tbuckley/cabot-search huggingface dataset:
502. Biomaterial-Mediated Lentiviral Delivery of Anti-Inflammatory Genes in Cartilage-Derived Matrix Hemispheres
Authors: Katherine A. Glass, Christopher R. Rowland, Adarsh R. Ettyreddy, Jonathan M. Brunger, Nguyen P.T. Huynh, Charles A. Gersbach, Farshid Guilak
Journal: Molecular Therapy (2016)

Objectives: Cartilage tissue engineering seeks to provide a functional replacement for damaged or degenerated articular surfaces that develop in osteoarthritis (OA). Human bone marrow-derived mesenchymal stem cells (MSCs) seeded within cartilage-derived matrix (CDM) hemispherical scaffolds exhibit robust chondrogenic differentiation and extracellular matrix (ECM) deposition without evidence of a hypertrophic phenotype. However, inflammation within an OA joint may inhibit chondrogenesis of MSCs and induce degradation of both native and engineered cartilage, particularly through the action of interleukin-1 (IL-1). The goal of this study was to develop an anatomically-shaped, tissue-engineered cartilage capable of tunable and inducible expression of IL-1 receptor antagonist (IL-1Ra) in MSCs via biomaterial-mediated lentiviral gene delivery. Methods: IL-1Ra or eGFP coding sequences were cloned into doxycycline(dox)-inducible lentiviral vectors. Hemispherical scaffolds were fabricated from resuspended cartilage powder in hemispherical molds (outer radius 4.76 mm, inner radius 3.175 mm). Scaffolds were crosslinked and sterilized via dehydrothermal treatment. Dox-inducible eGFP or IL-1Ra lentivirus was immobilized to PLL-coated CDM scaffolds to transduce MSCs upon seeding. Non-transduced (NT), eGFP-expressing, or IL-1Ra-expressing constructs were treated with 0 or 0.1 ng/mL IL-1 during 28 days of chondrogenesis (+10 ng/mL TGF-ß3) with 1 µg/mL dox. Results: Transduction of MSCs occurred throughout the CDM hemispheres (Fig 1A) and the transduction efficiency of MSCs isolated from the construct was 57±5% eGFP+ by flow cytometry. Hemispherical constructs maintained their anatomical shape throughout chondrogenic culture (Fig 1B). IL-1Ra-expressing constructs produced over 200 ng/mL of IL-1Ra, a concentration expected to inhibit pathologic IL-1 concentrations, and IL-1 treatment did not affect IL-1Ra production (Fig 1C). IL-1 treatment reduced ECM deposition by NT and eGFP-expressing MSCs but not IL-1Ra-expressing MSCs, as evidenced by safranin-O/fast green staining for glycosaminoglycans and total collagen, respectively (Fig 1D). After 28 days of chondrogenesis, IL-1 treatment significantly increased matrix metalloproteinase (MMP) activity in the conditioned media of NT and eGFP-expressing constructs but not in IL-1Ra-expressing constructs (p<0.05) (Fig 1E). Significance: We engineered an anatomically and compositionally mimetic cartilage hemisphere that is inflammation-resistant and shows promise for total articular resurfacing in an arthritic environment. Tunable production of IL-1Ra from an IL-1-resistant cartilage tissue may provide therapeutic effects to other joint tissues, such as the synovium or subchondral bone.
Granulocyte Colony Stimulating Factor Preferentially Causes Proliferation of Pre-Existing Monosomy 7 Cells in Aplastic Anemia and Myelodysplastic Syndrome Because of Abnormal Truncated GCSF-Receptors on These Cells.
