bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Maternal Autologous Neutralizing Antibody in Selective Perinatal Transmission of Human Immunodeficiency Virus Type 1 Escape Variants
Authors: Dickover Ruth , Garratty Eileen , Yusim Karina , Miller Catherine , Korber Bette , Bryson Yvonne 
Published: June 2006

ABSTRACT

Perinatal human immunodeficiency virus type 1 (HIV-1) transmission is characterized by acquisition of a homogeneous viral quasispecies, yet the selective factors responsible for this genetic bottleneck are unclear. We examined the role of maternal autologous neutralizing antibody (aNAB) in selective transmission of HIV-1 escape variants to infants. Maternal sera from 38 infected mothers at the time of delivery were assayed for autologous neutralizing antibody activity against maternal time-of-delivery HIV-1 isolates in vitro. Maternal sera were also tested for cross-neutralization of infected-infant-first-positive-time-point viral isolates. Heteroduplex and DNA sequence analyses were then performed to identify the initial infecting virus as a neutralization-sensitive or escape HIV-1 variant. In utero transmitters (
n
= 14) were significantly less likely to have aNAB to their own HIV-1 strains at delivery than nontransmitting mothers (
n
= 17, 14.3% versus 76.5%,
P
= 0.003). Cross-neutralization assays of infected-infant-first-positive-time-point HIV-1 isolates indicated that while 14/21 HIV-1-infected infant first positive time point isolates were resistant to their own mother's aNAB, no infant isolate was inherently resistant to antibody neutralization by all sera tested. Furthermore, both heteroduplex (
n
= 21) and phylogenetic (
n
= 9) analyses showed that selective perinatal transmission and/or outgrowth of maternal autologous neutralization escape HIV-1 variants occurs in utero and intrapartum. These data indicate that maternal autologous neutralizing antibody can exert powerful protective and selective effects in perinatal HIV-1 transmission and therefore has important implications for vaccine development.
Implementation of the 2005 Coroners Rules Amendments: a survey of practice in England and Wales: Table 1
Authors: Delaney Russell J , Roberts Ian S D 
Published: June 2006

Background:On 1 June 2005, amendments to the Coroners Rules 1984 were introduced in England and Wales. These principally cover the retention of tissues from autopsies and their subsequent disposal. This study assesses regional variations in the interpretations of the amendments, and their impact on local autopsy practice in Oxford.Methods:A questionnaire was circulated to pathologists in 120 coronial jurisdictions, addressing conditions under which histological material could be retained. A local review of autopsy practice was conducted before and after the introduction of the amendments.Results:Questionnaires were returned from 71 coronial jurisdictions. 35 (49%) coroners provided written guidelines on their interpretation of the amendments. In 52 (73%) jurisdictions, pathologists are authorised to retain material to confirm/refine causes of death from natural causes. In 77% of jurisdictions, coroner’s officers are responsible for obtaining instructions from the next of kin on subsequent retention, use or disposal of retained tissues. In Oxford, there has been a reduction in the proportion of cases in which histology is taken, but an increase in the proportion of cases in which a histology report is issued.Conclusions:There is considerable regional variation in the interpretation of the 2005 Coroners Rules Amendments. These variations have potentially important implications for clinical practice.
Nasal polyposis in Peutz–Jeghers syndrome: a distinct histopathological and molecular genetic entity
Authors: de Leng Wendy W J , Westerman Anne Marie , Weterman Marian A J , Jansen Marnix , van Dekken Herman , Giardiello Francis M , de Rooij Felix W M , Paul Wilson J H , Offerhaus G Johan A , Keller Josbert J 
Published: June 2006

