tbuckley/cabot-search huggingface dataset:
Fatigue with vascular endothelial growth factor receptor tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors in patients with malignancies: A meta-analysis of randomized clinical trials.
Authors: Youjin Je, Pooja Ghatalia, Paul Linh Nguyen, Quoc-Dien Trinh, Toni K. Choueiri, Guru Sonpavde
Journal: Journal of Clinical Oncology (2015)

e15583 Background: Fatigue is common in patients (pts) exposed to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORi) used to treat malignancies. We performed a meta-analysis of randomized trials to better quantify fatigue associated with FDA approved VEGFR TKIs and mTORi. Methods: MEDLINE, conferences and clinicaltrials.gov databases were searched for articles from January 1966 to September 2014. Eligible studies included randomized phase II and III trials comparing arms with single agent VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib) or mTORi (everolimus and temsirolimus) vs. placebo or no therapy in the control arm. Data abstraction was conducted according to the PRISMA statement and the relative risk (RR) and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity. Trial quality was graded by the Jadad score. Results: The RR of all grade and high grade fatigue in 7,304 pts from 3 phase II and 16 phase III trials was 1.35 (95% CI 1.22-1.49, p < 0.001) and 1.33 (95% CI 0.97-1.82, p = 0.08), respectively in pts receiving VEGFR TKIs or mTORi. The summary incidence of all grade and high grade ( ≥ 3) fatigue in the drug arm was 38.2% (95% CI 31.8-45.1) and 4.0% (95% CI 2.8-5.7), respectively. The type of drug (VEGFR TKI vs. mTORi), line of therapy, age, type of tumor (renal cell carcinoma vs others) and duration of therapy did not affect the risk of all grade fatigue. High grade fatigue was more common in pts who were younger or received a longer duration of therapy. No publication bias was detected. There was moderate heterogeneity among trials for all grade fatigue and none for high grade fatigue. Conclusions: We found a 35% significantly higher risk of all grade fatigue and a trend for increase of high-grade fatigue in pts receiving single agent VEGFR TKI or mTORi, compared to no anti-cancer therapy. The incidence of high grade fatigue was low. Awareness of fatigue can help in early detection and intervention.
Erythropoietin Stimulates Bone Resorption Via Direct Activation of the Monocytic Lineage and Via Increased RANKL Production By B Cells and Osteoblasts
Authors: Sahar Hiram-Bab, Naamit Deshet, Tamar Liron, Moshe Mittelman, Max Gassmann, Martina Rauner, Kristin Franke, Ben Wielockx, Yankel Gabet, Drorit Neumann
Journal: Blood (2014)
FLT3/ITD Expression Increases Expansion, Survival and Entry into Cell Cycle of Human Hematopoietic Stem Cells.
Authors: Li Li, Obdulio Piloto, Kyu-Tae Kim, Zhaohui Ye, Bao Nguyen, Xiaobing Yu, Mark Levis, Linzhao Cheng, Donald Small
Journal: Blood (2004)
Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1
Authors: A Abdelbaset-Ismail, S Borkowska-Rzeszotek, E Kubis, K Bujko, K Brzeźniakiewicz-Janus, L Bolkun, J Kloczko, M Moniuszko, G W Basak, W Wiktor-Jedrzejczak, M Z Ratajczak
Journal: Leukemia (2016)
PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition
Authors: Pau Castel, Haley Ellis, Ruzica Bago, Eneda Toska, Pedram Razavi, F. Javier Carmona, Srinivasaraghavan Kannan, Chandra S. Verma, Maura Dickler, Sarat Chandarlapaty, Edi Brogi, Dario R. Alessi, José Baselga, Maurizio Scaltriti
Journal: Cancer Cell (2016)
Diagnostic Utility of Isoelectric Focusing and High Performance Liquid Chromatography in Fetal Cord Blood Screening for Thalassemia and Non-Sickling Hemoglobinopathies,
Authors: Noppacharn Uaprasert, Rung Settapiboon, Supaporn Amornsiriwat, Patsita Sarnthammakul, Ponlapat Rojnuckarin, Pranee Sutcharitchan
Journal: Blood (2011)
Abstract 2655: Oncogenic chromatin factors drive cell type-specific transcription within megadomains in NUT midline carcinoma
Authors: Mitzi I. Kuroda, Artyom A. Alekseyenko, Erica M. Walsh, Xin Wang, Adlai Grayson, Peter T. Hsi, Peter V. Kharchenko, Christopher A. French
Journal: Cancer Research (2016)

Abstract NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we find correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These ‘megadomains’ appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones. Megadomains drive transcription of underlying DNA in NMC patient cells and in naïve cells induced to express BRD4-NUT. Here we characterize the constituents of BRD4-NUT chromatin complexes using a crosslinking approach, BioTAP-XL. We find many transcriptional activating proteins known to associate with BRD4, along with novel interactors including p300/CBP and a previously uncharacterized BRD4-NUT Megadomain Associated Protein (BMAP1). BMAP1 is expressed in primary NMC tissue and a subset of more common head and neck squamous cell carcinomas (HNSQC). Concurrently, we discovered a patient-derived NMC harboring a novel BMAP1-NUT fusion. BMAP-NUT blocks differentiation, and like BRD4-NUT recruits p300 to form hyperacetylated megadomains, including at the MYC locus. Thus, our proteomic and genetic approaches have converged on a novel mechanism that involves reprogramming very large regulatory regions to drive oncogenic transcription. Citation Format: Mitzi I. Kuroda, Artyom A. Alekseyenko, Erica M. Walsh, Xin Wang, Adlai Grayson, Peter T. Hsi, Peter V. Kharchenko, Christopher A. French. Oncogenic chromatin factors drive cell type-specific transcription within megadomains in NUT midline carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2655.
Abstract 4640: Doxorubicin induced cardiomyopathy associated with natural reproductive hormone cycling in female tumor-bearing spontaneously hypertensive rats
Authors: Kaytee L. Pokrzywinski, Elliot T. Rosen, Julia Bonnano, Thomas Biel, Delaram Moshkelani, Baikuntha Aryal, Steven Mog, V. Ashutosh Rao
Journal: Cancer Research (2016)

Abstract Doxorubicin (dox) is a widely used oncology agent known to induce dose-limiting cardiomyopathy, driven partially by the excess production of reactive oxygen species (ROS) in mitochondria. Cardiomyocytes are particularly sensitive to ROS due to higher densities of mitochondria and lower concentrations of antioxidants. The incidence of dox induced cardiomyopathy is lower in reproductively mature women compared to age matched men, while pre-pubescent and post-menopausal females are more sensitive. Previous studies have associated reproductive hormone levels with differences in cardiosensitivity based on gender and age. This is the second part of a two part study investigating the role that reproductive hormones play in dox induced cardiotoxicity in female, tumor-bearing spontaneously hypertensive rats (SHRs). In the current study, we investigated the impact of natural hormone cycling on dox induced cardiomyopathy. Before beginning the experiment, regular hormone cycling was established by monitoring daily changes in the estrous cycle by way of vaginal cytology. The animals were organized by phase (proestrus, estrus, metestrus, or diestrus) and implanted with SST-2 cells, a syngeneic breast cancer cell line derived from a SHR. Tumor-bearing animals were administered a single dose of saline, dox, the cardioprotectant dexrazoxane, or a combination thereof and monitored for 14 days. Daily vaginal cytologies were obtained throughout the experiment to monitor estrous cycling as a means of tracking hormone fluctuations. Serum was collected at various time points to correlate estrous cycling with circulating hormone levels (E2 and P4) and measure the cardiac health indicator cardiac troponin I (cTnI). In all hormone groups, dox treatment resulted in a net loss in bodyweight and significant anti-tumor activity, as measured by tumor volume, compared to respective saline controls. Interestingly, animals treated with saline in metestrus displayed increased tumor volumes compared to animals in different estrous phases. We are currently evaluating cardiac status by echocardiogram, histopathology, and cTnI. We are also measuring serum E2 and P4 hormone levels in an effort to understand the relationship between cardiomyopathy and circulating hormones. Citation Format: Kaytee L. Pokrzywinski, Elliot T. Rosen, Julia Bonnano, Thomas Biel, Delaram Moshkelani, Baikuntha Aryal, Steven Mog, V. Ashutosh Rao. Doxorubicin induced cardiomyopathy associated with natural reproductive hormone cycling in female tumor-bearing spontaneously hypertensive rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4640.
