The Role of Para-Aortic Lymphadenectomy in the Surgical Staging of Women with Intermediate and High-Risk Endometrial Adenocarcinomas

Objectives:. To characterize clinical outcomes in patients with intermediate or high-risk endometrial carcinoma who underwent surgical staging with or without para-aortic lymphadenectomy. Methods:. This is a retrospective cohort study of patients with intermediate or high-risk endometrial adenocarcinoma who underwent surgical staging with (PPALN group) or without (PLN) para-aortic lymphadenectomy. Data were collected, Kaplan-Meier curves were generated, and univariate and multivariate analyses performed to compare differences in adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS). Results. 118 patients were included in the PPALN group and 139 in the PLN group. Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5, P = 0.03) and less likely to receive adjuvant multimodal combination therapy (17.81% versus 28.8%, OR = 0.28, P = 0.002). DFS was improved in the PLN group as compared to PPALN (80% versus 62%, P = 0.02). OS was equivalent (P = 0.93). Patients in the PPALN group who had less than 10 para-aortic nodes removed were twice as likely to recur than patients who had 10 or more para-aortic nodes or patients in the PLN group (HR 2.08, CI 1.20–3.60, P = 0.009). Conclusions:. Patients in the PLN group were more likely to receive multimodal adjuvant therapy and had better DFS than the PPALN group. Pelvic lymphadenectomy followed by adjuvant radiation and chemotherapy may represent an effective treatment option for patients with intermediate or high-risk disease. If systematic para-aortic lymphadenectomy is performed and less than 10 para-aortic lymph nodes are obtained, multimodality adjuvant therapy should be considered to improve DFS

Attitudes and perceptions about ecological resources and hazards of people living around the Savannah River Site

Although considerable attention is devoted to environmental monitoring and assessment with respect to both pollutants and the status of particular plant or animal populations, less attention is devoted to assessing people\u27s attitudes about the relative importance of ecological resources. In this paper we examine the attitudes and perceptions about ecological resources of people living around the Department of Energy\u27s Savannah River Site (SRS), in South Carolina. Our overall hypothesis is that people who are directly affected by the possible outcomes and consequences of a particular hazard (i.e., those people employed at SRS) will undervalue the risks and overvalue the potential benefits from future land uses that favour continued site activity, compared to people who live near but are not employed at SRS. We interviewed 286 people attending the Aiken Trials horse show on 14 March 1997. There were few gender differences, although men hunted and fished more than women, women ranked three environmental concerns as more severe than did men, and women were more concerned about the effect of SRS on property values. Maintenance of SRS as a National Environmental Research Park ranked first as a future land use; nuclear production ranked second, followed by hunting and hiking. Only residential development ranked very low as a future land use. There were many differences as a function of employment history at SRS: (1) people who work at SRS think that the federal government should spend funds to clean up all nuclear facilities, and they think less money should be spent on other environmental problems than did non-employees, (2) people who work at SRS ranked continued current uses of SRS higher than did people who never worked at SRS, and (3) people who work at SRS are less concerned about the storage of nuclear material or accidents at the site than are people who never worked at the site

Attitudes and perceptions about ecological resources and hazards of people living around the Savannah River Site

Although considerable attention is devoted to environmental monitoring and assessment with respect to both pollutants and the status of particular plant or animal populations, less attention is devoted to assessing people\u27s attitudes about the relative importance of ecological resources. In this paper we examine the attitudes and perceptions about ecological resources of people living around the Department of Energy\u27s Savannah River Site (SRS), in South Carolina. Our overall hypothesis is that people who are directly affected by the possible outcomes and consequences of a particular hazard (i.e., those people employed at SRS) will undervalue the risks and overvalue the potential benefits from future land uses that favour continued site activity, compared to people who live near but are not employed at SRS. We interviewed 286 people attending the Aiken Trials horse show on 14 March 1997. There were few gender differences, although men hunted and fished more than women, women ranked three environmental concerns as more severe than did men, and women were more concerned about the effect of SRS on property values. Maintenance of SRS as a National Environmental Research Park ranked first as a future land use; nuclear production ranked second, followed by hunting and hiking. Only residential development ranked very low as a future land use. There were many differences as a function of employment history at SRS: (1) people who work at SRS think that the federal government should spend funds to clean up all nuclear facilities, and they think less money should be spent on other environmental problems than did non-employees, (2) people who work at SRS ranked continued current uses of SRS higher than did people who never worked at SRS, and (3) people who work at SRS are less concerned about the storage of nuclear material or accidents at the site than are people who never worked at the site

Gene Expression Changes Reflect Clinical Response in a Placebo-Controlled Randomized Trial of Abatacept in Patients with Diffuse Cutaneous Systemic Sclerosis

Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic

Stress Granules and RNA Processing Bodies are Novel Autoantibody Targets in Systemic Sclerosis

Autoantibody profiles represent important patient stratification markers in systemic sclerosis (SSc). Here, we performed serum-immunoprecipitations with patient antibodies followed by mass spectrometry (LC-MS/MS) to obtain an unbiased view of all possible autoantibody targets and their associated molecular complexes recognized by SSc

The protein that binds the 3' end of histone mRNA: a novel RNA-binding protein required for histone pre-mRNA processing.

