tbuckley/cabot-search huggingface dataset:
Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa
Authors: Shigeru Iida, Hirofumi Misaka, Miho Inoue, Mami Shibata, Ryosuke Nakano, Naoko Yamane-Ohnuki, Masako Wakitani, Keiichi Yano, Kenya Shitara, Mitsuo Satoh
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recent studies have revealed that fucosylated therapeutic IgG1s need high concentrations to compensate for FcγRIIIa-competitive inhibition of antibody-dependent cellular cytotoxicity (ADCC) by endogenous human plasma IgG. Here, we investigated whether ADCC of nonfucosylated therapeutic IgG1 is also influenced by plasma IgG in the same way as fucosylated IgG1s. Experimental Design: Ex vivo ADCC upon CD20+ human B cells was induced by incubation of human whole blood with nonfucosylated and/or fucosylated anti-CD20 IgG1s rituximab, and quantified by measuring the remaining CD19+ human B cells using flow cytometry. Results: Nonfucosylated anti-CD20 showed markedly higher (over 100-fold based on EC50) ex vivo B-cell depletion activity than its fucosylated counterpart in the presence of plasma IgG. The efficacy of fucosylated anti-CD20 was greatly diminished in plasma, resulting in the need for a high concentration (over 1.0 μg/mL) to achieve saturated efficacy. In contrast, nonfucosylated anti-CD20 reached saturated ADCC at lower concentrations (0.01-0.1 μg/mL) with much higher efficacy than fucosylated anti-CD20 in all nine donors through improved FcγRIIIa binding. Noteworthy, the high efficacy of nonfucosylated anti-CD20 was inhibited by addition of fucosylated anti-CD20. Thus, the efficacy of a 1:9 mixture (10 μg/mL) of nonfucosylated and fucosylated anti-CD20s was inferior to that of a 1,000-fold dilution (0.01 μg/mL) of nonfucosylated anti-CD20 alone. Conclusions: Our data showed that nonfucosylated IgG1, not including fucosylated counterparts, can evade the inhibitory effect of plasma IgG on ADCC through its high FcγRIIIa binding. Hence, nonfucosylated IgG1 exhibits strong therapeutic potential through dramatically enhanced ADCC at low doses in humans in vivo.
Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death
Authors: Elin Hallan Naderi, Seham Skah, Hege Ugland, Ola Myklebost, Dagny Lise Sandnes, Maria Lyngaas Torgersen, Dag Josefsen, Ellen Ruud, Soheil Naderi, Heidi Kiil Blomhoff
Journal: Molecular Cancer (2015)

B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts. Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E2 (PGE2) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells. Primary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE2-cAMP-PKA axis were assessed by inhibition of PGE2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test. We demonstrate that BM-derived MSCs produce PGE2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL. Our findings support our hypothesis that BM-derived PGE2, through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE2-cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL.
Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation
Authors: A T Whittle
Journal: Thorax (2001)

<h3>BACKGROUND</h3> The success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM) cytokine production, would predispose to such complications. <h3>METHODS</h3> AM were isolated from adult SCT recipients by bronchoalveolar lavage before SCT (n=32) and during post-transplant pancytopenia (n=23). Concentrations of tumour necrosis factor (TNF)α, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1β, IL-6, and IL-8 in 24 hour AM culture medium were measured by enzyme linked immunosorbent assay and compared with both the occurrence of post-SCT lung disease and with subjects9 previous respiratory histories. <h3>RESULTS</h3> Eleven subjects developed lung disease within 6 months of SCT. These subjects had higher median pre-transplant AM TNFα (8 (IQR 1–8)<i>v</i> 2 (1–5) ng/10<sup>6</sup>AM, p=0.01, median difference (D) = 3, 95% CI 0.1 to 7), GM-CSF (5 (0.7–8)<i>v</i> 0.2 (0.1–0.8), p=0.006, D = 4, 95% CI 0.5 to 7), and IL-6 (0.5 (0.1–1) <i>v</i> 0.1 (0.02–0.3), p=0.049, D = 0.3, 95% CI 0.0002 to 1) production than remaining subjects; IL-1β and IL-8 did not differ. During pancytopenia high AM GM-CSF production again predicted later lung disease (1 (0.7–9) <i>v</i> 0.1 (0.06–0.3), p=0.01, D = 1, 95% CI 0.1 to 6). A history of recent chest disease was associated with high AM TNFα and GM-CSF production and with post-SCT lung disease. Pre-SCT lung function was unrelated to post-SCT lung disease. <h3>CONCLUSIONS</h3> Recent respiratory disease and persistent proinflammatory AM behaviour detectable before transplantation are associated with lung disease following SCT. These associations may prove useful in pre-transplant risk assessment.
Stroke-induced Immunodeficiency Promotes Spontaneous Bacterial Infections and Is Mediated by Sympathetic Activation Reversal by Poststroke T Helper Cell Type 1–like Immunostimulation
Authors: Konstantin Prass, Christian Meisel, Conny Höflich, Johann Braun, Elke Halle, Tilo Wolf, Karsten Ruscher, Ilya V. Victorov, Josef Priller, Ulrich Dirnagl, Hans-Dieter Volk, Andreas Meisel
Journal: The Journal of Experimental Medicine (2003)

Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-γ–deficient mice, or administration of IFN-γ at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-γ response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the β-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.
Survival in Patients Operated on for Pathologic Fracture: Implications for End-of-Life Orthopedic Care
Authors: Saminathan S. Nathan, John H. Healey, Danilo Mellano, Bang Hoang, Isobel Lewis, Carol D. Morris, Edward A. Athanasian, Patrick J. Boland
Journal: Journal of Clinical Oncology (2005)

Life expectancy is routinely used as part of the decision-making process in deciding the value of surgery for the treatment of bone metastases. We sought to investigate the validity of frequently used indices in the prognostication of survival in patients with metastatic bone disease.The study prospectively assessed 191 patients who underwent surgery for metastatic bone disease. Diagnostic, staging, nutritional, and hematologic parameters cited to be related to life expectancy were evaluated. Preoperatively, the surgeon recorded an estimate of projected life expectancy for each patient. The time until death was recorded.Kaplan-Meier survival analyses indicated that the survival estimate, primary diagnosis, use of systemic therapy, Eastern Cooperative Oncology Group (ECOG) performance status, number of bone metastases, presence of visceral metastases, and serum hemoglobin, albumin, and lymphocyte counts were significant for predicting survival (P < .004). Cox regression analysis indicated that the independently significant predictors of survival were diagnosis (P < .006), ECOG performance status (P < .04), number of bone metastases (P < .008), presence of visceral metastases (P < .03), hemoglobin count (P < .009), and survival estimate (P < .00005). Diagnosis, ECOG performance status, and visceral metastases covaried with surgeon survival estimate. Linear regression and receiver-operator characteristic assessment confirmed that clinician estimation was the most accurate predictor of survival, followed by hemoglobin count, number of visceral metastases, ECOG performance status, primary diagnosis, and number of bone metastases. Nevertheless, survival estimate was accurate in predicting actual survival in only 33 (18%) of 181 patients.A better means of prognostication is needed. In this article, we present a sliding scale for this purpose.
Estrogens and Human Papilloma Virus Oncogenes Regulate Human <i>Ether-à-go-go-1</i> Potassium Channel Expression
Authors: Lorenza Díaz, Irais Ceja-Ochoa, Iván Restrepo-Angulo, Fernando Larrea, Euclides Avila-Chávez, Rocío García-Becerra, Elizabeth Borja-Cacho, David Barrera, Elías Ahumada, Patricio Gariglio, Elizabeth Alvarez-Rios, Rodolfo Ocadiz-Delgado, Enrique Garcia-Villa, Elizabeth Hernández-Gallegos, Ignacio Camacho-Arroyo, Angélica Morales, David Ordaz-Rosado, Ethel García-Latorre, Juan Escamilla, Luz Carmen Sánchez-Peña, Milena Saqui-Salces, Armando Gamboa-Dominguez, Eunice Vera, Marisela Uribe-Ramírez, Janet Murbartián, Cindy Sharon Ortiz, Claudia Rivera-Guevara, Andrea De Vizcaya-Ruiz, Javier Camacho
Journal: Cancer Research (2009)

Abstract Ether-à-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eag1 (hEag1) regulation by cancer-associated factors. We studied hEag1 gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type–dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-α. Eag1 protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eag1 channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eag1 antibodies inhibiting channel activity and by the nonspecific Eag1 inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/antiestrogen use and HPV infection. We also suggest Eag1 as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation. [Cancer Res 2009;69(8):3300–7]
Reappraisal of estrogen receptor negativity in Indian breast cancer
Authors: S. Navani, A. Bhaduri, R. Chopra
Journal: Journal of Clinical Oncology (2005)