Abstract 4885: Intratumoral injection of G100 (TLR4 agonist glycopyranosyl lipid A) modulates tumor microenvironment and induces CD8 T cell-dependent, systemic anti-tumor immunity
Authors: Hailing Lu, Jessica Hewitt, Jan ter Meulen.
Journal: Cancer Research (2016)

Abstract The tumor microenvironment (TME) plays a critical role in controlling the balance between tumor progression and immune surveillance. Increased infiltration of T cells, especially CD8 T cells has been associated with a good prognosis. We hypothesized that G100, a novel synthetic TLR4 agonist, can modulate TME when directly injected into the tumor and trigger both a local and systemic effective immune response. Balb/c mice with implanted syngeneic A20 lymphoma received intratumoral (IT) injection of G100 (10 ìg) or control PBS three times a week. This treatment significantly inhibited tumor growth and resulted in complete tumor regression in approximately 60% of treated mice. To investigate the effects of G100 on TME, tumors were collected after three IT G100 injections for gene expression analysis by Nanostring and immune phenotyping analysis by FACS. Out of the 770 immune response genes included in the mouse PanCancer Immune Profiling panel, 295 genes were significantly upregulated in G100 treated tumors. The upregulated genes include DC function-related genes (CD40, CD83, CD86, and Ly96) and T cell and NK cell function genes and multiple chemokines and cytokines (IL1b, IL12A, IL18, IL6, IFNã, FcãR4, ICOS, GZMB, CCL3, CCL5, CCL7, CXCL1, CXCL2, CXCL11, CCR5, CCR6, and CCR7). T cell exhaustion markers (CTLA4 and LAG3) and CD274 (PD-L1) were also induced. G100-induced inflammation is also reflected at the cellular level as shown by increased T cells and NK cells in tumor via FACS analysis. To determine the immune cells that mediated tumor rejection, mice were selectively depleted of CD4 or CD8 T cells during G100 treatment. Results showed that the anti-tumor effect of G100 is dependent on CD8 T cells. G100-induced tumor protection was durable as mice surviving the first tumor challenge rejected a secondary tumor challenge without additional G100 treatment. Altogether, our results showed that IT G100 induces a proinflammatory cytokine and chemokine milieu that changes a “cold” tumor to a “hot” tumor, which facilitates the development of a CD8 T cell-dependent potent and durable anti-tumor effect. The induction of PD-L1 also suggests the potential synergy between G100 and checkpoint blockade therapy. These preclinical data support an on-going clinical trial of IT G100 in patients with follicular non-Hodgkin's lymphoma (NCT02501473), alone and in combination with anti-PD-1 therapy (pembrolizumab). Citation Format: Hailing Lu, Jessica Hewitt, Jan ter Meulen. Intratumoral injection of G100 (TLR4 agonist glycopyranosyl lipid A) modulates tumor microenvironment and induces CD8 T cell-dependent, systemic anti-tumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4885.