Replication-dependent histone mRNAs are not polyadenylated but end in a conserved 26-nucleotide structure that contains a stem-loop. Much of the cell cycle regulation of histone mRNA is post-transcriptional and is mediated by the 3' end of histone mRNA. The stem-loop binding protein (SLBP) that binds the 3' end of histone mRNA is a candidate for the factor that participates in most, if not all, of the post-transcriptional regulatory events. We have cloned the cDNA for the SLBP from humans, mice, and frogs, using the recently developed yeast three-hybrid system. The human SLBP is a 31-kD protein and contains a novel RNA-binding domain, which has been mapped to a 73-amino-acid region of the protein. The cloned SLBP is the protein bound to the 3' end of histone mRNA as antibodies specific for the SLBP remove all specific binding activity from nuclear and polyribosomal extracts. These depleted extracts do not cleave histone pre-mRNA efficiently, demonstrating that the SLBP is required for efficient histone pre-mRNA processing

Characterization of the Histone H1-binding Protein, NASP, as a Cell Cycle-regulated Somatic Protein

Nuclear autoantigenic sperm protein (NASP), initially described as a highly autoimmunogenic testis and sperm-specific protein, is a histone-binding protein that is a homologue of the N1/N2 gene expressed in oocytes of Xenopus laevis. Here, we report a somatic form of NASP (sNASP) present in all mitotic cells examined, including mouse embryonic cells and several mouse and human tissue culture cell lines. Affinity chromatography and histone isolation demonstrate that NASP from myeloma cells is complexed only with H1, linker histones. Somatic NASP is a shorter version of testicular NASP (tNASP) with two deletions in the coding region arising from alternative splicing and differs from tNASP in its 5' untranslated regions. We examined the relationship between NASP mRNA expression and the cell cycle and report that in cultures of synchronized mouse 3T3 cells and HeLa cells sNASP mRNA levels increase during S-phase and decline in G(2), concomitant with histone mRNA levels. NASP protein levels remain stable in these cells but become undetectable in confluent cultures of nondividing CV-1 cells and in nonmitotic cells in various body tissues. Expression of sNASP mRNA is regulated during the cell cycle and, consistent with a role as a histone transport protein, NASP mRNA expression parallels histone mRNA expression

A multiprotein occupancy map of the mRNP on the 3′ end of histone mRNAs

The animal replication-dependent (RD) histone mRNAs are coordinately regulated with chromosome replication. The RD-histone mRNAs are the only known cellular mRNAs that are not polyadenylated. Instead, the mature transcripts end in a conserved stem–loop (SL) structure. This SL structure interacts with the stem–loop binding protein (SLBP), which is involved in all aspects of RD-histone mRNA metabolism. We used several genomic methods, including high-throughput sequencing of cross-linked immunoprecipitate (HITS-CLIP) to analyze the RNA-binding landscape of SLBP. SLBP was not bound to any RNAs other than histone mRNAs. We performed bioinformatic analyses of the HITS-CLIP data that included (i) clustering genes by sequencing read coverage using CVCA, (ii) mapping the bound RNA fragment termini, and (iii) mapping cross-linking induced mutation sites (CIMS) using CLIP-PyL software. These analyses allowed us to identify specific sites of molecular contact between SLBP and its RD-histone mRNA ligands. We performed in vitro crosslinking assays to refine the CIMS mapping and found that uracils one and three in the loop of the histone mRNA SL preferentially crosslink to SLBP, whereas uracil two in the loop preferentially crosslinks to a separate component, likely the 3′hExo. We also performed a secondary analysis of an iCLIP data set to map UPF1 occupancy across the RD-histone mRNAs and found that UPF1 is bound adjacent to the SLBP-binding site. Multiple proteins likely bind the 3′ end of RD-histone mRNAs together with SLBP

Fresolimumab Treatment Decreases Biomarkers and Improves Clinical Symptoms in Systemic Sclerosis Patients

BACKGROUND. TGF-β has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-β–regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-β may benefit these patients. METHODS. Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-β isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-β–regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS. In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P \u3c 0.001 at all time points). Expression levels of other TGF-β–regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P \u3c 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION. The rapid inhibition of TGF-β–regulated gene expression in response to fresolimumab strongly implicates TGF-β in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis