tbuckley/cabot-search huggingface dataset:
Differentiation Therapy: Targeting Human Renal Cancer Stem Cells with Interleukin 15
Authors: Sandy Azzi, Stefania Bruno, Julien Giron-Michel, Denis Clay, Aurore Devocelle, Michela Croce, Silvano Ferrini, Salem Chouaib, Aimé Vazquez, Bernard Charpentier, Giovanni Camussi, Bruno Azzarone, Pierre Eid
Journal: JNCI Journal of the National Cancer Institute (2011)

Many renal cancer patients experience disease recurrence after immunotherapy or combined treatments due to persistence of cancer stem cells (CSCs). The identification of reliable inducers of CSC differentiation may facilitate the development of efficient strategies for eliminating CSCs. We investigated whether interleukin 15 (IL-15), a regulator of kidney homeostasis, induces the differentiation of CD105-positive (CD105+) CSCs from human renal cancers. CD105+ CSCs were cultured to preserve their stem cell properties and treated with recombinant human IL-15 (rhIL-15) to evaluate their ability to differentiate, to acquire sensitivity to chemotherapeutic drugs, and to form spheroids in vitro and tumors in vivo. Expression of stem cell and epithelial markers were studied by flow cytometry, immunocytochemistry, and immunoblotting. Identification of a CSC side population fraction and its sensitivity to chemotherapy drugs and expression of ATP-binding cassette (ABC) transporters and aldehyde dehydrogenase (ALDH) activities were determined by flow cytometry. Spheroid formation was determined in limiting dilution assay. Xenograft tumors were generated in severe combined immunodeficient mice (n = 12–18 mice per group). All statistical tests were two-sided. CD105+ CSCs treated with rhIL-15 at 10 pg/mL differentiated into cells expressing epithelial markers. rhIL-15 induced epithelial differentiation of all CD105+ CSCs subsets and blocked CSC self-renewal (sphere-forming ability) and their tumorigenic properties in severe combined immunodeficient mice. Vinblastine and paclitaxel induced statistically significant higher levels of apoptosis in rhIL-15-differentiated epithelial cells compared with CD105+ CSCs (mean percentage of apoptotic cells, vinblastine: 33% vs 16.5%, difference = 16.5%, 95% confidence interval = 12.25% to 20.74%, P = .0025; paclitaxel: 35% vs 11.6%, difference = 23.4%, 95% confidence interval = 22.5% to 24.24%, P = .0015). The higher sensitivity of rhIL-15-differentiated epithelial cells to chemotherapeutic drugs was associated with loss of detoxifying mechanisms such as ALDH and ABC transporter activities. IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.
p53 Modulates RPA-Dependent and RPA-Independent WRN Helicase Activity
Authors: Joshua A. Sommers, Sudha Sharma, Kevin M. Doherty, Parimal Karmakar, Qin Yang, Mark K. Kenny, Curtis C. Harris, Robert M. Brosh
Journal: Cancer Research (2005)

Werner syndrome is a hereditary disorder characterized by the early onset of age-related symptoms, including cancer. The absence of a p53-WRN helicase interaction may disrupt the signal to direct S-phase cells into apoptosis for programmed cell death and contribute to the pronounced genomic instability and cancer predisposition in Werner syndrome cells. Results from coimmunoprecipitation studies indicate that WRN is associated with replication protein A (RPA) and p53 in vivo before and after treatment with the replication inhibitor hydroxyurea or gamma-irradiation that introduces DNA strand breaks. Analysis of the protein interactions among purified recombinant WRN, RPA, and p53 proteins indicate that all three protein pairs bind with similar affinity in the low nanomolar range. In vitro studies show that p53 inhibits RPA-stimulated WRN helicase activity on an 849-bp M13 partial duplex substrate. p53 also inhibited WRN unwinding of a short (19-bp) forked duplex substrate in the absence of RPA. WRN unwinding of the forked duplex substrate was specific, because helicase inhibition mediated by p53 was retained in the presence of excess competitor DNA and was significantly reduced or absent in helicase reactions catalyzed by a WRN helicase domain fragment lacking the p53 binding site or the human RECQ1 DNA helicase, respectively. p53 effectively inhibited WRN helicase activity on model DNA substrate intermediates of replication/repair, a 5' ssDNA flap structure and a synthetic replication fork. Regulation of WRN helicase activity by p53 is likely to play an important role in genomic integrity surveillance, a vital function in the prevention of tumor progression.
B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis
Authors: Stephen L. Hauser, Emmanuelle Waubant, Douglas L. Arnold, Timothy Vollmer, Jack Antel, Robert J. Fox, Amit Bar-Or, Michael Panzara, Neena Sarkar, Sunil Agarwal, Annette Langer-Gould, Craig H. Smith
Journal: New England Journal of Medicine (2008)

There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].).
Efficacy of allogeneic mesenchymal stem cell transplantation in patients with drug-resistant polymyositis and dermatomyositis
Authors: D. Wang, H. Zhang, M. Cao, Y. Tang, J. Liang, X. Feng, H. Wang, B. Hua, B. Liu, L. Sun
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To assess the safety and clinical efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in a small-scale pilot study with 10 patients with drug-resistant polymyositis (PM) or dermatomyositis (DM). <h3>Methods</h3> A single-arm trial involving 10 patients with DM/PM who were either refractory to standard treatment, or had severe systemic involvement. All patients consented and underwent allogeneic MSCT. Clinical and laboratory manifestations were compared before and after MSCT. <h3>Results</h3> Improvements were seen in serum creatine kinase (CK), CK-MB, patient global assessment by visual analogue scale and muscle strength by manual muscle test in all patients, as well as improvement in interstitial lung disease in selected patients. Improvement in chronic non-healing skin ulcers was noted in one patient. Clinical responses were also seen in patients undergoing a second MSCT for recurrence of disease. <h3>Conclusion</h3> MSCT appears safe and effective in drug-resistant patients with DM/PM. Larger-scale studies including a control group receiving standard treatment are needed to assess the long-term efficacy of allogeneic MSCT in refractory patients with DM/PM.
bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.
Authors: D A Grillot, R Merino, J C Pena, W C Fanslow, F D Finkelman, C B Thompson, G Nunez
Journal: The Journal of Experimental Medicine (1996)

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.
Regional Pulmonary Perfusion, Inflation, and Ventilation Defects in Bronchoconstricted Patients with Asthma
Authors: R. Scott Harris, Tilo Winkler, Nora Tgavalekos, Guido Musch, Marcos F. Vidal Melo, Tobias Schroeder, Yuchiao Chang, José G. Venegas
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Bronchoconstriction in asthma leads to heterogeneous ventilation and the formation of large and contiguous ventilation defects in the lungs. However, the regional adaptations of pulmonary perfusion (Q) to such ventilation defects have not been well studied.We used positron emission tomography to assess the intrapulmonary kinetics of intravenously infused tracer nitrogen-13 ((13)NN), and measured the regional distributions of ventilation and perfusion in 11 patients with mild asthma. For each subject, the regional washout kinetics of (13)NN before and during methacholine-induced bronchoconstriction were analyzed. Two regions of interest (ROIs) were defined: one over a spatially contiguous area of high tracer retention (TR) during bronchoconstriction and a second one covering an area of similar size, showing minimal tracer retention (NR).Both ROIs demonstrated heterogeneous washout kinetics, which could be described by a two-compartment model with fast and slow washout rates. We found a systematic reduction in regional Q to the TR ROI during bronchoconstriction and a variable and nonsignificant change in relative Q for NR regions. The reduction in regional Q was associated with an increase in regional gas content of the TR ROI, but its magnitude was greater than that anticipated solely by the change in regional lung inflation.During methacholine-induced bronchoconstriction, perfusion to ventilation defects are systematically reduced by a relative increase in regional pulmonary vascular resistance.
Reduced White Matter Integrity in Sibling Pairs Discordant for Bipolar Disorder
Authors: Emma Sprooten, Margaret S. Brumbaugh, Emma E.M. Knowles, D. Reese McKay, John Lewis, Jennifer Barrett, Stefanie Landau, Lindsay Cyr, Peter Kochunov, Anderson M. Winkler, Godfrey D. Pearlson, David C. Glahn
Journal: American Journal of Psychiatry (2013)

Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects.The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality.Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest.These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.
NK Cells and Trophoblasts
Authors: Peter Parham
Journal: The Journal of Experimental Medicine (2004)

In placental mammals, viviparity—the production of living young within the mother's body—evolved under the auspices of the immune system. Elements of immunity were incorporated, giving pregnancy a mildly inflammatory character. Formation of the placenta, the organ that feeds the fetus, involves a cooperation between maternal natural killer (NK) cells and fetal trophoblast cells that remodels the blood supply. Recent research reveals that this process and human reproductive success are influenced by polymorphic HLA-C ligands and their killer cell immunoglobulin-like receptors (KIR).
Molecular Imaging and Biological Evaluation of HuMV833 Anti-VEGF Antibody: Implications for Trial Design of Antiangiogenic Antibodies
Authors: G. C. Jayson, J. Zweit, A. Jackson, C. Mulatero, P. Julyan, M. Ranson, L. Broughton, J. Wagstaff, L. Hakannson, G. Groenewegen, J. Bailey, N. Smith, D. Hastings, J. Lawrance, H. Haroon, T. Ward, A. T. McGown, M. Tang, D. Levitt, S. Marreaud, F. F. Lehmann, M. Herold, H. Zwierzina
Journal: JNCI Journal of the National Cancer Institute (2002)

Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial.Twenty patients with progressive solid tumors were treated with various doses of HuMV833 (0.3, 1, 3, or 10 mg/kg). Positron emission tomography with (124)I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (k(fp)) to determine tumor vascular permeability.The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic endpoints could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumors. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in k(fp) 48 hours after the first treatment (median = 44%; range = 4%-91%).Because of the heterogeneity in tumor biology with respect to antibody uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with antiangiogenic compounds like HuMV833.
Stem Cell–based Therapy for Prevention of Delayed Fracture Union: A Randomized and Prospective Preliminary Study
Authors: Meir Liebergall, Josh Schroeder, Rami Mosheiff, Zulma Gazit, Zilberman Yoram, Linda Rasooly, Anat Daskal, Amal Khoury, Yoram Weil, Shaul Beyth
Journal: Molecular Therapy (2013)

Distal tibial fractures tend towards delayed- or nonunion. The purpose of this study was to evaluate the safety and efficacy of early minimally invasive intervention (MII) in the treatment of these fractures. A total 24 consecutive patients who underwent operative treatment for distal tibial fractures were randomized into a control and an intervention group. MII entailed aspirating iliac crest bone marrow and peripheral blood, yielding mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) respectively, that were mixed with demineralized bone matrix (DBM) and injected under fluoroscopic control into the fracture site. No complications occurred in either group. The median time to union was 1.5 months in the MII group and 3 months in the control group. MII was found to be a safe and efficient procedure. Distal tibial fractures tend towards delayed- or nonunion. The purpose of this study was to evaluate the safety and efficacy of early minimally invasive intervention (MII) in the treatment of these fractures. A total 24 consecutive patients who underwent operative treatment for distal tibial fractures were randomized into a control and an intervention group. MII entailed aspirating iliac crest bone marrow and peripheral blood, yielding mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) respectively, that were mixed with demineralized bone matrix (DBM) and injected under fluoroscopic control into the fracture site. No complications occurred in either group. The median time to union was 1.5 months in the MII group and 3 months in the control group. MII was found to be a safe and efficient procedure.
Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels
Authors: A. Prat, M. Parera, B. Adamo, S. Peralta, M.A. Perez-Benavente, A. Garcia, A. Gil-Moreno, J.M. Martinez-Palones, J. Baselga, J.M. del Campo
Journal: Annals of Oncology (2008)
Computational Molecular Modeling for Evaluating the Toxicity of Environmental Chemicals: Prioritizing Bioassay Requirements
Authors: James R. Rabinowitz, Michael-Rock Goldsmith, Stephen B. Little, Melissa A. Pasquinelli
Journal: Environmental Health Perspectives (2008)

The human health risk from exposure to environmental chemicals often must be evaluated when relevant elements of the preferred data are unavailable. Therefore, strategies are needed that can predict this information and prioritize the outstanding data requirements for the risk evaluation. Many modes of molecular toxicity require the chemical or one of its biotransformation products to interact with specific biologic macromolecules (i.e., proteins and DNA). Molecular modeling approaches may be adapted to study the interactions of environmental chemicals with biomolecular targets.In this commentary we provide an overview of the challenges that arise from applying molecular modeling tools developed and commonly used for pharmaceutical discovery to the problem of predicting the potential toxicities of environmental chemicals.The use of molecular modeling tools to predict the unintended health and environmental consequences of environmental chemicals differs strategically from the use of the same tools in the pharmaceutical discovery process in terms of the goals and potential applications. It also requires consideration of the greater diversity of chemical space and binding affinity domains than is covered by pharmaceuticals.Molecular modeling methods offer one of several complementary approaches to evaluate the risk to human health and the environment as a result of exposure to environmental chemicals. These tools can streamline the hazard assessment process by simulating possible modes of action and providing virtual screening tools that can help prioritize bioassay requirements. Tailoring these strategies to the particular challenges presented by environmental chemical interactions make them even more effective.
Kidney Injury Molecule-1 and the Loss of Kidney Function in Diabetic Nephropathy: A Likely Causal Link in Patients With Type 1 Diabetes
Authors: Nicolae M. Panduru, Niina Sandholm, Carol Forsblom, Markku Saraheimo, Emma H. Dahlström, Lena M. Thorn, Daniel Gordin, Nina Tolonen, Johan Wadén, Valma Harjutsalo, Angelika Bierhaus, Per M. Humpert, Per-Henrik Groop
Journal: Diabetes Care (2015)

We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach.We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable.KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship.KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.