761 Background: The incidence of estrogen receptor negative (ER negative) invasive breast carcinoma is reported to be as high as 67.6% in India, as compared to 30–33% in the western literature. It is not clear whether the high incidence among Indians is due to genetic differences between the two populations (“true ER negative status”), or an artefact (“false ER negative status”) from the use of suboptimal manual immunohistochemistry techniques. Accurate ER estimation is critical as patients with false ER negative tumors are often denied the benefits of hormonal therapy. Methods: We used automated immunohistochemistry to re-evaluate the ER status in 246 Indian patients with invasive breast carcinomas previously reported as ER negative by manual immunohistochemistry. Tumour blocks used for this study were the same that were used for the manual assay. The automated technique utilized different reagents (all US FDA approved for diagnostic immunohistochemistry) and staining protocols from those used in the manual assays. The “Quick” score method of assessment was used to assess the range of immunostaining. Results: Of the 246 previously ER negative tumors, 99 (40.24%) were found to be ER positive, and 147 (59.76%) tumors remained ER negative (Quick Score 0). Thirty-four of these 99 ER positive tumors (34.3%) had Quick Scores of 6 and 7 (“strong ER expression”) and 55 (55.55%) had Quick Scores between 1 and 5 (“moderate and low ER expression”). Conclusions: Our results indicate that the high incidence of ER negative breast cancer reported from India is most likely due to the use of suboptimal manual assays, rather than true genetic differences. ER expression in breast cancer among Indian women may be much higher than previously believed. Plausible reasons for increased sensitivity in ER detection in the current study include methods of antigen retrieval, differences in reagents, and automation. Optimal antigen retrieval could be the most critical reason for improved detection. Optimal immunohistochemical demonstration of ER is of critical importance. Patients with false ER negative tumours are denied hormonal therapy. Hormonal therapy is more suited in cost and management than chemotherapy in a limited resource country like India No significant financial relationships to disclose.
Quantifying the effects of exposure to indoor air pollution from biomass combustion on acute respiratory infections in developing countries.
Authors: M Ezzati, D M Kammen
Journal: Environmental Health Perspectives (2001)

Acute respiratory infections (ARI) are the leading cause of burden of disease worldwide and have been causally linked with exposure to pollutants from domestic biomass fuels in developing countries. We used longitudinal health data coupled with detailed monitoring and estimation of personal exposure from more than 2 years of field measurements in rural Kenya to estimate the exposure-response relationship for particulates < 10 microm diameter (PM(10)) generated from biomass combustion. Acute respiratory infections and acute lower respiratory infections are concave, increasing functions of average daily exposure to PM(10), with the rate of increase declining for exposures above approximately 1,000-2,000 microg/m(3). This first estimation of the exposure-response relationship for the high-exposure levels characteristic of developing countries has immediate and important consequences for international public health policies, energy and combustion research, and technology transfer efforts that affect more than 2 billion people worldwide.
Dietary glycemic index, glycemic load and ovarian cancer risk:a case–control study in Italy
Authors: L.S.A. Augustin, J. Polesel, C. Bosetti, C.W.C. Kendall, C. La Vecchia, M. Parpinel, E. Conti, M. Montella, S. Franceschi, D.J.A. Jenkins, L. Dal Maso
Journal: Annals of Oncology (2002)
Avosentan for Overt Diabetic Nephropathy
Authors: Johannes F.E. Mann, Damian Green, Kenneth Jamerson, Luis M. Ruilope, Susan J. Kuranoff, Thomas Littke, Giancarlo Viberti
Journal: Journal of the American Society of Nephrology (2010)

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.
Gene Therapy with Viral Vectors
Authors: Neeltje A. Kootstra, Inder M. Verma
Journal: The Annual Review of Pharmacology and Toxicology (2003)

A key factor in the success of gene therapy is the development of gene delivery systems that are capable of efficient gene transfer in a broad variety of tissues, without causing any pathogenic effect. Currently, viral vectors based on many different viruses have been developed, and their performance and pathogenicity has been evaluated in animal models. The results of these studies form the basis for the first clinical trials for correcting genetic disorders using retroviral, adenoviral, and adeno-associated viral vectors. Even though the results of these trials are encouraging, vector development is still required to improve and refine future treatment of hereditary disorders.
An official American Thoracic Society/European Respiratory Society statement: research questions in COPD
Authors: Bartolome R. Celli, Marc Decramer, Jadwiga A. Wedzicha, Kevin C. Wilson, Alvar Agustí, Gerard J. Criner, William MacNee, Barry J. Make, Stephen I. Rennard, Robert A. Stockley, Claus Vogelmeier, Antonio Anzueto, David H. Au, Peter J. Barnes, Pierre-Regis Burgel, Peter M. Calverley, Ciro Casanova, Enrico M. Clini, Christopher B. Cooper, Harvey O. Coxson, Daniel J. Dusser, Leonardo M. Fabbri, Bonnie Fahy, Gary T. Ferguson, Andrew Fisher, Monica J. Fletcher, Maurice Hayot, John R. Hurst, Paul W. Jones, Donald A. Mahler, François Maltais, David M. Mannino, Fernando J. Martinez, Marc Miravitlles, Paula M. Meek, Alberto Papi, Klaus F. Rabe, Nicolas Roche, Frank C. Sciurba, Sanjay Sethi, Nikos Siafakas, Don D. Sin, Joan B. Soriano, James K. Stoller, Donald P. Tashkin, Thierry Troosters, Geert M. Verleden, Johny Verschakelen, Jorgen Vestbo, John W. Walsh, George R. Washko, Robert A. Wise, Emiel F.M. Wouters, Richard L. ZuWallack
Journal: European Respiratory Journal (2015)

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes.