tbuckley/cabot-search huggingface dataset:
HIV-1 Vpr Enhances Viral Burden by Facilitating Infection of Tissue Macrophages but Not Nondividing CD4+ T Cells
Authors: Daniel A. Eckstein, Michael P. Sherman, Michael L. Penn, Peggy S. Chin, Carlos M.C. De Noronha, Warner C. Greene, Mark A. Goldsmith
Journal: The Journal of Experimental Medicine (2001)

Prior experiments in explants of human lymphoid tissue have demonstrated that human immunodeficiency virus type 1 (HIV-1) productively infects diverse cellular targets including T cells and tissue macrophages. We sought to determine the specific contribution of macrophages and T cells to the overall viral burden within lymphoid tissue. To block infection of macrophages selectively while preserving infection of T cells, we used viruses deficient for viral protein R (Vpr) that exhibit profound replication defects in nondividing cells in vitro. We inoculated tonsil histocultures with matched pairs of congenic viruses that differed only by the presence of a wild-type or truncated vpr gene. Although these viruses exhibited no reduction in the infection or depletion of T cells, the ability of the Vpr-deficient R5 virus to infect tissue macrophages was severely impaired compared with matched wild-type R5 virus. Interestingly, the Vpr-deficient R5 virus also exhibited a 50% reduction in overall virus replication compared with its wild-type counterpart despite the fact that macrophages represent a small fraction of the potential targets of HIV-1 infection in these tissues. Collectively, these data highlight the importance of tissue macrophages in local viral burden and further implicate roles for CC chemokine receptor 5, macrophages, and Vpr in the life cycle and pathogenesis of HIV-1.
CD11c <sup>+</sup> Dendritic Cells Maintain Antigen Processing, Presentation Capabilities, and CD4 <sup>+</sup> T-Cell Priming Efficacy Under Hypercholesterolemic Conditions Associated With Atherosclerosis
Authors: René R.S. Packard, Elena Maganto-García, Israel Gotsman, Ira Tabas, Peter Libby, Andrew H. Lichtman
Journal: Circulation Research (2008)

Recent reports suggest dyslipidemia impairs dendritic cell (DC) function and adaptive immunity. This study aimed to characterize the effect of hypercholesterolemia on antigen-presenting cell function of DCs and DC-dependent CD4 + T-cell responses. DCs incubated in vitro with acetylated low-density lipoprotein cholesterol with or without an acyl-coenzyme A:cholesterol acyl-transferase inhibitor maintained their ability to prime CD4 + T cells. Analysis of T-cell proliferation and interferon-γ and tumor necrosis factor-α production after ex vivo coculture of naïve CD4 + T cells with splenic, inguinal, or iliac DCs from low-density lipoprotein receptor–deficient ( LDLR −/− ) or apolipoprotein E–deficient ( ApoE −/− ) mice fed an atherogenic diet highlighted DC efficacy in effector T-cell generation under hypercholesterolemic conditions. Adoptive transfer of carboxyfluorescein diacetate, succinimidyl ester (CFSE)-labeled naïve CD4 + T cells in LDLR −/− recipients and subsequent immunization demonstrated effective priming of naïve T cells in hypercholesterolemic mice. CFSE dilution analyses revealed that hypercholesterolemic DCs were equipotent in naïve CD4 + T-cell priming efficacy with normocholesterolemic DCs. Quantitative real-time PCR and flow cytometric analyses demonstrated that DC expression of multiple molecules involved in antigen processing, presentation, and T-cell stimulation remained unaltered by dyslipidemia. Finally, endogenous antigen-primed CD4 + T cells responded equivalently to a secondary ex vivo antigenic challenge, regardless of whether they were primed in vivo under hypercholesterolemic or control conditions, demonstrating that all essential steps in CD4 + T-cell responses remain intact under atherogenic conditions. This study affirms that the adaptive immune response prevails under the hypercholesterolemic conditions present in atherosclerosis. In particular, DCs remain functional antigen-presenting cells and maintain their ability to prime CD4 + T cells even when cholesterol-loaded.
Documenting the Natural History of Patients With Resected Stage II Adenocarcinoma of the Colon After Random Assignment to Adjuvant Treatment With Edrecolomab or Observation: Results From CALGB 9581
Authors: Donna Niedzwiecki, Monica M. Bertagnolli, Robert S. Warren, Carolyn C. Compton, Nancy E. Kemeny, Al Bowen Benson, S. Gail Eckhardt, Steven Alberts, Gity N. Porjosh, David J. Kerr, Anthony Fields, Philippe Rougier, J. Marc Pipas, Joel H. Schwartz, James Atkins, Mark O'Rourke, Michael C. Perry, Richard M. Goldberg, Robert J. Mayer, Thomas A. Colacchio
Journal: Journal of Clinical Oncology (2011)

We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient- and tumor-specific markers of treatment outcome.After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy.Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer.Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.
Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning
Authors: Frédéric Baron, Michael B. Maris, Brenda M. Sandmaier, Barry E. Storer, Mohamed Sorror, Razvan Diaconescu, Ann E. Woolfrey, Thomas R. Chauncey, Mary E.D. Flowers, Marco Mielcarek, David G. Maloney, Rainer Storb
Journal: Journal of Clinical Oncology (2005)

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy.We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130).Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003).New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.
Inferring protein domain interactions from databases of interacting proteins
Authors: Robert Riley, Christopher Lee, Chiara Sabatti, David Eisenberg
Journal: Genome biology (2005)

Abstract We describe domain pair exclusion analysis (DPEA), a method for inferring domain interactions from databases of interacting proteins. DPEA features a log odds score, E ij , reflecting confidence that domains i and j interact. We analyzed 177,233 potential domain interactions underlying 26,032 protein interactions. In total, 3,005 high-confidence domain interactions were inferred, and were evaluated using known domain interactions in the Protein Data Bank. DPEA may prove useful in guiding experiment-based discovery of previously unrecognized domain interactions.
Comparison of <i>Tripterygium wilfordii</i> Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial
Authors: Qian-wen Lv, Wen Zhang, Qun Shi, Wen-jie Zheng, Xin Li, Hua Chen, Qing-jun Wu, Wan-lan Jiang, Hong-bin Li, Lu Gong, Wei Wei, Hui Liu, Ai-jing Liu, Hong-tao Jin, Jun-xiang Wang, Xiu-mei Liu, Zhen-bin Li, Bin Liu, Min Shen, Qian Wang, Xiang-ni Wu, Di Liang, Yu-feng Yin, Yun-yun Fei, Jing-mei Su, Li-dan Zhao, Ying Jiang, Jing Li, Fu-lin Tang, Feng-chun Zhang, Peter E Lipsky, Xuan Zhang
Journal: Annals of the Rheumatic Diseases (2014)

To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA).Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen.207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24.174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216).TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA.NCT01613079.
Independent Clonal Origins of Distinct Tumor Foci in Multifocal Papillary Thyroid Carcinoma
Authors: Trisha M. Shattuck, William H. Westra, Paul W. Ladenson, Andrew Arnold
Journal: New England Journal of Medicine (2005)

Papillary thyroid carcinoma is frequently multifocal. We investigated whether noncontiguous tumor foci arise from intraglandular metastases from a single primary tumor or originate as unrelated clones derived from independent precursors.Using a polymerase-chain-reaction assay involving the human androgen receptor gene (HUMARA), we analyzed the patterns of X-chromosome inactivation of multiple distinct foci of well-differentiated multifocal papillary thyroid cancer from 17 women.Multiple thyroid tumor foci from 10 of 17 patients yielded DNA of adequate quality and were heterozygous for the HUMARA polymorphism and hence suitable for analysis. A single X chromosome was inactivated in each focus, consistent with its monoclonality. When the specific monoclonal configurations of each patient's discrete tumor foci were compared, discordant patterns indicative of independent origins were observed among the tumors from five patients; results in the remaining five were consistent with either a shared or independent clonal origin.Individual tumor foci in patients with multifocal papillary thyroid cancer often arise as independent tumors.
The role of cell-substrate interaction in regulating osteoclast activation: potential implications in targeting bone loss in rheumatoid arthritis
Authors: K P McHugh, Z Shen, T N Crotti, M R Flannery, R P O'Sullivan, P E Purdue, S R Goldring
Journal: Annals of the Rheumatic Diseases (2009)

Analysis of tissues retrieved from the bone–pannus interface from patients with rheumatoid arthritis (RA) and studies in animal models of inflammatory arthritis provide strong evidence that osteoclasts, the cells that are essential for physiological bone resorption, are responsible for articular bone destruction in RA. However, current treatments that specifically target osteoclast-mediated bone resorption in RA have not been successful in preventing bone erosions, and new therapeutic strategies are needed. It has been noted that, although osteoclast precursors are present within the bone microenvironment at sites of pathological bone resorption, cells expressing the full morphological and functional properties of mature osteoclasts are restricted to the immediate bone surface and adjacent calcified cartilage. These findings provide evidence that, in addition to requirements for specific cytokines, interaction of osteoclast precursors with these mineralised matrices results in activation of specific signal pathways and the induction of unique gene products that are essential for terminal osteoclast differentiation and activation. These studies are designed to define the gene products and signalling pathways regulated by bone and calcified cartilage, to identify new molecular targets and novel therapeutic approaches for preventing osteoclast-mediated joint destruction in RA and related forms of pathological bone loss.
Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis.
Authors: E Engelmyer, H van Goor, D R Edwards, J R Diamond
Journal: Journal of the American Society of Nephrology (1995)

The pathophysiologic sequelae of both acute and chronic experimental unilateral ureteral obstruction (UUO) in the rat are the result of a variety of complex humoral and cellular interactions. The development of interstitial fibrosis is dependent on the tightly coupled regulation of synthesis and degradation of extracellular matrix proteins. This laboratory, among others, has shown an up-regulated expression of renal cortical transforming growth factor (TGF)-beta 1 within hours of the onset of UUO. Because a potential contribution of TGF-beta to fibrosis may be its ability to increase the expression of proteinase inhibitors such as members of the tissue inhibitor of metalloproteinase (TIMP) family, this laboratory now sought to delineate the kinetics of TIMP-1, TIMP-2, and TIMP-3 mRNA expression in the renal cortex after UUO. There was a marked elevation of TIMP-1 mRNA expression after UUO, which was first noted at 12 h after ureteral ligation. By 96 h after UUO; there was a 30-fold increment in TIMP-1 mRNA in the obstructed kidneys compared with the contralateral unobstructed kidney or sham-operated rat specimens. In contradistinction to TIMP-1, a decrease in TIMP-3 mRNA levels was noted at 12 h after ureteral obstruction and persisted at the 24-, 48-, and 96-h time intervals. TIMP-2 gene expression remained at a relatively constant level during the entire study. It is proposed that the increased expression of TGF-beta 1 post-UUO induces a profibrogenic state and initiates a cascade of dysregulatory events including the up-regulation of TIMP-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Spontaneous loss of heterozygosity leading to homozygous R132H in a patient-derived IDH1 mutant cell line
Authors: H. A. Luchman, C. Chesnelong, J. G. Cairncross, S. Weiss
Journal: Neuro-Oncology (2013)

Spontaneous loss of heterozygosity leading to homozygous R132H in a patient-derived IDH1 mutant cell line Dear Editor,We report a novel follow-up observation pertaining to "An in vivo patient-derived model of endogenous IDH1-mutant glioma," which was recently published in Neuro-Oncology. 1 Since publication, we have observed the gradual and repeated loss of the wild-type IDH1 allele in vitro with retention of the mutant allele.Sequencing of IDH1 exon 4 from 3 independent late passage cultures showed homozygosity for the R132H allele (mut/-), whereas both mutant and wild-type alleles were present in the original line (mut/wt) and tumor (Fig. 1A).In addition, a decreased copy number was seen at the IDH locus, consistent with loss of the IDH1 wild-type allele (Fig. 1B).The American Type Culture Collection (ATCC) has independently observed this phenomenon in BT142.The ATCC is preparing to distribute the BT142 mut/-, 2 while we test conditions that best preserve the heterozygous phenotype.The loss of the wild-type allele has been reported in vivo in patients and has been shown to be similar to phenotypically wild-type IDH, resulting in decreased 2-hydroxyglutarate production, 3,4 also observed in the BT142 mut/-line.This unforeseen change leading to a second cell line will be valuable for comparisons of the implications of mutant and wild-type IDH phenotypes on proliferation, tumorigenicity, and therapeutic resistance in a syngeneic setting. MethodsSequencing for IDH1 was performed as previously described. 1The TaqMan Copy Number Assay (Applied Biosystems) was used to assess copy-number variations.Briefly, genomic DNA was extracted using the DNeasy kit (Qiagen) and quantified using UV absorbance (A260/ A280 ratio .1.7).The genomic DNA samples were diluted to 5 ng/mL in nuclease-free water; 20 ng of genomic DNA was mixed with the IDH1 TaqMan Copy Number Assay and the RNase P Reference Assay in a PCR plate, and quantitative real-time PCR was performed according to the manufacturer's instructions.The manufacturer's software, Copy Caller, was used for analysis.
Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia
Authors: M. I. Restrepo, E. M. Mortensen, G. W. Waterer, R. G. Wunderink, J. J. Coalson, A. Anzueto
Journal: European Respiratory Journal (2008)

Recent studies suggest that macrolides may have beneficial effects for patients at risk for certain infections. The current authors examined the effect of macrolide therapy on 30- and 90-day mortality for patients with severe sepsis caused by pneumonia. A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had chest radiography consistent with, and had a discharge diagnosis of pneumonia and clinical criteria of severe sepsis. Subjects were considered to be on macrolides if they received at least one dose within 48 h of admission. Severe sepsis was present in 237 (30.1%) subjects, out of whom 104 (43.9%) received macrolides. Mortality was 20.3% at 30 days and 24.5% at 90 days. In the multivariable analysis, the use of macrolide was associated with decreased mortality at 30 days (hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.2-0.7) and at 90 days (HR 0.3, 95% CI 0.2-0.6) in patients with severe sepsis and in patients with macrolide-resistant pathogens (HR 0.1, 95% CI 0.02-0.5). Macrolide use was associated with decreased mortality in patients with severe sepsis due to pneumonia and macrolide-resistant pathogens. Confirmatory studies are needed to determine whether macrolide therapy may be protective for patients with sepsis.
Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents
Authors: David R. Holmes, Paul Teirstein, Lowell Satler, Michael Sketch, James O’Malley, Jeffery J. Popma, Richard E. Kuntz, Peter J. Fitzgerald, Hong Wang, Eileen Caramanica, Sidney A. Cohen, for the SISR Investigators
Journal: JAMA (2006)

Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited.To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent.Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005.Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259).Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure.Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55] mm vs 17.22 [7.97] mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63] mm vs 1.80 [0.63] mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60] vs 1.0 [0.61] mm; P<.001) due to stenting and no edge restenosis.Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent.ClinicalTrials.gov Identifier: NCT00231257.