Background:Peutz–Jeghers syndrome (PJS) is an autosomal dominant hamartomatous polyposis syndrome of the gastrointestinal tract, caused by a germlineSTK11/LKB1mutation. Nasal polyposis was described in the original report by Peutz. Recently, a molecular–genetic association between nasal polyposis and PJS has been reported.Objective:To further explore the occurrence and pathogenesis of PJS-related nasal polyposis.Methods:51 patients with PJS, 84 unaffected family members and 36 spouses from 18 families with PJS were questioned for the presence of nasal polyposis. 12 PJS-related nasal polyps, 1 carcinoma of the nasal cavity and 28 sporadic nasal polyps were analysed for loss of (wild type)STK11/LKB1, eosinophilia, squamous metaplasia, dysplasia and expression of cyclo-oxygenase 2 and p53.Results:Nasal polyps occurred in 8 of 51 patients with PJS, and were not reported by non-affected family members (p<0.001). GermlineSTK11/LKB1mutations were identified in all patients with PJS and nasal polyposis. Loss of heterozygosity was found in four of eight PJS-related nasal polyps, but not in sporadic nasal polyps (p = 0.002). PJS-related nasal polyps showed less eosinophilia than sporadic nasal polyps (p<0.001). Expression of cyclo-oxygenase 2 was found in 11 of 12 PJS-related nasal polyps and 19 of 28 sporadic nasal polyps (p>0.05). Overexpression of p53 was not found.Conclusions:Nasal polyposis occurs in a significant number of Dutch patients with PJS, one of whom developed a carcinoma in the nasal cavity. The loss of heterozygosity, and the absence of eosinophilia suggest a distinct pathogenesis compared with sporadic nasal polyposis.
Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand
Authors: Pérez-Martínez Francisco C , Alonso Verónica , Sarasa José L , Nam-Cha Syon-Ghyun , Vela-Navarrete Remigio , Manzarbeitia Félix , Calahorra Francisco J , Esbrit Pedro 
Published: June 2006

Aim:To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis.Methods:A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution (Fundación Jiménez Díaz (Grupo Capio), Madrid, Spain) between January 1991 and June 1998 were identified as low-grade (⩽4; n = 22) or high-grade (⩾7, excluding 7 (3+4) cases; n = 25) PCa according to Gleason grade. PCa specimens were immunostained for: parathyroid hormone (PTH)-related protein (PTHrP), the PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor-κ B ligand (RANKL), as well as Ki67 (a proliferation marker) and CD34 (an angiogenesis marker).Results:PCa samples showed an increased immunostaining for both osteoprotegerin and RANKL, associated with tumour grade and PTHrP positivity, in the tumoral epithelium. Using a score value of 4—corresponding to moderate staining—as cut-off, the best sensitivity value was for PTHrP (with C-terminal antiserum C6; 100 %); wheras the best specificity value was for RANKL (95 %).Conclusions:All the evaluated factors are overexpressed mainly in the high-grade tumours. Our findings indicate that, in most patients with PCa (with Ki67 values between 1% and 9%), sequential determination of C-terminal PTHrP and RANKL immunoreactivities is a useful approach to discriminate low-grade and high-grade tumours.
FLUCTUATIONS, ENVIRONMENT, MUTATIONS ACCUMULATION AND AGEING
Authors: BIECEK PRZEMYSŁAW , CEBRAT STANISŁAW 
Published: June 2006

We present a model of evolution of the age structured population based on the Monte Carlo method. We have assumed that the health status of an individual is described by variance of its fluctuations. Each expressed deleterious mutation increases the fluctuations. Additionally, the fluctuations of the environment are superimposed on the fluctuations of individuals in the population. An individual dies if the combination of both stochastic processes trespass the limit (level of homeostasis) set as the model parameter. The genes are switched on chronologically, what leads to accumulating defective genes expressed during the late periods of life in the genetic pool of the population. That results in the specific age structured population, in accordance with the predictions of Medawar's hypothesis of ageing and the results of the Penna model simulations. A decrease of the variation of the environmental noise increases the average expected lifespan of individuals.
The ERBB4/HER4 Intracellular Domain 4ICD Is a BH3-Only Protein Promoting Apoptosis of Breast Cancer Cells
Authors: Naresh Anjali , Long Weiwen , Vidal Gregory A. , Wimley William C. , Marrero Luis , Sartor Carolyn I. , Tovey Sian , Cooke Timothy G. , Bartlett John M.S. , Jones Frank E. 
Published: June 2006

Abstract
ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK. Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 4ICD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway. (Cancer Res 2006; 66(12): 6412-20)
Role of Hypoxia-Inducible Factor (HIF)-1α versus HIF-2α in the Regulation of HIF Target Genes in Response to Hypoxia, Insulin-Like Growth Factor-I, or Loss of von Hippel-Lindau Function: Implications for Targeting the HIF Pathway
Authors: Carroll Veronica A. , Ashcroft Margaret 
Published: June 2006

Abstract
Overexpression of hypoxia-inducible factors (HIF), HIF-1α and HIF-2α, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1α versus HIF-2α to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1α and/or HIF-2α expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1α and/or HIF-2α due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1α primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2α in MCF-7 cells. We also observed a reciprocal relationship between HIF-1α and HIF-2α expression in hypoxia in these cells: HIF-2α siRNA enhanced HIF-1α–mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1α siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1α and HIF-2α due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2α. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2α protein expression and HIF-2α–regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically. (Cancer Res 2006; 66(12): 6264-70)
HSulf-1 Inhibits Angiogenesis and Tumorigenesis In vivo
Authors: Narita Keishi , Staub Julie , Chien Jeremy , Meyer Kristy , Bauer Maret , Friedl Andreas , Ramakrishnan Sundaram , Shridhar Viji 
Published: June 2006

Abstract
We previously identified HSulf-1 as a down-regulated gene in several tumor types including ovarian, breast, and hepatocellular carcinomas. Loss of HSulf-1, which selectively removes 6-O-sulfate from heparan sulfate, up-regulates heparin-binding growth factor signaling and confers resistance to chemotherapy-induced apoptosis. Here we report that HSulf-1 expression in MDA-MB-468 breast carcinoma clonal lines leads to reduced proliferation in vitro and reduced tumor burden in athymic nude mice in vivo. Additionally, xenografts derived from HSulf-1–expressing stable clones of carcinoma cells showed reduced vessel density, marked necrosis, and apoptosis, indicative of inhibition of angiogenesis. Consistent with this observation, HSulf-1–expressing clonal lines showed reduced staining with the endothelial marker CD31 in Matrigel plug assay, indicating that HSulf-1 expression inhibits angiogenesis. More importantly, HSulf-1 expression in the xenografts was associated with a reduced ability of vascular endothelial cell heparan sulfate to participate in a complex with fibroblast growth factor 2 (FGF-2) and its receptor tyrosine kinase FGF receptor 1c. In vitro, short hairpin RNA–mediated down-regulation of HSulf-1 in human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation mediated by heparan sulfate–dependent FGF-2, hepatocyte growth factor, and vascular endothelial growth factor 165 (VEGF165) but not by heparan sulfate–independent VEGF121. HSulf-1 down-regulation also enhanced downstream signaling through the extracellular signal–regulated kinase pathway compared with untreated cells. Consistent with the role of heparan sulfate glycosaminoglycan sulfation in VEGF-mediated signaling, treatment of HUVEC cells with chlorate, which inhibits heparan sulfate glycosaminoglycan sulfation and therefore mimics HSulf-1 overexpression, led to an attenuated VEGF-mediated signaling. Collectively, these observations provide the first evidence of a novel mechanism by which HSulf-1 modulates the function of heparan sulfate binding VEGF165 in proliferation and angiogenesis. (Cancer Res 2006; 66(12): 6025-32)
Hydrogen Peroxide Produced by Angiopoietin-1 Mediates Angiogenesis
Authors: Kim Young Mee , Kim Kyung Eun , Koh Gou Young , Ho Ye-Shih , Lee Kong-Joo 
Published: June 2006

Abstract
Angiopoietin-1 (Ang1) mediates angiogenesis by enhancing endothelial cell survival and migration. It is also known that Ang1 activates Tie2, an endothelial-specific tyrosine kinase receptor, but the molecular mechanism of this process is not clear. In this study, we investigated whether reactive oxygen species (ROS) production plays a role in Ang1-mediated angiogenesis. We found that human umbilical vein endothelial cells treated with Ang1 produce ROS transiently, which was suppressed by NADPH oxidase inhibitor, diphenylene-iodonium chloride, and rotenone. The Ang1-induced ROS was identified as hydrogen peroxide (H2O2) using adenovirus-catalase infection. Removal of H2O2 by adenovirus-catalase significantly suppressed Ang1-induced in vitro endothelial cell migration, in vivo tubule formation and angiogenesis, and activation of p44/42 mitogen-activated protein kinase (MAPK), involved in cell migration, and delayed the deactivation of Akt phosphorylation involved in cell survival. Supporting to in vitro data, Ang1-induced vascular remodeling in catalase (−/−) mice was more prominent than in catalase (+/+) mice: Ang1-induced increases of the diameter of terminal arterioles and the postcapillary venules in catalase (−/−) mice were significant compared with catalase (+/+) mice. These results show that Ang1-induced H2O2 plays an important role in Ang1-mediated angiogenesis by modulating p44/42 MAPK activity. (Cancer Res 2006; 66(12): 6167-74)
Interleukin-23 and Interleukin-27 Exert Quite Different Antitumor and Vaccine Effects on Poorly Immunogenic Melanoma
Authors: Oniki Shuntaro , Nagai Hiroshi , Horikawa Tatsuya , Furukawa Junya , Belladonna Maria Laura , Yoshimoto Takayuki , Hara Isao , Nishigori Chikako 
Published: June 2006

AbstractRecent studies revealed that two novel interleukin (IL)-12-related cytokines, IL-23 and IL-27, have potent antitumor activities. However, the antitumor effects were mainly evaluated in relatively highly immunogenic tumors and have not been fully evaluated against nonimmunogenic or poorly immunogenic tumors. In this study, we investigated the antitumor efficacies of IL-23 and IL-27 on poorly immunogenic B16F10 melanoma and found that the antitumor responses mediated by IL-23 and IL-27 were clearly different. In syngeneic mice, mouse single-chain (sc) IL-23-transfected B16F10 (B16/IL-23) tumors exhibited almost the same growth curve as B16F10 parental tumor about until day 20 after tumor injection and then showed growth inhibition or even regression. In contrast, scIL-27-transfected B16F10 (B16/IL-27) tumors exhibited significant retardation of tumor growth from the early stage. In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-γ whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-γ. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Furthermore, B16/IL-23-vaccinated mice developed protective immunity against parental B16F10 tumors but B16/IL-27-vaccinated mice did not. When combined with prior in vivo depletion of CD25+ T cells, 80% of B16/IL-23-vaccinated mice completely rejected subsequent tumor challenge. Finally, we showed that the systemic administration of neither IL-23 nor IL-27 induced such intense toxicity as IL-12. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors. (Cancer Res 2006; 66(12): 6395-404)
Association of Circulating Tumor Cells with Serum Tumor-Related Methylated DNA in Peripheral Blood of Melanoma Patients
Authors: Koyanagi Kazuo , Mori Takuji , O'Day Steven J. , Martinez Steve R. , Wang He-Jing , Hoon Dave S.B. 
Published: June 2006

Abstract
Although previous studies have separately shown the utility of circulating tumor cells (CTC) or cell-free tumor-related DNA in blood of cancer patients, there has been no investigation of their association and/or the prognostic value of combining these assessments. To date, the true source of tumor-related DNA in serum remains unknown. We hypothesized that CTC is a possible origin of serum tumor-related methylated DNA and their combination can predict disease outcome. To test this hypothesis, we obtained matched pairs of peripheral blood lymphocytes and serum specimens simultaneously from 50 American Joint Committee on Cancer stage IV melanoma patients before administration of biochemotherapy. Peripheral blood leukocytes were analyzed for three mRNA markers of CTC: MART-1, GalNAc-T, and MAGE-A3. Sera were analyzed for two methylated DNA markers: RASSF1A and RAR-β2. CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA and only in 13 of 35 (37%) patients without methylated DNA (P = 0.001). The number of CTC markers detected significantly correlated with methylated DNA (P = 0.008). CTC and methylated DNA were significantly correlated with biochemotherapy-treated patients' outcome. Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy (P = 0.02) and worse time to progression and overall survival (P = 0.009 and 0.02, respectively). The correlation between CTC and serum tumor-related methylated DNA and the significant effect of this correlation on disease outcome indicate that a composite molecular assessment in blood may be a useful determinant of disease status and efficacy of systemic therapy for melanoma. (Cancer Res 2006; 66(12): 6111-7)
Hypermethylation of ASC/TMS1 Is a Sputum Marker for Late-Stage Lung Cancer
Authors: Machida Emi Ota , Brock Malcolm V. , Hooker Craig M. , Nakayama Jun , Ishida Akiko , Amano Jun , Picchi Maria A. , Belinsky Steven A. , Herman James G. , Taniguchi Shun'ichiro , Baylin Stephen B. 
Published: June 2006

Abstract
DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancer-free smokers, 15% (3 of 18) of patients with stage I non–small-cell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancer-free individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease. (Cancer Res 2006; 66(12): 6210-8)
Aptamer:Toxin Conjugates that Specifically Target Prostate Tumor Cells
Authors: Chu Ted C. , Marks John W. , Lavery Laura A. , Faulkner Sarah , Rosenblum Michael G. , Ellington Andrew D. , Levy Matthew 
Published: June 2006

Abstract
We have used RNA aptamer:gelonin conjugates to target and specifically destroy cells overexpressing the known cancer biomarker prostate-specific membrane antigen (PSMA). Aptamer:toxin conjugates have an IC50 of 27 nmol/L and display an increased potency of at least 600-fold relative to cells that do not express PSMA. The aptamer not only promotes uptake into target cells but also decreases the toxicity of gelonin in non-target cells. These results validate the notion that “escort aptamers” may be useful for the treatment of specific tumors expressing unique antigen targets.(Cancer Res 2006; 66(12): 5989-92)