tbuckley/cabot-search huggingface dataset:
Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study.
Authors: R J Wells, W G Woods, J D Buckley, L F Odom, D Benjamin, I Bernstein, D Betcher, S Feig, T Kim, F Ruymann
Journal: Journal of Clinical Oncology (1994)

PURPOSE The objectives of this study were to determine if the addition of etoposide, thioguanine, and dexamethasone to daunorubicin and cytarabine (five-drug regimen) during induction would improve remission induction rates and survival of children with acute myeloid leukemia (AML) when compared with the standard regimen of cytarabine and daunorubicin (7 + 3) and whether allogeneic bone marrow transplantation (BMT) or intensive chemotherapy consolidation with or without maintenance would give a superior outcome. PATIENTS AND METHODS A total of 591 assessable children with AML entered Childrens Cancer Group (CCG) trial 213 between January 1986 and February 1989. The status of patients as of September 1, 1992 forms the basis of this report. The results were compared with previous AML studies. RESULTS The projected survival rate of all patients at 5 years is 39% (event-free survival [EFS] rate, 31%), which is superior to that of the prior CCG study (P = .01). The induction rate was 79% for 7 + 3 and 76% for the five-drug regimen (not significant). Comparisons of BMT to chemotherapy favored BMT, but these differences do not always reach statistical significance (eg, 5-year disease-free survival [DFS] rate, 46% v 38% [P = .06] with donor available and 54% v 37% [P = .002] if treated according to protocol intent). No benefit for maintenance therapy was found and, in some comparisons, it was inferior to discontinuation of therapy (5-year survival rate, 46% v 68%, P &lt; .01). CONCLUSION The 5-year EFS rate of patients with AML is 31% and has improved. The five-drug induction regimen is no better than standard induction, BMT appears superior to chemotherapy, and maintenance therapy was not beneficial.
FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis
Authors: Boyi Gan, Carol Lim, Gerald Chu, Sujun Hua, Zhihu Ding, Michael Collins, Jian Hu, Shan Jiang, Eliot Fletcher-Sananikone, Li Zhuang, Michelle Chang, Hongwu Zheng, Y. Alan Wang, David J. Kwiatkowski, William G. Kaelin, Sabina Signoretti, Ronald A. DePinho
Journal: Cancer Cell (2010)
Preparation of bromfenac-loaded liposomes modified with chitosan for ophthalmic drug delivery and evaluation of physicochemical properties and drug release profile
Authors: Toshimasa Tsukamoto, Kohei Hironaka, Takuya Fujisawa, Daiki Yamaguchi, Kohei Tahara, Yuichi Tozuka, Hirofumi Takeuchi
Journal: Asian Journal of Pharmaceutical Sciences (2013)

The purpose of this study was to design a submicron-sized liposomal non-steroidal anti-inflammatory drug (NSAID) preparation that targets the retina via topical instillation of eye drops. Bromfenac (BRF)-loaded liposomes were prepared using the calcium acetate gradient method. Liposome sizes and encapsulation efficiencies were optimized by screening several liposome formulations of lipid, drug concentration, and buffer solution. BRF entrapment efficiency was greater than 90% using this method, and was low using conventional hydration methods. High initial BRF loading using the pH gradient method caused aggregation of liposomes. To circumvent aggregation, the negatively charged lipid dicetylphosphate was incorporated into liposomes, which formed anion layer preventing coalescence. Release of BRF from liposomes was sustained for several hours depending on lipid concentration, inner water phase, initial drug amounts, and surface properties. Surface modification with chitosan (CS), a mucoadhesive cationic polymer, was achieved using electrostatic interactions of negatively charged liposomes. The optimal concentration of CS for evasion of liposome aggregation was 0.15%.
Sex matters: secular and geographical trends in sex differences in coronary heart disease mortality
Authors: D A Lawlor, S Ebrahim, G Davey Smith
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To examine secular trends and geographical variations in sex differences in mortality from coronary heart disease and investigate how these relate to distributions in risk factors. <b>Design:</b> National and international data were used to examine secular trends and geographical variations in sex differences in mortality from coronary heart disease and risk factors. <b>Setting:</b> England and Wales, 1921-98; Australia, France, Japan, Sweden, and the United States, 1947-97; 50 countries, 1992-6. <b>Data sources:</b> Office for National Statistics, World Health Organization, and Food and Agriculture Organization of the United Nations. <b>Results:</b> The 20th century epidemic of coronary heart disease affected only men in most industrialised countries and had a very rapid onset in England and Wales, which has been examined in detail. If this male only epidemic had not occurred there would have been 1.2 million fewer deaths from coronary heart disease in men in England and Wales over the past 50 years. Secular trends in mean per capita fat consumption show a similar pattern to secular trends in coronary heart disease mortality in men. Fat consumption is positively correlated with coronary heart disease mortality in men (<i>r s</i> =0.79; 95% confidence interval 0.70 to 0.86) and inversely associated with coronary heart disease mortality in women (—0.30; —0.49 to —0.08) over this time. Although sex ratios for mortality from coronary heart disease show a clear period effect, those for lung cancer show a cohort effect. Sex ratios for stroke mortality were constant and close to unity for the entire period. Geographical variations in the sex ratio for coronary heart disease were associated with mean per capita fat consumption (0.64; 0.44 to 0.78) but were not associated with the sex ratio for smoking. <b>Conclusion:</b> Sex differences are largely the result of environmental factors and hence not inevitable. Understanding the factors that determine sex differences has important implications for public health, particularly for countries and parts of countries where the death rates for coronary heart disease are currently increasing. <h3>What is already known on this topic</h3> Mortality for coronary heart disease is greater in men than women in most industrialised countries The most widely accepted explanation for this difference is that women are protected by oestrogen <h3>What this study adds</h3> The sex difference in mortality from coronary heart disease varies over time and between countries in a way that cannot be explained by endogenous oestrogen These trends indicate that sex differences in mortality from coronary heart disease are driven primarily by environmental factors Sex differences in coronary heart disease are not inevitable Understanding more about the factors that cause the sex differences in mortality from coronary heart disease has important public health implications
Myopodin-Mediated Suppression of Prostate Cancer Cell Migration Involves Interaction with Zyxin
Authors: Yan Ping Yu, Jian-Hua Luo
Journal: Cancer Research (2006)

Abstract Myopodin was identified as a tumor suppressor gene that is frequently deleted in aggressive prostate cancer. Expression of myopodin protein suppresses both tumor growth and metastasis in vitro and in vivo. In the present study employing a yeast two-hybrid system, we found that zyxin, a molecule known to regulate cell motility and migration, binds with myopodin with high affinity. The binding between zyxin and myopodin seems to be direct. Screening of a series of myopodin deletion mutants and peptide competition analyses revealed that myopodin is bound by zyxin at a site located within the sequence of the 19 amino acids at the myopodin COOH terminus. Importantly, this is the same region where the tumor suppressor activity of myopodin is located. The motility and invasion suppression activity of myopodin were significantly weakened in myopodin mutants lacking this sequence. Thus, our studies suggest that zyxin may be a critical functional regulator of myopodin. (Cancer Res 2006; 66(15): 7414-9)
Relationship of precipitating antibodies to soluble cellular antigens and histologically defined renal lesions in systemic lupus erythematosus.
Authors: P J Venables, T Yi, D F Woodrow, J Moss, R N Maini
Journal: Annals of the Rheumatic Diseases (1983)