Authors: Elaine M. Sloand, Shakti Ramkissoon, Lori Mainwaring, John Barrett, Neal S. Young
Journal: Blood (2004)
Abstract 276: Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate cancer
Authors: Xiao X. Wei, Stephen Chan, Jera Lewis, Serena Kwek, Vinh Dao, Lawrence Fong
Journal: Cancer Research (2015)

Abstract Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) is a bone marrow growth factor that is often used as an adjuvant in cancer vaccine clinical trials and has the potential to enhance antitumor efficacy in combination with immune checkpoint blockade in preclinical studies and clinical trials. The effect of GM-CSF remains controversial, however. In this study, we sought to characterize the systemic and tissue-specific effects of GM-CSF in prostate cancer patients in the preoperative setting. Methods: Patients with localized prostate cancer were treated on an open-label phase I/II study of neoadjuvant GM-CSF prior to planned radical prostatectomy (NCT00305669). Patients received GM-CSF 250mcg/m2 subcutaneously on days 1-14 (cohort 1), days1-21 (cohort 2), or days 1-28 (cohort 3), and underwent radical prostatectomy (RP) within 5 days after the last dose of GM-CSF. Blood collected at baseline, day 14, pre-RP, and 6 weeks post-RP were analyzed for immune cell subsets by flow cytometry. Immune infiltration in RP tissue were evaluated by immunohistochemistry and quantified by digital image analysis with comparison to RP tissue from untreated prostate cancer patients as controls. Results: 18 patients were evaluated with 6 patients at each dose level. Treatment with GM-CSF was associated with an increase in the number of myeloid cells including myeloid dendritic cells. Treatment was also associated with increases in circulating conventional CD4 and CD8 T cells and NK cells. The number of FoxP3+ regulatory CD4+ T cells was also increased, but to a much lower magnitude. At the time of radical prostatectomy, treatment was associated with a recruitment of CD3+ T cells to the tumor rim, and with cohort 3, at the centers of tumor. These T cells were predominantly CD8+ T cells, although conventional CD4+ T cells were also increased. No increase in monocytes or dendritic cells was seen in the tissue. Conclusion: Daily injection of systemic GM-CSF induces an increase in circulating antigen presenting cells as well as T and NK cells. While this treatment does not enhance the frequency of antigen presenting cells in the tumor microenvironment, this treatment recruits effector CD8+ T cells into the tumor rims. Citation Format: Xiao X. Wei, Stephen Chan, Jera Lewis, Serena Kwek, Vinh Dao, Lawrence Fong. Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 276. doi:10.1158/1538-7445.AM2015-276
Concomitant mutations in EGFR, KRAS, and BRAF genes in patients with radically resected non-small cell lung cancer (NSCLC) in Brazil.
Authors: A. C. D. Melo, H. K. P. Inada, F. A. Soares, M. Barros, S. B. S. P. Terra, I. A. Small, C. Sternberg, C. G. M. Ferreira
Journal: Journal of Clinical Oncology (2011)

e21046 Background: Over the last few years a substantial amount of data has clarified the mechanisms of lung cancer tumorigenesis. Different pathways are altered in NSCLC with considerable impact on targeted therapy. EGFR, KRAS, and BRAF pathway play a fundamental role in the carcinogenesis and progression of NSCLC. Furthermore, several drugs targeting those pathways are either available or under development. It is postulated that mutations in those genes are overall mutually exclusive (mutations of only 1 out of 3 genes occur within any individual tumor). Nevertheless, some reports of co-occurring oncogene mutations have emerged. Methods: Paraffin-embedded tumor specimens of 153 radically resected NSCLC patients (pts) from Brazil were retrospectively