted MSCs overexpressing MYOCD and TERT in a murine model of hindlimb ischemia. Methods and Results: MSCs from adipose or bone marrow tissues of young (1 month old) and aged (12 months old) male C57BL/6 and apolipoprotein E–null mice were transiently transduced with lentiviral vectors encoding TERT, MYOCD, or both TERT and MYOCD. Flow cytometry and bromodeoxyuridine cell proliferation assays showed that transduction with TERT and, to a lesser extent, MYOCD, increased MSC viability and proliferation. In colony-forming assays, MSCs overexpressing TERT and MYOCD were more clonogenic than mock-transduced MSCs. Fas-induced apoptosis was inhibited in MSCs overexpressing MYOCD or TERT. When compared with aged mock-transduced MSCs, aged MSCs overexpressing TERT, MYOCD, or both TERT and MYOCD increased myogenic marker expression, blood flow, and arteriogenesis when transplanted into the ischemic hindlimbs of apolipoprotein E–null mice. Conclusions: The delivery of the TERT and MYOCD genes into MSCs may have therapeutic applications for restoring, or rejuvenating, aged MSCs from adipose and bone marrow tissues.
Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans
Authors: James Pritchett, Emma Harvey, Varinder Athwal, Andrew Berry, Cliff Rowe, Fiona Oakley, Anna Moles, Derek A. Mann, Nicoletta Bobola, Andrew D. Sharrocks, Brian J. Thomson, Abed M. Zaitoun, William L. Irving, Indra N. Guha, Neil A. Hanley, Karen Piper Hanley
Journal: Hepatology (2012)

Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis.
A SELF-RETAINING ANOSCOPE
Authors: W. D. Pennington
Journal: JAMA (1927)

This instrument is composed of three parts: (1) the anoscope proper; (2) a sliding bar; (3) an insulated detachable lamp. It is made in one length, 3½ inches, and is one half, three fourths or 1 inch in outside diameter. The proximal end is provided with a conical flange 2 inches in diameter with a slot which permits easy withdrawal of a sliding bar, so that fields in the anal region to be explored and inspected are successfully exposed. The distal end is conical to permit easy introduction, and is so constructed that it provides shoulders, 2 inches from the proximal end, to prevent expulsion of the instrument while the operator is at work, thus eliminating the need of an assistant. The lamp attached to an insulated device is anchored to the 2 inch flange in a position best to illuminate the field to be observed. The insulation prevents shock
Abstract BS02-1: Hypoxia metabolism in breast cancer – How to overcome resistance to anti-angiogenic therapy
Authors: AL Harris, FM Buffa, S Haider, K Bensaad, A McIntyre, S Lord, S Mehta, H Choudhry, E Favaro, I Ledaki, D Singleton
Journal: Cancer Research (2013)

Abstract Background. Hypoxia is recognised to induce a multigene programme mainly via HIF1a and also HIF2a transcription factors. Bioinformatics analysis of multiple gene array data sets in breast cancer showed a core hypoxia response programme of approximately 90 genes associated with poor outcome independently of other factors. This core response was significantly over-expressed in triple receptor negative cancers. Additionally, microRNAs associated with hypoxia were shown to give additional worse prognosis associations (mir-210). mir-210 targeted the mitochondrial iron chaperone responsible for regulation of key enzymes in the Krebs cycle and showed an adaptive response to hypoxia involving switching off the mitochondrial metabolism. Aims and methods. To assess in human breast cancer the hypoxia transcriptome we conducted gene microarray studies before and after 2 weeks of bevacizumab 15mg/kg single dose before neoadjuvant chemotherapy. This was correlated with imaging by DCE-MRI Ktrans analysis. Results. The study showed that high Ktrans was an excellent predictor for the biological affect of VEGF inhibition and extensive gene induction occurred, including many components of the HIF pathway, but also glycogen metabolism and lipid metabolism. We investigated these further in xenograft models to see which of the adaption pathways may be most important for survival under hypoxic conditions. We showed that induction of CA9, a key enzyme regulating extracellular pH, was critical for survival under anti-angiogenic therapy and blocking CA9 could synergise and also produce radiosensitivity. Reactivating mitochondria under hypoxic conditions induced by angiogenesis also showed additional anti-cancer benefits and is the basis now for a new phase I study in our department. Additionally, surprisingly, induction of glycogen and lipid storage occurred and this was essential for survival on reoxygenation and for protection against free radical damage, which greatly increased when either pathway was inhibited. We investigated, by bioinformatic approaches, the expression of 133 key enzymes in metabolism, showed that they were strongly associated with different subtypes of breast cancer, which may help in selection of patients for future intervention studies. To additionally define the hypoxia transcription, we conducted RNA sequencing of MCF7 cells in normoxia and mild hypoxia. This revealed marked induction of many long non-coding RNAs, suppression of all transfer RNAs and induction of novel antisense RNAs. Conclusions. Overall, therefore, although anti-angiogenic therapy alone is now withdrawn from clinical utility in breast cancer, the massive induction of hypoxic microenvironment and synergy with many other therapeutics, suggests that as new approach using induced essentiality should be reassessed in breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-1.
Male Sexual Behavior and Human Papillomavirus DNA: Key Risk Factors for Cervical Cancer in Spain
Authors: F. X. Bosch, X. Castellsague, N. Munoz, S. de Sanjose, A. M. Ghaffari, L. C. Gonzalez, M. Gili, I. Izarzugaza, P. Viladiu, C. Navarro, A. Vergara, N. Ascunce, E. Guerrero, K. V. Shah
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:It is now established that certain types of human papillomaviruses (HPVs) are the sexually transmitted agents etiologically linked to cervical cancer. Studies assessing the contribution of the male's sexual behavior and genital HPV DNA status to the risk of development of cervical neoplasia in sexual partners have yielded inconsistent results.
Occurrence and Prognostic Significance of Ventricular Arrhythmia Is Related to Pulmonary Function
Authors: Gunnar Engström, Per Wollmer, Bo Hedblad, Steen Juul-Möller, Sven Valind, Lars Janzon
Journal: Circulation (2001)

