tbuckley/cabot-search huggingface dataset:
Glutathione Depletion Enhances Arsenic Trioxide-Induced Apoptosis in Lymphoma Cells through Mitochondrial and Caspase-Independent Mechanisms.
Authors: Savita Bhalla, Leo I. Gordon, Amareshwar Singh, Sheila Prachand, Shuo Yang, Jane N. Winter, Dongsheng Guo, Thomas O'Halloran, Leonidas C Platanias, Andrew M. Evens
Journal: Blood (2009)
606. cGMP Compliant Process to Produce Day-14 Transplantable Dopaminergic Neuron Precursors
Authors: Sylvana Couture, Chih-Min Lin, Christine Hall, John Gutierrez, Lopez Lopez, Patricia Huang, Aparna Krishnan, Derek Kong, Heather Javier, Wei Dang, Xianmin Zeng, David Hsu, Larry A. Couture
Journal: Molecular Therapy (2015)

One of the key issues to bringing human embryonic stem cell (hESC)-based technology from bench to bedside is developing defined hESC culture processes and differentiation processes to produce sufficient amount of therapeutically relevant cells under Current Good Manufacture Practice (cGMP). Here we report a successful adaptation of a laboratory procedure into a scalable and cGMP compliant process, focusing on optimization of the process for day-14 transplantable dopaminergic (DA) neuron precursor production and the selection of cGMP-compliant reagents. We showed the equivalency between laboratory procedure and the cGMP process generated DA progenitors. The cells generated under cGMP compliant process exhibited similar culture growth characteristic and marker expression as the cells produced by the laboratory procedure as demonstrated by the following analysis: FACS analysis of PAX6 expression as a marker for neural stem cell (NSC); immunocytochemistry staining of TH and B-tubulin-III as marker for dopaminergic neuron; RT-qPCR of DBH and SERT as contaminant markers of noradrenergic and hindbrain neurons. In addition, we demonstrated the feasibility of generating a large intermediate cell bank (ICB) of neural stem cell for the production of DA neuron precursors. A cryopreserved ICB would greatly streamline the manufacturing process and reduce the lot-to-lot variability. In conclusion, we have successfully optimized and adapted a laboratory procedure for producing day-14 transplantable DA neuron precursor into scalable cGMP-compliant manufacture process which would provide great potential for clinical application.
The Reciprocal t(9;22)-Translocation Products ABL/BCR Have Leukemogenic Potential Independently from BCR/ABL.
Authors: Xiaomin Zheng, Saskia Güller, Gesine Bug, Bithia Grace, Roxana Bistrian, Dieter Hoelzer, Oliver G. Ottmann, Reinhard Henschler, Martin Ruthardt
Journal: Blood (2004)
Active combination of platins/paclitaxel/gemcitabine/bortezomib in a child with metastatic renal medullary carcinoma (RMC).
Authors: M. M. Al-Rahawan, L. Rapkin, S. D. Smith
Journal: Journal of Clinical Oncology (2011)

e20002 Background: RMC is a rare but highly aggressive malignancy that affects adolescents and young adults with sickle cell trait and disease. Most patients with RMC present with metastatic disease and commonly die within 1 year. Several small series report an average survival of 12 weeks and only a few cases with localized disease survive long term. Patients often experience transient response to chemotherapy before they develop drug resistance. While children with RMC are eligible for the current COG AREN0321 protocol for renal malignancies, the treatment for unresectable RMC is ‘institutional preference’. One report suggests response to monotherapy bortezomib in metastatic RMC; however, systemic therapy has not been standardized in this group. Methods: A 10 y/o African American female presented with respiratory failure. An infectious disease and immunodeficiency evaluation was negative. A CT scan showed extensive 5 lobe interstitial lung disease, enlarged mesenteric lymph nodes in the chest and abdomen and a 5 cm renal mass. A lung biopsy revealed RMC and hemoglobin electrophoresis showed sickle cell trait. With family consent, the patient received 3 cycles of cisplatin (70 mg/m2 d 1), paclitaxel and gemcitabine (80 mg/m2 and 1 g/m2 d 1, 8, and 15) (CiPG). Response assessment was followed by 5 cycles of carboplatin (0.4 g/m2 d 1), gemcitabine (1 g/m2 d 1 and 8) and bortezomib (1 mg/m2 d 1, 5 and 8) (CaGB) alternating with cycles of CiPG. After 12 months of combination chemotherapy, bortezomib was continued for 1 year. Results: The lung and kidney disease regressed after 3 cycles of CiPG, and a right nephrectomy showed extensive fibrosis and minimal neoplastic cells. After nine more months of alternating cycles of CiPG and CaGB, only minimal lung disease was detected and a biopsy of the remaining lung nodules revealed no evidence of malignancy. Two months ago, the patient completed an additional 1 year of bortezumab and now has no evidence of disease 26 months from diagnosis. Conclusions: The combination of platins, paclitaxel, gemcitabine and bortezomib was very well tolerated in our patient. Her durable complete response calls for considering this chemotherapy regimen to treat other patients with RMC.
501. In Vivo Gene Editing for Duchenne Muscular Dystrophy
Authors: Niclas E. Bengtsson, John K. Hall, Guy L. Odom, James Allen, Joel R. Chamberlain, Jeffrey S. Chamberlain
Journal: Molecular Therapy (2016)