collected and analyzed for EGFR (exons 18-21), KRAS (exon 2) and BRAF (exons 11 and 15) mutation (mt) status by DNA sequencing. Results: Median pt age was 62.6 years. Concomitant mutations were identified in 4.6% (n=7) of the patients (2 pts harbored EGFR and BRAF mt, 4 pts EGFR and KRAS mt and 1 pt KRAS and BRAF mt). Remarkably 5 out 7 cases with concomitant mutations have squamous histology (SCC). Moreover concomitant mutations occurred in both female (F) and male (M) and current or former smokers. Characteristics are summarized in the table. Conclusions: Concomitant mutations in EGFR, KRAS, and BRAF in early stage patients not exposed previously to chemotherapy or radiotherapy may exist, suggesting their primary relation to carcinogenesis in those patients. The dogma that targetable oncogenic mutant kinases are mutually exclusive should be reviewed, as well as workflow of patient testing, since coincidence of mutations can be found and could correlate with worse prognosis and lower responses to target therapy. Case Gender Histology Smoking status (pack year) Mutations 1 M SCC Former (30) EGFR E19 P733S BRAF E15 H585Y, T589I, Q609STOP 2 M SCC Current (90) EGFR E19 E746-A750del BRAF E11 T470I 3 M SCC Former (200) KRAS E2 T20M BRAF E15 D594N 4 F Adenocarcinoma (ADC) Former (59) EGFR E19 E746-A750del KRAS E2 A18D 5 F SCC Current (7) EGFR E19 W731STOP KRAS E2 G12D 6 F ADC Unknown EGFR E20 C775Y, R776H KRAS E2 G12C 7 F ADC Current (35) EGFR E19 E749K KRAS E2 G12C
PWE-053 Individualised, cost-effective hepatitis C virus treatment – the tailored Taunton algorithm achieves equal sustained virological response with less weeks of combined anti-viral therapy: Abstract PWE-053
Authors: M Naseer, W Matull, A Tarr, P D Thomas, S Pugh
Journal: Gut (2010)

<h3>Introduction</h3> Measurement of rapid viral response (RVR; non-detectable viral load (ND-VL) at 4/52) and early viral response (EVR; ND-VL at 12/52) allow treatment to be individually tailored. Our hepatitis C (HCV) treatment protocol (“standard”=SP) was changed in 2007, from 24/52 for genotype (GT) 2+3, 48/52 for GT1+4 (if EVR) to an “individualised” new protocol (IP): 16/52 for GT2+3 and 24/52 for GT1+4 if RVR; standard length (24 or 48/52) if full EVR; and pro-longed (48 or 72/52) if partial EVR (&gt;2log-VL-reduction at 12/52). <h3>Methods</h3> Retrospective case note analysis of HCV patients treated between 01.01.2006–31.12.2008; n=74. 24 patients were managed according to SP, 50 according to IP. Health professionals, medication (Peg-INF-2α+Ribavirin) and dosages did not change. Primary outcome was sustained virological response (SVR) (ND-VL 6/12 after treatment end). Secondary outcome was “mean length of treatment” and “overall treatment costs”. <h3>Results</h3> The two cohorts (SP/IP) were similar with regards to age (mean;42 years/44 years), sex (M;60%/50%), weight (mean;81 kg/75 kg), GT (2+3;75%/72%) and baseline VL (mean; 1×106/3×106). 80% (59/74) were pre-cirrhotic and treatment-naïve. Dropout-rates were 20% (5/24) for SP, 20% (10/50) for IP. On intention-to-treat (ITT), 50% (12/24) of SP-managed patients achieved SVR, compared with 58% (29/50) with IP (p=0.62). Per-protocol analysis (PPA) revealed 63% (12/19) SVR for SP and 70% (28/40) SVR for IP (p=0.76). The following table shows the average length of treatment and overall costs (drug estimates) according to GT and protocol (Abstract 053). <h3>Conclusion</h3> The individualised treatment protocol was non-inferior to standard in achieving SVR. On average, we saved £10 200 for GT1+4 patients and £3000 for GT2+3. This equates to approximately £162 000 per year (for 30 patients treated). Those savings shall be reinvested (eg, specialist hepatitis nurse provision), which is likely to translate into reduced dropout rates and higher SVR.
The Interaction Between Stromal Cell-Derived Factor 1 Alpha (SDF-1α) and Dickkopf-1 (DKK-1) Mediates Myeloma Bone Disease
Authors: Junling Zhuang, Yi Da, Xuan Wang, Tianjiao Li, Shujie Wang, Yongji Wu, Daobin Zhou, Yongqiang Zhao
Journal: Blood (2012)
Abstract SY11-04: Genetics of immune escape
Authors: Nir Hacohen
Journal: Cancer Research (2015)

Abstract How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity. Citation Format: Nir Hacohen. Genetics of immune escape. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY11-04. doi:10.1158/1538-7445.AM2015-SY11-04
A novel bispecific <scp>DARP</scp>in targeting Fcγ<scp>RIIB</scp> and Fcε<scp>RI</scp>‐bound IgE inhibits allergic responses
Authors: F. Zellweger, P. Gasser, D. Brigger, P. Buschor, M. Vogel, A. Eggel
Journal: Allergy (2016)

Abstract Background Binding of allergen‐specific IgE to its high‐affinity receptor Fcε RI on basophils and mast cells is a central event in the development of allergies. Exposure of these cells to allergens induces the release of soluble mediators causing allergic symptoms. The inhibitory low‐affinity IgG Fc‐receptor Fcγ RIIB is co‐expressed on allergic effector cells and has been implicated in negative regulation of immediate hypersensitivity responses. In order to harvest the inhibitory function of this receptor, we aimed to select specific binders against Fcγ RIIB and to generate a bispecific molecule simultaneously targeting Fcγ RIIB and Fcε RI ‐bound IgE on the surface of allergic effector cells. Methods We selected Fcγ RIIB ‐specific binding molecules from a library of designed ankyrin repeat proteins using ribosome display technology. The bispecific binding modality was generated by molecular cloning and recombinant protein expression. We determined binding characteristics on molecular and cellular levels using SPR , ELISA , and flow cytometry. The inhibitory potential of the newly described molecules was assessed in different cellular degranulation assays ex vivo and in a mouse model of passive systemic anaphylaxis. Results We demonstrate that the selected DARP in ® proteins recognize Fcγ RIIB with high affinity. Furthermore, the bispecific binding protein successfully interferes with allergen‐induced cell degranulation and efficiently inhibits systemic anaphylaxis in vivo . Mechanistically, we report that Fcγ RIIB ‐mediated inhibition of effector cell activation requires direct ligation to an activating Fcε RI receptor. Conclusion The described bispecific DARP in protein has the ability to co‐ligate Fcγ RIIB with Fcε RI ‐bound IgE on allergic effector cells and represents an efficient dual‐modality to interfere with allergic hypersensitivity reactions.
Varieties of Contemplative Practice
Authors: Richard J. Davidson, Cortland J. Dahl
Journal: JAMA Psychiatry (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study
Authors: Roisin M. Connolly, Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeter, Shannon A. Slater, Penny Powers, Antonio C. Wolff, John H. Fetting, Adam Brufsky, Richard Piekarz, Nita Ahuja, Peter W. Laird, Hui Shen, Daniel J. Weisenberger, Leslie Cope, James G. Herman, George Somlo, Agustin A. Garcia, Peter A. Jones, Stephen B. Baylin, Nancy E. Davidson, Cynthia A. Zahnow, Vered Stearns
Journal: Clinical Cancer Research (2016)

Abstract Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1–5, 8–10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%). Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0–19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort. Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691–701. ©2016 AACR.