Terbutaline: level the playing field for inhaled β<sub>2</sub>-agonists by introducing a dosing and urine threshold
Authors: Glenn A Jacobson, Morten Hostrup
Journal: British Journal of Sports Medicine (2016)

Terbutaline, a short-acting β 2 -agonist similar to salbutamol, is widely used in Europe in the treatment of asthma and exercise-induced bronchoconstriction. Unlike salbutamol, terbutaline requires therapeutic use exemption (TUE) for therapeutic inhaled use in competitive sport. There is now compelling evidence that supratherapeutic use of terbutaline is performance enhancing, via oral dosing and inhalation. It is likely that the ergogenic effects of terbutaline are class specific for all β 2 -agonists. The World Anti-Doping Agency (WADA) has introduced dosing and urine threshold and decision limits for other common β 2 -agonists. This allows athletes to use these drugs for therapeutic purposes while minimising the potential for doping and administrative burden of TUEs. However, no such threshold limits currently exist for terbutaline. For terbutaline, athletes can be granted a TUE, then administer the drug via inhalation at supratherapeutic doses with impunity. The introduction of threshold dosing and urine limits for terbutaline should be a high priority, given the drug's demonstrated ergogenic effects.
Abstract LB-091: Inhibition of Siglec-15 prevents bone loss in a mouse model of multiple myeloma
Authors: Gilles B. Tremblay, Anna Moraitis, Karin Vanderkerken, Mario Filion
Journal: Cancer Research (2016)

Abstract Multiple myeloma (MM) is a B-cell malignancy associated with infiltration and growth of plasma cells in the bone marrow resulting in end-organ damage including devastating osteolytic bone disease. We examined the ability of 25B2, an antibody targeting Siglec-15, to prevent bone loss in the 5T2MM syngeneic model of MM. C57BlKaLwRij male mice (n = 10/group) were injected with 5T2MM cells and 24h later treated for 12 weeks with the PBS, 25B2 (10 mg/kg, q3d), bortezomib (0.7 mg/kg, q3d) or a combination of 25B2 and bortezomib. 25B2 treatment caused a 3.7-, 5.4- and 1.2-fold increase in bone volume (%BV/TV) compared to PBS-treated mice in the tibia, femur and lumbar vertebra (LV), respectively. Increases in bone volume were also seen with bortezomib with 3.1-, 4.1- and 1.4-fold increases in the tibia, femur and LV, respectively. Combination of the two agents further increased%BV/TV by 6.9-, 10.5- and 1.5-fold in the tibia, femur and LV, respectively, when compared to the PBS treated mice. All of the changes were statistically significant with the exception of those in the LV. Unlike bortezomib treatment, which inhibits the growth of 5T2MM cells in this model, there was no direct effect of 25B2 on tumor burden in 5T2MM mice when the percentage of plasmacytosis and the serum paraprotein levels were measured. However, 25B2 caused a significant decrease in the number of bone lesions by 49.5%. The number of lesions in the bortezomib group decreased by 71.7%, but there was no significant difference between the 25B2 and bortezomib groups. The number of lesions decreased by 89.4% in the combination group. Consistent with the mechanism of action of Siglec-15 antibodies, osteoclasts were rendered inactive, however cross-talk with bone-forming osteoblasts was likely maintained. This unique mechanism of action would be particularly appropriate for MM, where osteolytic disease is not only the result of increased osteoclast activity but also decreased osteoblast-mediated bone formation. The 5T2MM model is one of the most representative of the human pathology and therefore, the effect observed in response to the Siglec-15 antibody holds the promise that such a treatment in MM patients could provide benefit and further delay skeletal related events. Citation Format: Gilles B. Tremblay, Anna Moraitis, Karin Vanderkerken, Mario Filion. Inhibition of Siglec-15 prevents bone loss in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-091.
