tbuckley/cabot-search huggingface dataset:
Potency of new duplex drugs linking 3'-C-ethynylcytidine and 5-fluoro-2'-deoxyuridine against human melanoma in vitro and in vivo.
Authors: S. Schott, H. Niessner, T. Sinnberg, S. Venturelli, A. Berger, S. Noor, D. Mailaender-Sanchez, C. Garbe, C. Busch
Journal: Journal of Clinical Oncology (2011)

8570 Background: Melanoma is increasingly common and currently no cure exists for patients with stage IV disease. There is an urgent need for noval drugs in order to effectively treat this potentially fatal malignancy. 2’-Deoxy-5-fluorouridylyl-(3’-5’)-3’-C-ethynylcytidine [5-FdU(3’-5’)ECyd] and 3’-C-ethynylcytidinylyl-(5’->1-O)-2-O-octadecyl-sn-glycerylyl-(3-Oà5’)-2’-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] are so called duplex drugs that chemically link two antimetabolites into one molecule. They act as cytostatics by metabolisation into a mixture of active antimetabolites with different properties. This concept could use the advantage of a combination therapy avoiding its inconveniences Methods: The duplex drugs were evaluated along the National Cancer Institute (NCI) Developmental Therapeutic Program up to xenograft models. We assessed the cytotoxicity and mechanism of these heterodinucleoside phosphate analogues and their corresponding monomers ECyd and 5-FdU on six metastatic melanoma cell lines and six ex-vivo patient-derived melanoma cells in comparison to current standard cytostatic agents and combinations thereof. Further, in vitro (real-time)-proliferation assays were performed. The embryotoxixity was also evaluated in the chick embryo model. Results: Cell proliferation assays demonstrated that 5-FdU(3’-5’)ECyd and ECyd-lipid-5-FdU had a high cytostatic efficacy causing 75% melanoma cell death at concentrations ranging between nano- and micromolar. Cytotoxicity was conducted by induction of DNA cleavage/apoptosis, and via senescence in cells not undergoing apoptosis. Embryotoxicity demonstrated that the duplex drugs were less toxic than their parental monomers. In vivo results of the NCI showed that the duplex drug 5-FdU(3’-5’)ECyd was efficacious in the LOX IMVI solid tumor xenograph model when 11.2mg/kg/injection were administered every fourth day. Conclusions: Both duplex drugs represent potential new chemotherapeutic drug combinations for malignant melanoma which are more potent than available standard monocytostatica and mixture thereof and thus further development is justified and desirable.
Reduced Erythrocyte Equlibrative Nucleoside Transporter Expression Underlies Increased Circulating Adenosine Levels and Contributes to Pathophysiology of Sickle Cell Disease
Authors: Anren Song, Yujin Zhang, Chen Ning, Almut Grenz, Holger Etlzschig, Rodney E. Kellems, Harinder S. Juneja, Yang Xia
Journal: Blood (2012)
Prolongation of Post Relapse and Overall Survival in Patients with Multiple Myeloma by Salvage Strategy with the Combination of Thalidomide and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation Based on the Nature of Disease Progression after Autologous Bone Marrow Transplantation.
Authors: Izhar Hardan, Avichai Shimoni, Abraham Kneller, Abraham Avigdor, Noga Shemtov, Miriam Berkowicz, Yaron Davidowitz, Moshe Yeshurun, Ronit Yerushalmi, Leiba Meirav, Bar-Nathan Michal, Ben-Bassat Izaac, Nagler Arnon
Journal: Blood (2005)
Frequent Loss of the SLP-65 Adapter Protein in Childhood Acute B-Precursor Lymphoblastic Leukemia (ALL) with TEL/AML1 Rearrangement.
Authors: Arndt Borkhardt, Christine Damm-Welk, Thomas Wossning, Bettina Storch, Uta Fuchs, Susanne Viehmann, Jochen Harbott, Martin Zimmermann, Wolf-Dieter Ludwig, Martin Schrappe, Michael Reth, Hasan Jumaa
Journal: Blood (2005)
Abstract 2309: Murine model of dual mTORC kinase inhibition identifies CDK6 as a synergistic target in T-ALL
Authors: Joy M. Gary, Jinfei Xu, John Simmons, Shuling Zhang, Benjamin Gamache, Ke Zhang, Alexander Kovalchuk, Aleksandra Michalowski, Jin-Qiu Chen, Michelle Herrmann, Wendy Dubois, Joseph Testa, Beverly A. Mock
Journal: Cancer Research (2015)

