bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunodetection of DNA Repair Endonuclease ERCC1-XPF in Human Tissue
Authors: Bhagwat Nikhil R. , Roginskaya Vera Y. , Acquafondata Marie B. , Dhir Rajiv , Wood Richard D. , Niedernhofer Laura J. 
Published: September 2009

AbstractThe high incidence of resistance to DNA-damaging chemotherapeutic drugs and severe side effects of chemotherapy have led to a search for biomarkers able to predict which patients are most likely to respond to therapy. ERCC1-XPF nuclease is required for nucleotide excision repair of helix-distorting DNA damage and the repair of DNA interstrand crosslinks. Thus, it is essential for several pathways of repair of DNA damage by cisplatin and related drugs, which are widely used in the treatment of non–small cell lung carcinoma and other late-stage tumors. Consequently, there is tremendous interest in measuring ERCC1-XPF expression in tumor samples. Many immunohistochemistry studies have been done, but the antibodies for ERCC1-XPF were not rigorously tested for antigen specificity. Herein, we survey a battery of antibodies raised against human ERCC1 or XPF for their specificity using ERCC1-XPF–deficient cells as a negative control. Antibodies were tested for the following applications: immunoblotting, immunoprecipitation from cell extracts, immunofluorescence detection in fixed cells, colocalization of ERCC1-XPF with UV radiation–induced DNA damage in fixed cells, and immunohistochemistry in paraffin-embedded samples. Although several commercially available antibodies are suitable for immunodetection of ERCC1-XPF in some applications, only a select subset is appropriate for detection of this repair complex in fixed specimens. The most commonly used antibody, 8F1, is not suitable for immunodetection in tissue. The results with validated antibodies reveal marked differences in ERCC1-XPF protein levels between samples and cell types. [Cancer Res 2009;69(17):6831–8]
A Retrospective Analysis of AIDS-Associated Kaposi’s Sarcoma in Patients With Undetectable HIV Viral Loads and CD4 Counts Greater Than 300 cells/mm3
Authors: Mani Deepthi , Neil Nancy , Israel Rebecca , Aboulafia David M. 
Published: September 2009

Objective: To compare the clinical course of patients with AIDS-related Kaposi’s sarcoma (KS) with CD4 counts >300 cells/mm3 and undetectable HIV viral loads (VLs) to patients with AIDS-KS with lesser CD4 counts and detectable HIV VLs. Methods: We retrospectively analyzed a cohort of 91 patients with AIDS-KS in a multispeciality clinic. We used χ2 and Student t tests to analyze intragroup differences; survival was determined by Kaplan-Meier analysis. Results: Twenty (22%) of the 91 patients had newly diagnosed, persistent or progressive KS despite CD4 counts >300 cells/mm3 and undetectable HIV VLs. Age, gender, ethnicity, mode and duration of HIV acquisition, type of antiretroviral therapy (ART), and KS therapy did not differ significantly (P ≤ .005) between this group and the remaining 71 patients. Although tumor stage and response to KS therapy were similar, there was a significantly greater risk of death among the patients with CD4 counts <300 cells/mm3 and detectable HIV VLs (P = .048). Conclusions: In the highly active antiretroviral (HAART) era, a substantial proportion of patients with KS had undetectable HIV VLs and CD4 counts greater than the level typically associated with opportunistic diseases. They required systemic therapy to control their KS but were significantly less likely to die and demonstrated a trend toward better 15-year survival than patients having KS with lesser CD4 counts and detectable HIV VLs.
Protective Athletic Mouthguards: Do They Cause Harm?
Authors: Glass Richard T. , Conrad Robert S. , Wood Charles Rieger , Warren Aric J. , Kohler Gerwald A. , Bullard James W. , Benson Gifty , Gulden Judyth M. 
Published: September 2009