Background —Reduced lung function has been associated with increased rates of myocardial infarction. Whether the occurrence and prognostic significance of ventricular arrhythmia is related to lung function is largely unknown. Methods and Results —We performed a population-based study of 68-year-old men without a history of stroke or myocardial infarction; 402 men participated. Mortality and coronary events (fatal or nonfatal) were studied in relation to ventricular arrhythmia during 24 hours, percentage of the predicted forced expiratory volume (FEV1 %pred ), vital capacity (VC %pred ), and the FEV/VC ratio. During 14 years of follow-up, 181 men died and 87 experienced a coronary event. Occurrence of frequent or complex ventricular arrhythmia (Lown class 2 to 5) was significantly and inversely associated with FEV1 %pred . Men with Lown class 2 to 5 and a low FEV1 %pred (below median) had significantly higher mortality (71.5 versus 26.8 per 1000 person-years; P &lt;0.0001) and coronary event rates (37.7 versus 18.0; P =0.02) than men with Lown class 2 to 5 and a high FEV1 %pred . These associations remained significant after adjustments for potential confounders (mortality: relative risk [RR], 2.91; 95% CI,1.68 to 5.04; coronary events: RR, 2.16; 95% CI, 1.07 to 4.37). In men without frequent or complex arrhythmia (Lown 0 to 1), a low FEV1 %pred was not significantly associated with mortality (RR, 1.37; 95% CI, 0.92 to 2.05) or coronary events (RR, 1.24; 95% CI, 0.67 to 2.27) after adjustments for confounders. The FEV/VC ratio showed similar associations with arrhythmia, mortality, and coronary events. Conclusions —Lung function is inversely associated with the occurrence of ventricular arrhythmia. The increased incidence of myocardial infarction and death associated with arrhythmia was mainly limited to men with a low FEV1 %pred or FEV/VC. We suggest that lung function should be considered when assessing the prognostic significance of ventricular arrhythmia.
INFECTION INDUCED BY ORAL ADMINISTRATION OF ATTENUATED POLIOVIRUS TO PERSONS POSSESSING HOMOTYPIC ANTIBODY
Authors: Dorothy M. Horstmann, J. R. Paul, J. L. Melnick, Joyce V. Deutsch
Journal: The Journal of Experimental Medicine (1957)