Abstract The PI3K/AKT/mTOR pathway is frequently hyperactivated in T- cell acute lymphoblastic leukemia (T-ALL). To model inhibition of this pathway in lymphoma, mice with constitutively-active AKT specific to T-lymphocytes (Lck-MyrAkt2) were crossed with mice that have genetically-reduced mTOR expression (mTOR knock-down, KD). Lck-MyrAkt2 mice with mTOR KD had altered thymic T-lymphocyte development; these mice also had delayed thymic pre-T cell lymphoblastic leukemia/lymphoma (pre-T LBL) progression and increased survival relative to wild type (WT) mTOR/ Lck-MyrAkt2 mice (average survival of 24 versus 14 weeks, respectively). Delayed pre-T LBL formation was also observed when WT mTOR/Lck-MyrAkt2 mice were treated for 8 weeks with the rapamycin analog, everolimus, an inhibitor of the mTOR TORC1 complex. Transcriptional profiling of thymic lymphomas from the WT vs KD mTOR/ Lck-MyrAkt2 mice revealed that mTOR KD was associated with decreased expression of Cdk6, a critical proliferative control node in T- cell development and oncogenic transformation. Pharmacologic inhibition of mTOR in tumor cells also decreased CDK6. Tumor cells from WT mTOR/Lck-MyrAkt2 mice were more sensitive to CDK4/6 inhibitors than tumor cells from KD mTOR/Lck-MyrAkt2 mice. Combining an mTOR inhibitor (rapamycin) with a CDK4/6 inhibitor (PD-0332991) synergistically inhibited the viability and decreased downstream signaling in both mouse lymphoma cells and human T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Combining a dual mTORC inhibitor (PP242) with a CDK4/6 inhibitor decreased downstream signaling to an even greater extent in human T-ALL cell lines. Our results suggest that an mTORi/CDKi combination may be beneficial in the treatment of human T-ALL. Citation Format: Joy M. Gary, Jinfei Xu, John Simmons, Shuling Zhang, Benjamin Gamache, Ke Zhang, Alexander Kovalchuk, Aleksandra Michalowski, Jin-Qiu Chen, Michelle Herrmann, Wendy Dubois, Joseph Testa, Beverly A. Mock. Murine model of dual mTORC kinase inhibition identifies CDK6 as a synergistic target in T-ALL. [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 2309. doi:10.1158/1538-7445.AM2015-2309
Extraprostatic Extension Is Extremely Rare for Contemporary Gleason Score 6 Prostate Cancer
Authors: Blake B. Anderson, Daniel T. Oberlin, Aria A. Razmaria, Bonnie Choy, Gregory P. Zagaja, Arieh L. Shalhav, Joshua J. Meeks, Ximing J. Yang, Gladell P. Paner, Scott E. Eggener
Journal: European Urology (2016)
Favorable Outcome in Patients with Lymphoid Malignancies Following Allogeneic Stem Cell Transplantation Using Fludarabine and Treosulfan As the Preparative Regimen
Authors: Ronit Yerushalmi, Avichai Shimoni, Noga Shem-Tov, Yulia Volchek, Abraham Avigdor, Arnon Nagler
Journal: Blood (2012)
748. A Clinical Trial Using Third Generation CD19 Targeting CAR T Cells for Relapsed Lymphoma and Leukemia
Authors: Gunilla Enblad, Hannah Karlsson, Jessica Wenthe, Kristina I. Wikstrom, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Hoglund, Helene Hallbook, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog
Journal: Molecular Therapy (2016)

Chimeric antigen receptor (CAR) T cells have shown promising results in patients with B cell malignancy. Herein, we report initial results from a phase I/IIa study (NCT:02132624) using CD19-targeting (CD28/4-1BB) CAR T cells. Patients with refractory CD19+ B cell malignancy were eligible, provided there was no other curative treatment available. Of 18 enrolled, 14 patients have received CAR T cells. Eleven had lymphoma and 3 patients had acute lymphoblastic leukemia (ALL). Autologous CAR T cells were manufactured by expansion using aCD3/aCD28 and IL2, and engineered using a gamma retrovirus encoding the CAR. During T cell manufacture, all lymphoma patients received conventional treatment to control tumor burden. Prior to T cell infusion, day -5 to -1, patients #6-17 received cyclophosphamide (500mg/m2) and fludarabine (25mg/m2) as preconditioning to decrease immunosuppressive cells. The patients received one infusion of CAR T cells ranging from 2×107 to 2×108 cells/m2. Six of 14 patients had initial complete responses (CR) but 5 progressed later and 2 of those had another CR to additional chemotherapy to which they were previously refractory. Six patients are still alive of which 2 have been alive for >1.5 years post CAR therapy, 1 >10 months, and the 3 patients >3 months. The two last patients received anti-PD1 antibody therapy post CAR infusion. Blood samples from the patients have been analyzed for CAR T cells (PCR) and immunosuppressive cells such as T regulatory cells (Treg), myeloid-derived suppressor cells (MDSCs) and M2 macrophages (CD163+). The CAR gene could be detected at the highest levels 1w post infusion and then the copy number varied over time. The levels were not correlated to ongoing response in terms of CR or PD but patients with higher levels commonly had a response to treatment and/or an ongoing cytokine release syndrome (CRS). Mild CRS or signs of neurological toxicity were noted in several patients but only 3 CRS and 1 neurological toxicity required hospitalization. The level of suppressive cells at enrollment did not correlate to response but a decline of suppressive cells over time was more often noted in responding patients. Proteomic analysis (ProSeek platform) has been done on patient plasma and is under evaluation to define response biomarkers. In summary, 14 patients have been treated with increasing doses of CAR T cells in Sweden. The conditioning has been relatively mild as compared to previous published studies and no lethal toxicity occurred. Six of the 14 treated patients had an initial CR, two of them and four other patients are still alive.
Abstract AS30: BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin
Authors: Bibbin T. Paul, Zannel Blanchard, Mildred Ridgway, Wael M. ElShamy
Journal: Clinical Cancer Research (2015)

Abstract Ovarian cancer is the first in mortalities among gynecological cancers in the USA, often due to late diagnosis and/or acquired platinum-resistant recurrences. This study investigates whether BRCA1-IRIS is a novel treatment target for ovarian cancers and their platinum-resistant recurrences. Here we show that more than half of ovarian cancer samples analyzed showed BRCA1-IRIS and survivin overexpression and lacked nuclear FOXO3a expression. Normal ovarian epithelial cells overexpressing BRCA1-IRIS formed metastasis in mice when injected in the peritoneal cavity, whereas aggressive ovarian cancer cell lines failed to form tumors or metastases in mice when BRCA1-IRIS was silenced in them. We show that BRCA1-IRIS activates two autocrine signaling loops, BDNF/TrkB and NRG1/ErbB2. These loops are involved in anoikis resistance and metastasis promotion. These loops operate in several ovarian cancer cell lines and BRCA1-IRIS silencing or inactivation using a novel inhibitory peptide renders both non-functional and promoted cell death. In a mouse xenograft model BRCA1-IRIS inactivation using this novel inhibitory peptide resulted in significant reduction in ovarian tumor growth. More importantly, this treatment sensitized ovarian tumors to low Cisplatin concentrations. Taken together, these data strongly suggest that BRCA1-IRIS and/or BDNF/TrkB and NRG1/ErbB2 could serve as rational therapeutic targets for advanced ovarian cancers. Citation Format: Bibbin T. Paul, Zannel Blanchard, Mildred Ridgway, Wael M. ElShamy. BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS30.
Inflammatory mechanisms linking obesity and metabolic disease
Authors: Alan R. Saltiel, Jerrold M. Olefsky
Journal: Journal of Clinical Investigation (2017)

There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.
Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial
Authors: Kimmo Porkka, Michele Baccarani, Andreas Hochhaus, Hagop Kantarjian, Satu Mustjoki, M. Brigid Bradley-Garelik, Chao Zhu, Jorge E. Cortes
Journal: Blood (2010)
Abstract 5094: Capsaicin inhibits invasion of human non-small cell lung cancer cells in a TRPV1 receptor independent manner
Authors: Matthew N. Eskew, Kathleen C. Brown, Piyali Dasgupta
Journal: Cancer Research (2015)

Abstract Non-small cell lung cancer (NSCLC) comprises 85% of lung cancer cases and is characterized by aggressive clinical course and rapid metastasis. One of the challenges of NSCLCs is that the tumor has frequently metastasized to distant organs at the time of diagnosis. The invasion of tumor cells is a key step in the metastatic cascade. Dietary compounds like capsaicin have been known to cause apoptosis in human NSCLCs. However, the effect of capsaicin on the pro-invasive ability of NSCLC cells has not yet been studied. The present study investigates the impact of capsaicin on the invasion of human NSCLCs. Boyden chamber assays show that capsaicin inhibits the invasion of NSCLC in a concentration-dependent and time-dependent manner. The pro-invasive activity of capsaicin was verified by a second invasion assay, the spherical invasion assay, and similar results were obtained. The anti-invasive activity of capsaicin was independent of its growth-inhibitory activity and manifested at a lower concentration. The heat-sensation activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of proteins. Capsaicin functions as an agonist of the TRPV1 receptor. However, the anti-invasive activity of capsaicin was not affected by the generalized TRPV receptor antagonist ruthenium red. Specific antagonists to TRPV1, namely capsazepine and SB36671, did not reverse the anti-invasive activity of capsaicin. Taken together, capsaicin potently suppresses invasion of human NSCLCs independent of the TRPV receptor family. Citation Format: Matthew N. Eskew, Kathleen C. Brown, Piyali Dasgupta. Capsaicin inhibits invasion of human non-small cell lung cancer cells in a TRPV1 receptor independent manner. [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 5094. doi:10.1158/1538-7445.AM2015-5094
Abstract 2274: The dual role of fibronectin in lung cancer progression
Authors: Hung-Chi Cheng, Ming-Min Chang, Yau-Lin Tseng
Journal: Cancer Research (2015)

Abstract Tumor cells chronically progress, involving a series of aberrant activities within distinct organs, to accomplish final metastasis. The role of fibronectin (FN) in tumor progression has been controversial, being either tumor-suppressive or metastatic-promoting. Nevertheless, little effort has been made to reconcile these discrepancies in a systemic manner. Here, we deprived metastatic tumor cells of pericellular FN (periFN) in the spontaneous metastasis assay and demonstrated a dual role of FN. We found that, while knocking down FN expression of Lewis lung carcinoma cells (FNKD-LLC) increased the tumor sizes and migratory activities, it significantly decreased the tumor metastasis in the lungs. Histological examination revealed that subcutaneous tumors of mice bearing FNKD LLC invaded the surrounding tissues to a higher extent than those of mice bearing control scramble-LLC. Immunohistochemical staining with antibodies against CD31, FN, and casepase 3, revealed that FNKD-LLC rendered more angiogenesis, tumor intravasation, and fibrous FN deposited in the surrounding inflammatory tissues, without altering the tumor apoptosis, suggesting that the FN expression in tumor cells indeed plays a role in suppressing the tumor progression in the primary tumor tissues. Conversely, the metastatic tumor nodule numbers in the lungs were significantly reduced for the FNKD-LLC cells, clearly indicative of a metastatic-promoting role of periFN. We reasoned these seemingly conflicting phenomena by hypothesizing that the FN expression of neoplastic lung carcinoma cells is initially downregulated to trigger fibrotic microenvironments (FN deposition in extracellular matrices) to which pro-inflammatory leukocytes are recruited, leading to the enhanced angiogenesis and tumor intravasation. However, the early circulating lung cancer cells fail to colonize distant organs (including lungs) until periFN is re-assembled in the later progression stages, thus facilitating the tumor cell adhesion to CD26 on endothelial cells and consequently extravasation and metastasis. This hypothesis of temporal-spatial regulations was clinically supported by comparing and statistically analyzing the FN expression levels in lung cancer tissues collected from patients hospitalized by the NCKU hospital for surgery within 2003 through 2006 with low and high survivals. This study was supported by Grant # MOST 102-2320-B-006 -031- and MOST 103-2325-B-006 -009 -. Citation Format: Hung-Chi Cheng, Ming-Min Chang, Yau-Lin Tseng. The dual role of fibronectin in lung cancer progression. [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 2274. doi:10.1158/1538-7445.AM2015-2274
Association of Albumin Levels With Outcome in Intravenous Immunoglobulin–Treated Guillain-Barré Syndrome
Authors: Willem-Jan R. Fokkink, Christa Walgaard, Krista Kuitwaard, Anne P. Tio-Gillen, Pieter A. van Doorn, Bart C. Jacobs
Journal: JAMA Neurology (2016)

There is an urgent need for biomarkers to monitor treatment efficacy and anticipate outcome in patients with Guillain-Barré syndrome (GBS).To assess whether there is an association between serum albumin levels, a widely used and relatively easily measurable biomarker of health and inflammation, and the clinical course and outcome of GBS in patients treated with intravenous immunoglobulin (IVIG).We used serum samples derived from a cohort of patients with GBS admitted to hospitals across the Netherlands participating in national GBS studies from May 5, 1986, through August 2, 2000. Serum albumin was measured from January 13 to 20, 2011. Analysis was performed from February 25, 2013, to September 6, 2016. All patients fulfilled the criteria for GBS and had severe disease (defined as not being able to walk unaided >10 m). Patients misdiagnosed as having GBS were retrospectively excluded from the study. Serum samples were obtained before and after IVIG treatment at 4 standardized time points from 174 patients. Albumin levels were determined by routine diagnostic turbidimetry and related to demographics and clinical course during a follow-up of 6 months.Serum albumin concentration was determined before and after treatment with IVIG and related to clinical outcome: muscle weakness (measured by Medical Research Council sum score), respiratory failure (measured by requirement and duration of mechanical ventilation), and ability to walk (measured by GBS disability score).Serum albumin levels were determined in 174 patients with GBS (mean [SD] age, 49.6 [20.1] years; 99 males [56.9%]). Before treatment, the median serum albumin level was 4.2 g/dL (interquartile range, 3.8-4.5 g/dL), with hypoalbuminemia (albumin, <3.5 g/dL) in 20 (12.8%) of 156 patients. Two weeks after commencing treatment with IVIG (2 g/kg), the median serum albumin level decreased to 3.7 g/dL (interquartile range, 3.2-4.1 g/dL) (P < .001), and the number with hypoalbuminemia increased to 60 (34.5%) of 174 (P < .001). Hypoalbuminemia was associated with an increased chance of respiratory failure before (16 [36.4%] of 44, P = .001) or after (29 [54.7%] of 53, P < .001) IVIG treatment, inability to walk unaided (21 [35.0%] of 60 vs 6 [5.3%] of 114, P < .001), and severe muscle weakness at 4 weeks (Medical Research Council sum score, 31.8 vs 52.9, P < .001) and 6 months (Medical Research Council sum score, 49.4 vs 58.4, P < .001).Patients with GBS may develop hypoalbuminemia after treatment with IVIG, which is related to a more severe clinical course and a poorer outcome. Further studies are required to confirm that serum albumin can be used as a biomarker to monitor disease activity and treatment response to IVIG in patients with GBS.
Colorectal cancer (CRC) KRAS mutational status and response to chemotherapy in absence of influence of epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) therapy.
Authors: Nirit Yarom, Nana Boame, Gillian Gresham, David Hill, Derek J. Jonker
Journal: Journal of Clinical Oncology (2012)

504 Background: KRAS mutations (MUT), present in ~40% of CRC, predict benefit from EGFR MAb treatment. The effect of mutation status on benefit from chemotherapy alone is less clear. Methods: Following ethics approval, 223 CRC patients with known KRAS status treated at a single institution were retrospectively analyzed for response to chemotherapy prior to initiation of EGFR MAb therapy. Tumour response rate and progression-free survival (PFS) were determined retrospectively. Given chemotherapy sequencing variability, a measure of the time to chemotherapy-refractory state (TTCR) was defined as time from start of first line therapy to progression on all drugs; ie fluoropyrimidines (F), irinotecan (I), and oxaliplatin (O), +/- bevacizumab (B). Results: Patients were median age 60 years (25-86), 58/42% male/female, 38% rectal or rectosigmoid, 18% liver-only metastases, 45.6% stage I-III and 54.4% stage IV at initial diagnosis, 43% prior adjuvant chemotherapy, 43/57% KRAS MUT/wild-type(WT) status. With a median follow-up of 27 months, 64 (29%) are alive. TTCR did not vary by KRAS status, with median 16.7 vs 14.8 months in WT vs MUT status patients, respectively, HR 0.85 [0.65-1.12], p=0.26. Overall survival (which now includes influence of any subsequent EGFR MAb therapy, received by 76/126 (60%) of KRAS WT status patients) did not differ significantly by KRAS status, with median survival 34.3 vs 29.2 months for WT vs MUT status, respectively, 0.79 [0.58-1.08], p=0.14. Conclusions: For most treatment strategies KRAS status did not affect 1 st line PFS or time to chemotherapy-refractory state. However, for patients who received triple combination therapy, MUT status was associated with early progression. Small sample size, chance or some yet-to-be-elucidated molecular interaction may account for this finding. [Table: see text]