Gene replacement therapies utilizing adeno-associated viral vector delivery of truncated versions of dystrophin (mini- and microdystrophins) hold great potential for the treatment of Duchenne muscular dystrophy (DMD). However, these truncated dystrophins are not fully functional and episomal AAV vectors are not permanently retained following delivery to muscle. A more long-lasting and effective approach to gene therapy could result from methods to modify the dystrophin gene using gene editing strategies. The CRISPR/Cas9 system has been shown to be a highly specific method for genetic modifications, and recently has been proven applicable to correct mutations responsible for DMD. Here we present in vivo approaches for targeted correction of the dystrophin gene in the mdx4cv mouse model of DMD using both single- and dual adeno-associated viral (AAV) vector delivery systems of Cas9 and DMD mutation specific targeting guide RNA's. Treated muscles demonstrated successful targeting of the dystrophin gene leading to a corrected open reading frame in the messenger RNA resulting in a restoration of near-to full-length dystrophin expression in up to 70% of treated muscle cross-sectional area. These results demonstrate that successful in vivo dystrophin correction can be achieved following AAV mediated delivery of CRISPR/Cas9, showing promise for the development of future clinical application of technologies for permanent correction of mutations leading to DMD and other genetic muscle disorders.
A phase I study evaluating the combination of OSI-906, a dual inhibitor of insulin growth factor-1 receptor (IGF-1R) and insulin receptor (IR) with weekly paclitaxel (PAC) in patients with advanced solid tumors.
Authors: W. A. Harb, C. Sessa, H. W. Hirte, S. B. Kaye, R. Simantov, S. N. Banerjee, A. Christinat, D. W. Sternberg, M. Singh, R. Light, S. Poondru
Journal: Journal of Clinical Oncology (2011)

3099 Background: OSI-906 is an oral inhibitor of IGF-1R and IR. Increased IGF-1R and IR activity is observed in human cancers and implicated in resistance to chemotherapy. In preclinical studies, OSI-906 blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This is the first study that combines OSI-906 with a cytotoxic agent. Methods: Patients (pts) with advanced solid tumors received weekly (qw) IV PAC (80 mg/m2) with intermittent OSI-906 (Arm A, d1-3q7d) or continuous OSI-906 (Arm B, BID d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of OSI-906 + PAC using a standard 3x3 phase I design. Results: 55 pts were treated (46F:9M, median age 57 yrs). OSI-906 doses of 300 mg to 600 mg QD d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were explored. Dose-limiting toxicities in Arm A (450mg QD, n=9) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (150mg BID, n=11) were G3 hyperglycemia, G3 fatigue and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to OSI-906. Complete adverse event data are available on 46 pts. Most common drug-related toxicities were (any grade; grade 3): fatigue (54%; 15%), nausea (48%; 0%), alopecia (41%; 0%), diarrhea (35%; 7%), rash (30%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). Median treatment duration was 11 weeks (range 1-68 wks); 11 pts (21%) were on study for ≥24 wks, and 11 pts are ongoing. In pts with ovarian cancer (n=29), 5 had partial response and 11 had stable disease. Preliminary PK results suggest no relevant PK interaction when OSI-906 administered 2 hours prior to PAC. Conclusions: OSI-906 + PAC was well tolerated at doses up to the single agent MTDs. A phase II study of OSI-906 + PAC in pts with ovarian cancer is planned.
623. Immune Checkpoint Modulation Enhances Oncolytic Measles Virus Therapy
Authors: Christine E. Engeland, Rūta Veinalde, Christian Grossardt, Dirk Jäger, Christof von Kalle, Guy Ungerechts
Journal: Molecular Therapy (2015)