Antibodies to nuclear ribonucleoprotein (nRNP), Sm, SS-A, and SS-B, were studied by a quantitative immunodiffusion technique in 48 patients with systemic lupus erythematosus (SLE). There was no correlation between the presence or titre of antibodies to any of these antigens and clinically apparent renal disease. However, among 34 patients who had renal biopsies antibodies to nRNP, Sm, and/or SS-A were seen in all 8 patients with membranous glomerulonephritis. Low-titre antibodies (less than 1:4) were seen in 3 out of 7 patients with diffuse proliferative glomerulonephritis. Longitudinal studies in 4 patients who had serial biopsies indicated that the association between serological and histological findings was maintained for prolonged periods. In 2 patients whose biopsy pattern changed, antibodies to nRNP, Sm, and SS-A antedated the development of membranous nephritis.
Iris Pigment Epithelium Expressing CD86 (B7-2) Directly Suppresses T Cell Activation In Vitro via Binding to Cytotoxic T Lymphocyte–associated Antigen 4
Authors: Sunao Sugita, J. Wayne Streilein
Journal: The Journal of Experimental Medicine (2003)

A monolayer of pigment epithelium (PE) lines the iris PE (IPE), ciliary body PE, and retina PE of the inner eye, an immune-privileged site. These neural crest-derived epithelial cells participate in ocular immune privilege through poorly defined molecular mechanisms. Murine PE cells cultured from different ocular tissues suppress T cell activation by differing mechanisms. In particular, IPE cells suppress primarily via direct cell to cell contact. By examining surface expression of numerous candidate molecules (tumor necrosis factor receptor [TNFR]1, TNFR2, CD36, CD40, CD47, CD80, CD86, PD-L1, CD95 ligand, and type I interferon receptor), we report that IPE cells uniquely express on their surface the costimulatory molecule CD86. When IPE were blocked with anti-CD86 or were derived from CD80/CD86 (but not CD80) knockout (KO) mice, the cells displayed reduced capacity to suppress T cell activation. IPE also failed to suppress activation of T cells in the presence of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immunoglobulin or if the T cells were obtained from CTLA-4 (but not CD28) KO mice. We conclude that iris pigment epithelial cells constitutively express cell surface CD86, which enables the cells to contact inhibit T cells via direct interaction with CTLA-4. Thus, ocular immune privilege is achieved in part by subversion of molecules that are usually used for conventional immune costimulation.
The influence of highly active antiretroviral therapy on AIDS-associated Kaposi's sarcoma
Authors: N Dupin, V Rubin De Cervens, I Gorin, V Calvez, E Pessis, M Grandadam, C Rabian, J P Viard, J M Huraux, J Escande
Journal: British Journal of Dermatology (1999)

To assess the clinical and biological benefit of highly active antiretroviral therapy on AIDS-associated Kaposi's sarcoma (KS), 13 patients with AIDS-associated Kaposi's sarcoma (five pulmonary KS and eight cutaneous KS) were prospectively followed for a mean duration of 12 months. Six patients were treated with specific anti-KS chemotherapy before or simultaneously with the introduction of antiretroviral therapy. Clinical response was assessed according to the AIDS Clinical Trial Group (ACTG) criteria. CD4 cell counts, plasma HIV-1 RNA and human herpesvirus 8 (HHV-8) viraemia were measured at baseline and at different points. Among patients with pulmonary KS, we observed three complete responses (CR), one partial response (PR) and one progression. The median survival time after the diagnosis of pulmonary KS was 15 months with a median duration of the response after the discontinuation of specific chemotherapy for KS of 8 months. Among patients with cutaneous KS, we observed four CR, three PR and one stable response. A complete response was significantly associated with a reversal in HHV-8 viraemia (five of six vs. one of six; P = 0.02, Mann–Whitney test).
Sentinel-Node Biopsy in Melanoma
Authors: Roger P A'Hern
Journal: New England Journal of Medicine (2007)