Abstract 1506: Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell carcinoma
Authors: Patrizia Cammareri, Aidan M. Rose, David F. Vincent, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip Coates, Angela McHugh, Celine Pourreyron, Jonas Larsson, Lindsay C. Spender, Gopal Sapkota, Karin Purdie, Charlotte Proby, Catherine A. Harwood, Irene M. Leigh, Hans Clevers, Nicholas Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Andrew P. South, Owen J. Sansom, Gareth J. Inman
Journal: Cancer Research (2015)

Abstract Solid tumors are typically considered to arise from the accumulation of mutations within either stem or differentiated cells and to evolve over several years. However, melanoma patients treated with inhibitors of oncogenic BRAF frequently present with keratoacanthomas and/or cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, possibly driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent HRAS, TGFβR1 and TGFβR2 mutations in skin lesions from vemurafenib treated patients. Analysis of 98 human sporadic cSCC tumor samples and 21 cSCC cell lines revealed mutation of TGFβ receptors in 42% of samples and activating RAS mutations in 9% of samples. Functional analysis indicates that TGFβ receptor mutations frequently result in loss of canonical signaling. Analysis of normal human skin revealed localised TGFβ signaling in hair follicle bulge stem cells. In murine skin autocrine TGFβ signaling was highly localised to Lgr5+ve stem cells. We modelled hyperactivation of the MAPK pathway (through knockin of BRafV600E or KRASG12D) and the consequences of TGFβ signalling ablation (through the deletion of Tgfβr1) in Lgr5+ve cells. Whist BRaf or KRAS activation alone did not lead to cancer, homozygous deletion of Tgfβr1 enabled rapid cSCC development. Taken together, our results indicate that Lgr5+ve stem cells can act as the cell of origin for cSCC and that hyperactivation of the RAS-RAF-MAPK pathway, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis. Citation Format: Patrizia Cammareri, Aidan M. Rose, David F. Vincent, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip Coates, Angela McHugh, Celine Pourreyron, Jonas Larsson, Lindsay C. Spender, Gopal Sapkota, Karin Purdie, Charlotte Proby, Catherine A. Harwood, Irene M. Leigh, Hans Clevers, Nicholas Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Andrew P. South, Owen J. Sansom, Gareth J. Inman. Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1506. doi:10.1158/1538-7445.AM2015-1506
Outcomes of Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Authors: John D. Dickinson, Fausto Loberiza, Victoria Whalen, Philip J. Bierman, Julie M. Vose, Marcel P. Devetten, Lori J. Maness, James O. Armitage, Greg Bociek
Journal: Blood (2007)
Engineering Mesenchymal Cells with Interleukin 7 Gene: In Vitro Effects on Naive T Cell Population.
Authors: Paolo Sportoletti, Beatrice Del Papa, Mariangela De Ioanni, Lorenzo Moretti, Elisabetta Bonifacio, Katia Fettucciari, Tiziana Zei, Franca Falzetti, Mauro Di Ianni, Antonio Tabilio
Journal: Blood (2006)
Treatment with Sequential Valproic Acid (VPA) +/− Low Doses All Trans Retinoic Acid (LoATRA) and Low Doses Ara-C (LoDAC) for “De Novo” or Relapsed Acute Myeloid Leukaemia (AML).
Authors: Susanna Fenu, Clara Nervi, Carolina Nobile, Anna Chierichini, Paola Anticoli Borza, Barbara Anaclerico, Velia Bongarzoni, Loredana Bove, Stefania Cortese, Fulivio Pauselli, Carla Tozzi, Su Ellen Vignetti, Giuseppe G. Cimino, Luciana Annino
Journal: Blood (2007)
Extensive Pleural and Pericardial Effusion In 4 CML Patients Treated with Dasatinib at 100 Mg or 50 Mg Once Daily.
Authors: Maria-Theresa Krauth, Susanne Herndlhofer, Maria-Theresa Schmook, Gerlinde Mitterbauer, Ernst Schloegl, Peter Valent
Journal: Blood (2010)
Analysis of Thrombi Retrieved from Cerebral Arteries of Patients with Acute Ischemic Stroke.
Authors: Victor J. Marder, Dennis J. Chute, Sidney Starkman, Anna M. Abolian, Chelsea Kidwell, David Liebeskind, Bruce Obviagele, Fernando Vinuela, Gary Duckwiler, Reza Jahan, Paul M. Vespa, Scott Selco, Krishna Rajajee, Jeffrey L. Saver
Journal: Blood (2005)