Abstract 4087: Mammary fibroblasts exert divergent effects on the survival of invasive breast cancer cells
Authors: Kimberly Hagel, Kelsey Weigel, Meaghan Boyd, Luke McCormack, Matthew Champion, Zachary Schafer
Journal: Cancer Research (2016)

Abstract Cancer development and progression are inherently inefficient processes riddled with anti-tumorigenic obstacles. Anoikis, or apoptosis induced by detachment from the extracellular matrix (ECM), represents one prominent hindrance to cancer progression that transformed cells must overcome in order to survive, particularly during the ECM-bereft metastatic cascade. Far from acting in isolation, we report that one mechanisms of anoikis evasion by invasive breast cancer cells involves the exploitation of carcinoma-associated fibroblasts (CAFs) from the surrounding tumor microenvironment. CAFs secrete insulin-like growth factor-binding proteins (IGFBPs) that facilitate non-canonical activation of integrin-linked kinase (ILK), activation of ERK/MAPK, and ultimately stabilization of the anti-apoptotic protein Mcl-1 to promote cancer cell survival during ECM detachment. Further investigation into the influence of the tumor microenvironment on cancer cell survival revealed that, contrary to the role of CAFs, normal mammary fibroblasts (NMFs) appear to exert anti-tumorigenic effects on ECM attached cancer cells. Utilizing conditioned media from NMFs, we have found that NMFs secrete factors that increase caspase activation in multiple cancer cell lines, suggestive of NMF-mediated cancer cell death. Because cancer progression necessitates the intermingling of cancer cells with normal stromal cells, particularly at early time points in primary tumor and metastases formation, we hypothesize that this NMFs pose yet another obstacle to disease progression that may compliment the process of anoikis by capping the metastatic cascade with environments that are inhospitable to cancer cell survival. Similar to anoikis evasion, our data suggests that cancer cells must evade NMF-induced death stimuli in order to survive, possibly through the accrual of CAFs in the tumor microenvironment to combat or replace the pro-apoptotic NMFs. Using traditional and 3D mammalian cell culture in combination with in vivo studies, we aim to delineate the roles of both CAFs and NMFs on cancer cell survival under conditions of differential ECM availability. A more complete understanding of the nuances dictating cancer cell-fibroblast interactions could yield informative data relevant to chemotherapeutic research and development. Citation Format: Kimberly Hagel, Kelsey Weigel, Meaghan Boyd, Luke McCormack, Matthew Champion, Zachary Schafer. Mammary fibroblasts exert divergent effects on the survival of invasive breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4087.
Phase II study of intraperitoneal paclitaxel plus S-1/oxaliplatin for gastric cancer with peritoneal metastasis: SOX+IP PTX trial.
Authors: Yoshiyuki Fujiwara, Hironori Ishigami, Hiroto Miwa, Tsutomu Tanaka, Yasuhiro Kodera, Haruhiko Imamoto, Motohiro Imano, Ryoji Fukushima, Akio Hidemura, Shugo Ueda, Atsushi Nashimoto, Hiroshi Yabusaki, Tetsuya Kusumoto, Yoshikazu Uenosono, Hiroharu Yamashita, Hironori Yamaguchi, Toshiaki Watanabe, Joji Kitayama
Journal: Journal of Clinical Oncology (2016)

4040 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously reported the safety and efficacy of IP paclitaxel (PTX) plus S-1/PTX in phase I and II studies. S-1/oxaliplatin (SOX) showed non-inferiority to S-1/cisplatin in PFS, and is considered as a new standard regimen for the first-line treatment of advanced gastric cancer on an outpatient basis in Japan. We designed a new regimen combining IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. The recommended dose of IP PTX was determined to be 40 mg/m2 in a phase I study. A phase II study of SOX plus IP PTX regimen was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled. PTX was administered intraperitoneally at 40 mg/m2 on days 1 and 8. Oxaliplatin was administered intravenously at 100 mg/m2 on day 1, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, repeated every 21 days. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Sixty patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 10 (range 1-19). The 1-year OS rate was 71% (95% CI, 58-81%). The overall response rate was 67% (95% CI, 22-96%) in 6 patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 35 (75%) of 47 patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 55% and 44%, respectively. The frequent grade 3/4 toxicities included neutropenia (50%), leukopenia (27%), anemia (18%) febrile neutropenia (12%) and anorexia (12%). Catheter obstruction and infection of the peritoneal implantable port were observed in one patient each. There were no treatment-related deaths. Conclusions: Combination chemotherapy of SOX plus IP PTX regimen is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000012834.