Four of five individuals possessing homotypic antibody in titers of 8 to 64 were infected on being fed Type III (Leon KP-34) poliovirus attenuated by Sabin by passage through tissue culture. None of the infected subjects or controls showed any evidence of illness which could be attributed to virus infection. There was no evidence of spread of infection to any of the control adult wardmates of the experimental subjects, although the two groups were in close contact: none of the controls excreted virus, none showed any antibody shift. One control who had no Type III antibodies at the start of the experiment was still antibody-negative on the 63rd day of the experiment. Three of the four individuals who became infected had naturally acquired-Type III antibodies; the other had antibodies induced by formalinized vaccine. Virus excretion in the stool was of short duration (7 to 13 days) in the three with natural antibodies, and lasted at least 6 weeks after feeding in the vaccinated child. Virus in the throat was detected only in the two persons receiving the larger virus dose (10(7.5) TCD(50)). In them it was present in small amounts between the 2nd and 6th day after feeding. No virus was detected in the blood of any of the infected individuals. The antibody responses of the four infected individuals were variable. There was no clear correlation with virus dosage, amount of virus excretion in the stools, or presence of virus in the throat. Only the child whose neutralizing antibodies were "Salk" vaccine induced showed a marked CF response. The virus excreted by two of the individuals who became infected, as tested in the 2nd tissue culture passage by monkey inoculation, was slightly more neurotropic than the virus which was ingested. Virus excreted by one of these individuals behaved as a virulent strain when tested by the in vitro plaque virulence test, while that isolated from the other had the characteristics of an attenuated strain in this test.
Consequences of Cell Death
Authors: Birthe Sauter, Matthew L. Albert, Loise Francisco, Marie Larsson, Selin Somersan, Nina Bhardwaj
Journal: The Journal of Experimental Medicine (2000)

Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis. We have identified additional distinctions between the two types of death that occur at the level of dendritic cells (DCs) and which influence the induction of immunity. DCs must undergo changes termed maturation to act as potent antigen-presenting cells. Here, we investigated whether exposure to apoptotic or necrotic cells affected DC maturation. We found that immature DCs efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However, only exposure to the latter induces maturation. The mature DCs express high levels of the DC-restricted markers CD83 and lysosome-associated membrane glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86. Furthermore, they develop into powerful stimulators of both CD4(+) and CD8(+) T cells. Cross-presentation of antigens to CD8(+) T cells occurs after uptake of apoptotic cells. We demonstrate here that optimal cross-presentation of antigens from tumor cells requires two steps: phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for major histocompatibility complex class I and class II presentation, and a maturation signal that is delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two types of tumor cell death, with necrosis providing a control that is critical for the initiation of immunity.
Radical Prostatectomy by Open or Laparoscopic/Robotic Techniques: An Issue of Surgical Device or Surgical Expertise?
Authors: Michael L. Blute
Journal: Journal of Clinical Oncology (2008)

In the study reported by Hu et al 1 in this issue of the Journal, the authors identified 2,702 men who underwent radical prostatectomy from 2003 to 2005 from a national sample representing 5% of Medicare beneficiaries.During this time interval, the data showed a 30% increase in use of what is termed laparoscopic radical prostatectomy (LRP) and a 12% decrease in standard open technique, most likely due to the introduction of robotic-assisted radical prostatectomy (RARP).Although RARP is different from LRP, the authors are unable to separate LRP from RARP.Patient interest in RARP has been the result of a highly successful marketing campaign with resultant consumer demand.Patients have been led to believe that hospital and recovery times are shorter and outcomes are better, but study has shown this expectation not to be the case. 2 RARP is simply an alternative method to extract the prostate.In this study, patients undergoing LRP were found to have shorter lengths of stay (mean, 1.42 days v 4.35 days; P Ͻ .001),but were more likely to require salvage therapy (27.8% v 9.1%; P Ͻ .001) with radiation therapy plus androgen deprivation therapy for local relapse.Patients who underwent LRP/RARP appeared to have more anastomotic strictures than open surgery (15.2% v 12%; P ϭ .11).However, the authors did note that high-volume LRP/RARP surgeons were able to reduce these complication rates and the likelihood of local relapse, though both were still more frequent after LRP/RARP than after open technique.Obviously, in any analysis of the Medicare-age population, beneficiary claims data represent a 35,000-ft view of the practice since Medicare claims data cannot reliably be a surrogate for surgical outcome data.However, we believe the trends are more than likely true.The decrement in oncologic outcome (requiring more salvage therapy for local relapse) and increased incidence of anastomotic stricture may be related to do the steep initial learning curve for both LRP/RARP, though more analysis of detailed data would be required to determine this with certainty.Certainly, almost 30% of patients in the LRP/RARP group requiring salvage therapy compared with 9% in the open technique would imply greater oncologic efficacy in the latter.However, without multivariate analysis including clinical and pathologic data, one cannot reliably account for these differences.It is disconcerting that the anastomotic stricture rate is higher than, and not superior to, open technique.Good technique prevents strictures.Anastomotic stricture results in a significant decrease in urinary quality of life including difficult bladder emptying, recurrent urinary tract infection, and bleeding.Necessary repeated corrective procedures