Background: Protective athletic mouthguards (PAMs) have been worn in competitive sports for more than 100 years. Today, participants in contact and noncontact sports wear PAMs. Hypothesis: Wearing a PAM produces oral injury. Study Type: Case series. Study Design and Methods: Sixty-two Division I football players voluntarily participated in the study. Before the beginning of the season, each player underwent a thorough oral examination, and all abnormal oral findings were photographed (hyperkeratosis, erythema, ulceration, and combinations thereof). At midseason, 14 players were given complete oral examinations, with all abnormal oral findings documented. At season end, all remaining players (n = 53) had complete oral examinations and photographs taken of abnormal oral findings. Results: The preseason examination of 62 players found a total of 85 lesions (1.4 lesions per player) on the gingiva (n = 17), buccal mucosa (n = 60), and palate (n = 8). The 14 midseason players had 28 lesions (2.0 lesions per player) on gingiva (n = 8), buccal mucosa (n = 16), and tongue (n = 4). At season end, the 53 remaining players had 198 lesions (3.7 per player) on the gingiva (n = 96), buccal mucosa (n = 79), tongue (n = 18), and palate (n = 5). In addition, the lesion intensity scores progressively increased over the season. Because the palate did not come into direct contact with the PAM, it was used as an internal control. Conclusion: The wearing of a PAM may increase the number and intensity of oral mucosal injuries, which may cause localized soft tissue reactions such as hyperkeratosis, erythema, and ulceration. Clinical Relevance: Because the PAM reduces tooth injury but may cause oral lesions, it should be sanitized daily and changed regularly and replaced whenever it becomes sharp and jagged or when the athlete develops an irritation in the mouth.
Colony-stimulating factor-1–induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages
Authors: Jacquel Arnaud , Benikhlef Naïma , Paggetti Jérôme , Lalaoui Najoua , Guery Leslie , Dufour Erick K. , Ciudad Marion , Racoeur Cindy , Micheau Olivier , Delva Laurent , Droin Nathalie , Solary Eric 
Published: September 2009

Abstract
The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasing amplitude and duration are required to provoke the formation of the caspase-8–activating molecular platform. CSF-1 and its receptor are both required for oscillations in AKT activation to occur, and expression of a constitutively active AKT mutant prevents the macrophage differentiation process. The extracellular receptor kinase 1/2 pathway is activated with a coordinated oscillatory kinetics in a CSF-1R–dependent manner but plays an accessory role in caspase activation and nucleophosmin cleavage. Altogether, CSF-1 stimulation activates a molecular clock that involves phosphatidylinositol-3 kinase and AKT to promote caspase activation. This oscillatory signaling pathway, which is coordinated with extracellular receptor kinase 1/2 oscillatory activation, involves CSF-1 and CSF-1R and controls the terminal differentiation of macrophages.
Obesity accelerates thymic aging
Authors: Yang Hyunwon , Youm Yun-Hee , Vandanmagsar Bolormaa , Rood Jennifer , Kumar K. Ganesh , Butler Andrew A. , Dixit Vishwa Deep 
Published: September 2009

Abstract
As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.
Superagonistic CD28 stimulation of allogeneic T cells protects from acute graft-versus-host disease
Authors: Beyersdorf Niklas , Ding Xin , Hünig Thomas , Kerkau Thomas 
Published: September 2009

AbstractAcute graft-versus-host disease (aGVHD) often precludes successful immunotherapy of hematologic malignancies with allogeneic T cells. Therefore, we investigated the effect of immunomodulatory superagonistic anti-CD28 monoclonal antibodies (CD28-SA) on the capacity of allogeneic T cells to mediate both aGVHD and the protective graft-versus-tumor (GVT) response. In vivo pretreatment of donor C57BL/6 mice or short-term in vitro culture of donor lymph node cells with a CD28-SA efficiently protected BALB/c recipient mice from aGVHD. This protection strongly relied on the presence of CD28-SA–activated CD4+ CD25+ Foxp3+ regulatory T cells in the donor T-cell inoculum. With respect to the GVT response, CD28-SA–prestimulated T cells were still as potent in clearing lymphoma cells as were T cells without CD28-SA preactivation. Taken together, our data suggest that CD28-SA stimulation of bulk leukocyte cultures in vitro markedly increases the therapeutic window for adoptive immunotherapy with allogeneic T cells in vivo.
"hCG priming" effect in controlled ovarian stimulation through a long protocol
Authors: Beretsos Panagiotis , Partsinevelos George A , Arabatzi Eleni , Drakakis Peter , Mavrogianni Depy , Anagnostou Elli , Stefanidis Kostas , Antsaklis Aris , Loutradis Dimitris 
Published: September 2009

Abstract

Background
Recently, it has been demonstrated that, in patients down-regulated by GnRH analogues (GnRHa), a short-term pre-treatment with recombinant LH (rLH), prior to recombinant FSH (rFSH) administration, increases the number of small antral follicle prior to FSH stimulation and the yield of normally fertilized embryos. However, no data exist in the literature regarding the potential beneficial effect of "hCG priming" in controlled ovarian hyperstimulation (COH) through a long GnRH-a protocol, which binds the same receptor (LH/hCGR), though it is a much more potent compared to LH. The primary aims of this study were to assess the effect of short-term pre-rFSH administration of hCG in women entering an ICSI treatment cycle on follicular development, quality of oocytes and early embryo development. The secondary endpoints were to record the effects on endometrial quality and pregnancy rate.

Methods
Patients with a history of at least one previous unsuccessful ICSI cycle were randomly assigned into two groups to receive treatment with either a long protocol with rFSH (control group) or a long protocol with rFSH and pre-treatment with hCG (hCG group). In particular, in the latter group, a fixed 7 days course of 200 IU/day hCG was administered as soon as pituitary desensitization was confirmed.

Results
The mean number of oocytes retrieved was not significantly different between the two treatment groups, although the percentage of mature oocytes tended to be higher but not significantly different in hCG-treated patients. The percentage of patients with more than one grade 3 embryos was higher in the pre-treatment group, which also showed a higher pregnancy rate.

Conclusion
All the above clinical observations, in conjunction with previous data, suggest a point towards a beneficial "hCG priming" effect in controlled ovarian hyperstimulation through a long GnRH-a down-regulation protocol, particularly in patients with previous ART failures.
Talking to chromatin: post-translational modulation of polycomb group function
Authors: Niessen Hanneke EC , Demmers Jeroen A , Voncken Jan Willem 
Published: September 2009

Abstract
Polycomb Group proteins are important epigenetic regulators of gene expression. Epigenetic control by polycomb Group proteins involves intrinsic as well as associated enzymatic activities. Polycomb target genes change with cellular context, lineage commitment and differentiation status, revealing dynamic regulation of polycomb function. It is currently unclear how this dynamic modulation is controlled and how signaling affects polycomb-mediated epigenetic processes at the molecular level. Experimental evidence on regulation of polycomb function by post-translational mechanisms is steadily emerging: Polycomb Group proteins are targeted for ubiquitylation, sumoylation and phosphorylation. In addition, specific Polycomb Group proteins modify other (chromatin) associated proteins via similar post-translational modifications. Such modifications affect protein function by affecting protein stability, protein-protein interactions and enzymatic activities. Here, we review current insights in covalent modification of Polycomb Group proteins in the context of protein function and present a tentative view of integrated signaling to chromatin in the context of phosphorylation. Clearly, the available literature reveals just the tip of the iceberg, and exact molecular mechanisms in, and the biological relevance of post-translational regulation of polycomb function await further elucidation. Our understanding of causes and consequences of post-translational modification of polycomb proteins will gain significantly from in vivo validation experiments. Impaired polycomb function has important repercussions for stem cell function, development and disease. Ultimately, increased understanding of signaling to chromatin and the mechanisms involved in epigenetic remodeling will contribute to the development of therapeutic interventions in cell fate decisions in development and disease.
The drug-resistance to gefitinib in PTEN low expression cancer cells is reversed by irradiation in vitro
Authors: Zhuang Hong-Qing , Wang Jun , Yuan Zhi-Yong , Zhao Lu-Jun , Wang Ping , Wang Chang-Li 
Published: September 2009

Abstract

Background
Despite of the recent success of EGFR inhibitory agents, the primary drug-resistant becomes a major challenge for EGFR inhibitor therapies. PTEN gene is an important positive regulatory factor for response to EGFR inhibitor therapy. Low-expression of PTEN is clearly one of the important reasons why tumor cells resisted to tyrosine kinase inhibitors.

Methods
To investigate the drug-resistance reversal to gefitinb and the mechanism in PTEN low expression cells which radiated with X-rays in vitro, We demonstrated that H-157 lung cancer cells (low-expression of PTEN but phospho-EGFR overexpressed tumor cells) exposed to X-rays. The PTEN expressions and radiosensitizing effects of tyrosine kinase inhibitor before and after irradiation were observed. The cell-survival rates were evaluated by colony-forming assays. The cell apoptosis was investigated using FCM. The expressions of phospho-EGFR and PTEN were determined by Western blot analysis.

Results
The results showed that the PTEN expressions were significantly enhanced by X-rays. Moreover, the cell growth curve and survival curve were down-regulated in the gefitinib-treated groups after irradiation. Meanwhile, the radiation-induced apoptosis of tumor cells was increased by inhibition of the EGFR through up-regulation of PTEN.

Conclusion
These results suggested that PTEN gene is an important regulator on TKI inhibition, and the resistance to tyrosine kinase inhibitors might be reversed by irradiation in PTEN low expression cancer cells.
Nucleosome deposition and DNA methylation at coding region boundaries
Authors: Choi Jung Kyoon , Bae Jae-Bum , Lyu Jaemyun , Kim Tae-Yoon , Kim Young-Joon 
Published: September 2009

Abstract
Background
Nucleosome deposition downstream of transcription initiation and DNA methylation in the gene body suggest that control of transcription elongation is a key aspect of epigenetic regulation.

Results
Here we report a genome-wide observation of distinct peaks of nucleosomes and methylation at both ends of a protein coding unit. Elongating polymerases tend to pause near both coding ends immediately upstream of the epigenetic peaks, causing a significant reduction in elongation efficiency. Conserved features in underlying protein coding sequences seem to dictate their evolutionary conservation across multiple species. The nucleosomal and methylation marks are commonly associated with high sequence-encoded DNA-bending propensity but differentially with CpG density. As the gene grows longer, the epigenetic codes seem to be shifted from variable inner sequences toward boundary regions, rendering the peaks more prominent in higher organisms.

Conclusions
Recent studies suggest that epigenetic inhibition of transcription elongation facilitates the inclusion of constitutive exons during RNA splicing. The epigenetic marks we identified here seem to secure the first and last coding exons from exon skipping as they are indispensable for accurate translation.
Jo Handelsman
Authors: Mays Hoopes Laura L. 
Published: September 2009

Note from the Editor Educator Highlights for CBE-LSE show how professors at different kinds of institutions educate students in life sciences with inspiration and panache. If you have a particularly creative teaching portfolio yourself, or if you wish to nominate an inspiring colleague to be profiled, please e-mail Laura Hoopes at lhoopes@pomona.edu.
Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer
Authors: Hansen Nora M. , Grube Baiba , Ye Xing , Turner Roderick R. , Brenner R. James , Sim Myung-Shin , Giuliano Armando E. 
Published: September 2009

Purpose Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria. Patients and Methods Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i–), no evidence of tumor (n = 486); pN0(i+), tumor deposit ≤ 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but ≤ 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups. Results At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS. Conclusion Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.
Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Authors: Friedman Henry S. , Prados Michael D. , Wen Patrick Y. , Mikkelsen Tom , Schiff David , Abrey Lauren E. , Yung W.K. Alfred , Paleologos Nina , Nicholas Martin K. , Jensen Randy , Vredenburgh James , Huang Jane , Zheng Maoxia , Cloughesy Timothy 
Published: September 2009

Purpose We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. Patients and Methods One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. Results In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Conclusion Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.