We hypothesized that combining oncolytic Measles virus (MV) with immune checkpoint modulation using antibodies which block CTLA-4 and PD-1/PD-L1 signaling can provide synergistic antitumor effects. Targeted immunomodulatory MV vectors encoding checkpoint modulating antibodies were cloned and characterized in vitro. Oncolytic efficacy was equal to parental MV in human melanoma xenografts. Immunotherapeutic efficacy was evaluated in a fully immunocompetent murine model of subcutaneous syngeneic malignant melanoma (B16-CD20) and compared to parental MV with or without systemic administration of CTLA-4 or PD-1/PD-L1 blocking antibodies. Treatment with MV encoding checkpoint modulators led to an increase in tumor-infiltrating cytotoxic T cells as well as a decrease in regulatory T cells. Therapeutic benefits in terms of delayed tumor growth and prolonged median overall survival were observed for animals treated with checkpoint modulating MV. Further investigations in preparation of a Phase I trial are currently ongoing. Thus, combining oncolytic MV with immune checkpoint modulation is a promising approach with direct implications for future clinical application.
Multicentric prospective Study of Differential Treatment for Elderly Patients Affected by Aggressive Non Hodgkin Lymphoma Based On a Geriatric Multidimensional Analysis.
Authors: Guido Gini, Attilio Olivieri, Caterina Bocci, Massimo Catarini, Giuseppe Visani, Mauro Montanari, Barbara Guiducci, Alessandro Isidori, Marino Brunori, Francesco Alesiani, Luciano Giuliodori, Massimo Marcellini, Massimo Offidani, Patrizia Caraffa, Andrea Stronati, Debora Capelli, Silvia Trappolini, Pietro Leoni
Journal: Blood (2009)
Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006–2014
Authors: J. van Beek, A.A. van der Eijk, P.L.A. Fraaij, K. Caliskan, K. Cransberg, M. Dalinghaus, R.A.S. Hoek, H.J. Metselaar, J. Roodnat, H. Vennema, M.P.G. Koopmans
Journal: Clinical Microbiology and Infection (2016)
PWE-124 Complex Colorectal Polyps: A Tertiary Centre Experience; Tailoring The EMR Technique to ThePolyp
Authors: ZPP Tsiamoulos, T Elliott, N Suzuki, P Bassett, BP Saunders
Journal: Gut (2016)

<h3>Introduction</h3> Features that characterise polyp complexity should be clearly defined and recognised to avert suboptimal piecemeal endoscopic mucosal resection (p-EMR) strategies and need for salvage surgery. <h3>Methods</h3> A prospective database of all colorectal polyps excised at our tertiary referral centre between Jan 2010 and August 2012 was collected. Standard p-EMR, p-EMR using a 20 mm spiral snare (sp-EMR), and hybrid p-EMR (hp-EMR; p-EMR plus endoscopic mucosal ablation or endoscopic submucosal dissection) were performed. Multinomial regression analysis was utilised to define characteristic features of complex polyps and factors associated with the chosen resection technique. <h3>Results</h3> Of 330 patients with 341 polyps (mean size 3.7 cm), 81% (261/323, p &lt; 0.001) were tertiary and 19% were local referrals. 94/261 (36%, p &lt; 0.001) tertiary referrals mentioned one or more previous endoscopic resection attempts. Endoscopic polyp access was described as difficult in 174/341 (51%, p = 0.001), incomplete polyp lift in 179/341 (52%, p = 0.002) cases and polyp size ≥ 4 cm (median size 5 cm) in 123/341 (36%, p &lt; 0.001) cases. Polyps ≥4 cm were more frequently in a difficult position (≥4 cm; 63% vs &lt;4 cm; 37%, p &lt; 0.001). Polyps &lt;4 cm were more likely to be in the caecum or ascending colon (&lt;4cm; 35% vs ≥4 cm; 16%, p &lt; 0.001).Endoscopically complete polypectomy was achieved in one session in 336/341 (98%, p &lt; 0.001) polyps. Procedural and delayed bleeding were significantly higher in the ≥ 4 cm group where 2 of the 3 micro-perforations also occurred (3/341, 0.9%, p &lt; 0.001) that were all treated successfully with endoscopic clipping. The overall long-term recurrence at 24 months was 17% (28% for ≥4 cm/p = 0.02). Only eleven patients (4 benign recurrence/7 cancer at histology, 3%) in this cohort underwent surgery. Using multivariable analysis, factors associated with need for sp-EMR or hp-EMR were; <b>i) tertiary referrals</b> (sp-EMR, OR 3.41, p &lt; 0.001<b>), ii) incomplete polyp lift</b> (hp-EMR, OR 8.3 &gt; sp-EMR, OR 1.19 p &lt; 0.001), <b>iii) previous polypectomy attempt</b> (hp-EMR, OR 2.77, p = 0.02), <b>iv) larger polyp size</b> (for an increase of 1 cm – hp-EMR (OR 1.37)/sp-EMR (OR 1.66,) p &lt; 0.001, <b>v) polyps in the rectosigmoid location</b> (sp-EMR and hp-EMR, p &lt; 0.001) and <b>vi) Paris IIa+IIb polyps</b> (sp-EMR, OR 5.01 and hp-EMR, OR 2.9, p –0.007). <h3>Conclusion</h3> Complex colorectal polyps referred to this tertiary centre were characterised by polyp size ≥ 4 cm, caecal location, previous unsuccessful polypectomy, difficult endoscopic access, or incomplete polyp lift. Advanced techniques such as hybrid-pEMR and spiral p-EMR were required in 33% of tertiary referrals. <h3>Disclosure of Interest</h3> None Declared
Abstract 4646: Cumin extract prevents estrogen-associated breast cancer in ACI rats
Authors: Farrukh Aqil, Jeyaprakash Jeyabalan, Radha Munagala, Ramesh C. Gupta
Journal: Cancer Research (2015)