Thomas suggests that prevention of melanoma recurrence is neither desirable in nor beneficial to patients.This curious position is inconsistent with a trial for which he was principal investigator, which used loco-regional recurrence as the primary end point. 1He equates outcomes from early treatment of nodal metastases with delayed treatment, which MSLT-I clearly disproves.Early treatment, guided by sentinel-node biopsy, halves the extent of nodal involvement at surgery 2 and decreases the rate of surgical complications. 3 Early treatment also results in a clinically and statistically significant decreased risk of death from melanoma among patients with nodal metastases from intermediate-thickness melanomas.His appeal to the NCI actually evoked a clear statement in 2007 from the chief of the Clinical Investigations Branch that the NCI "does not interfere with the peer review process and depends on journal reviewers and editors to fairly referee scientific disagreements" (Abrams J: personal communication).This process was vigorously undertaken by the reviewers and editors of the Journal.Reviewers thought the addition of distant disease-free survival for the entire population (which insignificantly favored the biopsy group [hazard ratio for distant metastasis, 0.89; 95% confidence interval, 0.70 to 1.13; P = 0.34]) did not warrant displacement of the presented results.Thomas's statement that the curves showing the cumulative incidence of nodal metastasis are parallel between 8 and 10 years of follow-up is inaccurate.More than one fourth of the remaining minimal numerical difference between the curves evaporates during those 2 years.The criticism is, in any case, irrelevant since the rates are not statistically different, even with existing follow-up.His repetition of the illogical concept of "prognostic false positivity" therefore remains entirely without merit.Cady comments that a survival benefit in one subgroup may offset a disadvantage in another.In MSLT-I, a separate analysis involving a prospectively defined subgroup of patients with node-positive disease was justified by a strong biologic rationale.Survival
Gram stain and culture of morning and 24 h sputum in the diagnosis of bacterial exacerbation of chronic bronchitis: a dogma disputed
Authors: TC Medici, A von Graevenitz, H Shang, E Bohni, M Wall
Journal: European Respiratory Journal (1988)

Bacteriological results from microscopic and cultural examinations of morning and 24 h sputum were compared in an attempt to optimize the diagnosis of bacterial exacerbations of chronic bronchitis. Twelve patients collected sputum randomly on two consecutive days, either fresh morning sputum (3 h sputum) first, followed by 24 h sputum or vice-versa. Sputa were washed three times in 0.9% NaCl and then examined microscopically before and after homogenization with 2% pancreatin. Cultural examinations were performed on homogenized sputum. Haemophilus influenzae, pneumococci and neisseriae were identified more often in Gram stains than in cultures; staphylococci and Gram-negative rods less frequently so. About 50% of organisms microscopically identified as pneumococci failed to grow in cultures. Microscopic examinations revealed a marked reduction of cells and bacteria after homogenization with pancreatin. Gram stains of 24 h sputum show comparable results to those of morning sputum. No differences were found in cultures. Microscopic examination of the Gram stains was found to be superior to cultural examination. The value of microscopic examination was impaired by the addition of pancreatin.
Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury
Authors: Subhashini Bolisetty, Amie M. Traylor, Junghyun Kim, Reny Joseph, Karina Ricart, Aimee Landar, Anupam Agarwal
Journal: Journal of the American Society of Nephrology (2010)

Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1(-/-) PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1-deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1-deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.
Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease
Authors: C. S. Ma
Journal: Journal of Clinical Investigation (2006)

Individuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27+ memory B cells, and those few that are present are IgM+. Recent studies have suggested that IgM+CD27+ B cells are not true memory cells, but rather B cells that guard against T cell–independent pathogens. Here we show that human XLP IgM+CD27+ B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgM+CD27+ B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell–dependent and –independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgM+CD27+ B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM+ and Ig isotype–switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgM+CD27+ B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.
The Molecular Basis of Turcot's Syndrome
Authors: Stanley R. Hamilton, Bo Liu, Ramon E. Parsons, Nickolas Papadopoulos, Jin Jen, Steven M. Powell, Anne J. Krush, Theresa Berk, Zane Cohen, Bernard Tetu, Peter C. Burger, Patricia A. Wood, Fowzia Taqi, Susan V. Booker, Gloria M. Petersen, G. Johan A. Offerhaus, Anne C. Tersmette, Francis M. Giardiello, Bert Vogelstein, Kenneth W. Kinzler
Journal: New England Journal of Medicine (1995)

Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level.
Oncogenic B-RafV600E Induces Spindle Abnormalities, Supernumerary Centrosomes, and Aneuploidy in Human Melanocytic Cells
Authors: Yongping Cui, Meghan K. Borysova, Joseph O. Johnson, Thomas M. Guadagno
Journal: Cancer Research (2010)

Abstract Activating B-Raf mutations arise in 60% to 70% of human melanomas and are thought to play a vital role in tumorigenesis, although how this occurs remains poorly understood. Wild-type B-Raf is critical for normal mitosis of human somatic cells, suggesting that mutational activation of B-Raf might compromise mitosis. We examined this hypothesis by introducing oncogenic mutant B-RafV600E into established human melanoma cells, assessing the effects on mitosis and their possible relationship to extracellular signal–regulated kinase (ERK) pathway activation. Exogenous expression of this activated B-Raf mutant led to a high incidence of aberrant spindles and supernumerary centrosomes. These mitotic abnormalities were suppressed by expression of a B-RafV600E mutant–specific shRNA or by the addition of the mitogen-activated protein/ERK kinase–specific inhibitor U0126. Mitotic abnormalities generated by B-RafV600E also caused missegregation of chromosomes leading to aneuploidy. Because activating B-Raf mutations are detected frequently in benign nevi, we extended our studies to primary human melanocytes. Remarkably, short-term expression of B-RafV600E was sufficient to induce aneuploidy in human melanocytes or in immortalized human mammary epithelial cells. Collectively, our studies identify a novel role for the B-Raf oncogene in driving aneuploidy in melanocytic cells. We propose that disruption of mitotic controls by oncogenic B-Raf has important implications for understanding melanoma tumor development. Cancer Res; 70(2); 675–84
Reduced annexin A6 expression promotes the degradation of activated epidermal growth factor receptor and sensitizes invasive breast cancer cells to EGFR-targeted tyrosine kinase inhibitors
Authors: Rainelli B Koumangoye, Gladys N Nangami, Pamela D Thompson, Vincent K Agboto, Josiah Ochieng, Amos M Sakwe
Journal: Molecular Cancer (2013)

The expression of annexin A6 (AnxA6) in AnxA6-deficient non-invasive tumor cells has been shown to terminate epidermal growth factor receptor (EGFR) activation and downstream signaling. However, as a scaffolding protein, AnxA6 may stabilize activated cell-surface receptors to promote cellular processes such as tumor cell motility and invasiveness. In this study, we investigated the contribution of AnxA6 in the activity of EGFR in invasive breast cancer cells and examined whether the expression status of AnxA6 influences the response of these cells to EGFR-targeted tyrosine kinase inhibitors (TKIs) and/or patient survival.We demonstrate that in invasive BT-549 breast cancer cells AnxA6 expression is required for sustained membrane localization of activated (phosho-Y1068) EGFR and consequently, persistent activation of MAP kinase ERK1/2 and phosphoinositide 3-kinase/Akt pathways. Depletion of AnxA6 in these cells was accompanied by rapid degradation of activated EGFR, attenuated downstream signaling and as expected enhanced anchorage-independent growth. Besides inhibition of cell motility and invasiveness, AnxA6-depleted cells were also more sensitive to the EGFR-targeted TKIs lapatinib and PD153035. We also provide evidence suggesting that reduced AnxA6 expression is associated with a better relapse-free survival but poorer distant metastasis-free and overall survival of basal-like breast cancer patients.Together this demonstrates that the rapid degradation of activated EGFR in AnxA6-depleted invasive tumor cells underlies their sensitivity to EGFR-targeted TKIs and reduced motility. These data also suggest that AnxA6 expression status may be useful for the prediction of the survival and likelihood of basal-like breast cancer patients to respond to EGFR-targeted therapies.