Abstract Spices are highly chemoprotective because of their antioxidant, antiproliferative, and anti-inflammatory activities. We have previously demonstrated significant chemoprotective effects of cumin seed powder (7.5%, w/w) against estrogen-induced mammary tumorigenesis in ACI rats by inhibiting cell proliferation as well as cellular and molecular markers. Here we report the inhibition of E2-mediated mammary tumorigenesis by cumin extract (1%, w/w) that is equivalent to the dietary dose in our previous study. Three extractions of cumin seeds with 80% aqueous ethanol followed by evaporation provided 13% of total dried extract (w/w). Groups of female ACI rats were given either AIN-93M diet or diet supplemented with cumin extract and then treated with subcutaneous 17ß-estradiol silastic implants (1.2 cm; 9 mg). Two additional groups were maintained on control or experimental diet. Rats received diet and water ad libitum. Five-six animals from each group were euthanized three weeks after the E2 treatment to determine the effect of interventions on early biomarkers. The remaining animals (n = 20-22) were euthanized when estrogen-treated group on control diet reached over 90% tumor incidence. Diet consumption and body weight gain was found to be largely unaffected by the cumin extract, suggesting that it was well tolerated. The first tumor incidence in control group was after 92 days, this was significantly delayed by 35 days in cumin extract treated group. Experimental diet significantly offset estrogen-related growth of pituitary prolactinomas as early as after three weeks (p = 0.019), the effect was more pronounced at tumor time point (p &amp;lt; 0.0001). At the end of the study (25 wks), the tumor incidence was found to be 96% in control group whereas only 45% animals had tumors in the intervention group. Significant reduction in average tumor volume (474 vs. 75 mm3) and tumor multiplicity (4.1 vs. 0.8 tumors/animal) was also observed by cumin extract compared to control. The mechanistic studies including effect on the plasma prolactin levels, and the cell proliferation marker, PCNA, estrogen-associated expression of the ERα and cyclin D1 in the mammary tissues are being evaluated. Together, our data show that cumin extract can significantly delay and prevent estrogen-mediated mammary tumorigenesis. This data further support our ultimate goal to develop these spice bioactives as clinically translatable chemopreventives and therapeutics against breast cancer. (Supported by CA-125152, Helmsley Fund, and Agnes Brown Duggan Endowment). Citation Format: Farrukh Aqil, Jeyaprakash Jeyabalan, Radha Munagala, Ramesh C. Gupta. Cumin extract prevents estrogen-associated breast cancer in ACI rats. [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 4646. doi:10.1158/1538-7445.AM2015-4646
Abstract LB-110: Expression of multiple androgen receptor splice variants in late stage prostate cancer
Authors: Zara Ghazoui, Emma Jones, Margaret Veldman-Jones, Vivien N. Jacobs, Neil R. Smith, Michele Johnstone, J. Carl Barrett, Elizabeth A. Harrington, Paul Elvin
Journal: Cancer Research (2015)

Abstract The androgen receptor (AR) remains a key driver of disease progression even with the advent of new therapeutic agents such as abiraterone (A) and enzalutamide (E). Relapse after treatment with A or E has been associated with the emergence of tumour cells expressing AR splice variants, and at least one mutation in AR has been associated with resistance to E. We have investigated the expression of AR splice variants in late stage prostate cancers using Nanostring (nCounter®) to quantify the levels of AR transcripts and by IHC using antibodies targeting the N- and C-terminal AR domains. We also examined the expression of putative AR regulated genes found to be expressed in prostate cancer reported in publically available expression data. Formalin fixed paraffin embedded tissue from 38 commercially sourced (TriStar Technology Group; Asterand; Avaden Biosciences) late stage prostate cancers including 10 castrate resistant prostate cancers (CRPC), were confirmed by pathology review. Total mRNA was isolated from a single 5μm section and gene expression from nCounter® analysis was expressed as normalised Log2 values. Immunohistochemical analysis of AR expression was determined by a pathologist using a H score. Our analysis of AR splice variant expression, relative to a Nanostring detection threshold based on housekeeping genes, has shown the presence of more than one constitutively active AR splice variant in individual tumours. ARV7 was detected in 4/10 CRPC and always found together with ARV1, AR45, and the constitutively active ARV12. All of the CRPC that were negative for ARV7 expressed AR45 and ARV12. Unsupervised clustering of 507 putative AR regulated genes revealed three molecular subgroups among the 38 prostate tumours. One of these subgroups was characterised by the presence of 12/14 AR splice variants including ARV7. Of the other two subgroups, one contained AR45, the other ARV12. Pathway analysis of genes that were expressed to a higher level (&amp;gt;1.5 Log2 fold) in the ARV7 positive compared to ARV7 negative tumours were predominantly associated with cell cycle and proliferation functions. Our data suggests complexity in the molecular landscape of prostate cancer associated with AR splice variants, and that multiple AR splice variants may be of importance to identify patients likely to relapse on treatment with emerging therapy. Citation Format: Zara Ghazoui, Emma Jones, Margaret Veldman-Jones, Vivien N. Jacobs, Neil R. Smith, Michele Johnstone, J. Carl Barrett, Elizabeth A. Harrington, Paul Elvin. Expression of multiple androgen receptor splice variants in late stage 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 LB-110. doi:10.1158/1538-7445.AM2015-LB-110
Can you have your cake and eat it too? The sunlight D-lema
Authors: M.F. Holick
Journal: British Journal of Dermatology (2016)

In this issue of the BJD, Felton et al.1 report the results of their elegantly designed study to determine the impact on vitamin D status and skin DNA damage for healthy adults with skin types 2 and 5 of low‐level simulated summer sunlight exposure as would be experienced at a latitude in the U.K. The photosynthesis of vitamin D has been occurring on this planet for more than 500 million years ever since phytoplankton were producing vitamin D during sun exposure.2 Although vitamin D's function in early life forms is not well understood, recent evidence has suggested that vitamin D3 stabilizes membranes that may be important in regulating immune function.3 Throughout evolution, many organisms, including vertebrates, have depended on sun exposure for their vitamin D requirement. Our hairy dark‐skinned ancestors in Equatorial Africa had both their hair and skin pigment as mechanisms to prevent sun‐induced skin damage. As our ancestors evolved, they lost their protective hair, and in turn increased melanin production as an effective natural sunscreen. However, the increased amount of melanin in the skin still resulted in a small amount of vitamin D3‐producing‐ultraviolet (UV) B radiation to reach the basal layer, promoting the production of vitamin D3 throughout the epidermis, which was essential for the maintenance of skeletal health throughout life. As our ancestors migrated north and south of the equator, the increase in the zenith angle of the sun reduced the amount of vitamin D3‐UVB‐producing photons reaching the skin to produce an adequate amount of vitamin D3. To compensate for vitamin D deficiency, mutations occurred resulting in a reduction in skin melanin content for those who migrated to the farthest northern and southern regions including the Neanderthals who likely had a Celtic skin tone.4