tbuckley/cabot-search huggingface dataset:
The use of a microfluidic chip platform for the ex vivo rapid measurement of chemotherapeutic responses in 3D sub millimeter biopsy samples.
Authors: Muhammad Abdul Lateef, Benjamin Péant, Euridice Carmona, Nassim Rousset, Kayla Simeone, Jennifer Kendall-Dupont, Adriana Mari Orimoto, Anne-Marie Mes-Masson, Thomas Gervais, Fred Saad
Journal: Journal of Clinical Oncology (2016)

e16621 Background: Evaluating prostate cancer response to therapy can often take 3 months and decisions should not be made before that time according to PCWG2 recommendations. Early response predictor identification is a major objective towards personalized medicine. The emergence of microfluidic devices has allowed for ex vivo response measurement to a given therapy in 3D tumor tissue. We have optimized a method to obtain micro-dissected tissues (MDTs) from patient biopsies, with a viability that is maintained for 14 days. Using a microfluidic, on-chip system, we studied the ex-vivo response of the MDTs to a given chemotherapeutic drug by flow cytometry. Methods: We have developed a method to precisely section biopsies into MDTs of sub-millimeter size. We have also designed a microfluidic chip, capable of trapping 25 MDTs, in which they can be exposed to different drugs. With our novel approach, we have initiated drug testing on patient samples using different combinations of Docetaxel alone (100 nM) or in combination with bicalutamide (1 mM). The treatment regimen was initiated after 24-48 hr of tissue recovery, post-surgery. The following cycles of treatment was performed on chip: 1st treatment for 24 hr, 1st recovery for 48 hr, 2nd treatment for 24 hr, 2nd recovery for 48 hr., then cell viability analysis. Results: After 24 hr in culture we observed more than 85% viability of MDTs. We observed a variable response in individual patient samples treated with per protocol on chip (less than 65% to 100% survival). For each patient included in our study, we predicted a personalized potential drug response profile based on the ex vivo response to tested drugs. We are presently comparing these profiles to the clinical response to ongoing therapy in these patients. Conclusions: The ex-vivo drug response of MDTs from patient biopsy samples on chip can be performed in a time effective manner and may eventually contribute to a more personalized approach to clinical decision making.
T-LAK cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in ovarian cancer.
Authors: Yuji Ikeda, Jae Hyun Park, Takashi Miyamoto, Naofumi Takamatsu, Akiko Iwasa, Shuhei Okabe, Yuichi Imai, Keiichi Fujiwara, Yusuke Nakamura, Kosei Hasegawa
Journal: Journal of Clinical Oncology (2016)

e17091 Background: TOPK (T-lymphokine-activated killer cell-originated protein kinase) status in ovarian cancer is not well known. We aimed to clarify the clinical significance of TOPK expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells. Methods: TOPK expression was examined by immunohistochemistry using 106 epithelial ovarian cancer (EOC) and 26 borderline ovarian tumor tissues. Expression levels of TOPK in 11 ovarian cancer cell lines and their half-maximum inhibitory concentration (IC50 ) values against TOPK inhibitors were examined by western blot analysis and by MTT assay, respectively. Using of peritoneal dissemination model of ES-2 ovarian cancer cells, we examined in vivo efficacy of OTS514. In addition, cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined by cell counting assay. Results: TOPK was expressed very highly in 49 (46%) of 106 EOC tissues and high TOPK expression was significantly associated with poor progression free survival and overall survival, especially in early-stage cases of EOC (P = 0.012 and P = 0.025, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on cancer cell lines with IC50 values of 3.0-46 nM and 14-110 nM, respectively. Oral administration of OTS514 significantly elongated overall survival in an ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless to tumor sites or histological subtypes. Conclusions: Our results demonstrated the clinical significance of high TOPK expression, and clinical potential of TOPK inhibitors to treat ovarian cancer.
Mendelian Randomization as an Approach to Assess Causality Using Observational Data
Authors: Peggy Sekula, Fabiola Del Greco M, Cristian Pattaro, Anna Köttgen
Journal: Journal of the American Society of Nephrology (2016)

Mendelian randomization refers to an analytic approach to assess the causality of an observed association between a modifiable exposure or risk factor and a clinically relevant outcome. It presents a valuable tool, especially when randomized controlled trials to examine causality are not feasible and observational studies provide biased associations because of confounding or reverse causality. These issues are addressed by using genetic variants as instrumental variables for the tested exposure: the alleles of this exposure-associated genetic variant are randomly allocated and not subject to reverse causation. This, together with the wide availability of published genetic associations to screen for suitable genetic instrumental variables make Mendelian randomization a time- and cost-efficient approach and contribute to its increasing popularity for assessing and screening for potentially causal associations. An observed association between the genetic instrumental variable and the outcome supports the hypothesis that the exposure in question is causally related to the outcome. This review provides an overview of the Mendelian randomization method, addresses assumptions and implications, and includes illustrative examples. We also discuss special issues in nephrology, such as inverse risk factor associations in advanced disease, and outline opportunities to design Mendelian randomization studies around kidney function and disease.
99 Episodes of Delayed Hemolysis Post transfusion Reaction among Adult Patients with Sickle Cell Disease; Clinical Presentation, Prognosis, and Treatment
Authors: Anoosha Habibi, Constance Guillaud, Armand Mekontso-Dessap, Keyvan Razazi, Justine Gellen- Dautremer, Marc Michel, Bertrand Godeau, Frédéric Galacteros, Pablo Bartolucci, France Noizat-Pirenne
Journal: Blood (2014)
Abstract 2877: Effects of metabolic stressors on cellular differentiation
Authors: Juan Manuel Schvartzman, Craig B. Thompson
Journal: Cancer Research (2016)

Abstract Poor differentiation (the divergence of tumor cell morphology from the cellular morphology of the normal tissue of origin) is associated with unfavorable responses to chemotherapy and poor clinical outcomes in solid tumors. Recurrent somatic mutations in the genes encoding for the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 have recently been identified in patients with acute myeloid leukemias, chrondrosarcomas, cholangiocarcinomas and glioblastomas. Point mutations in IDH lead to production of 2-hydroxyglutarate (2HG). 2HG acts as a potent inhibitor of enzymes involved in the removal of chromatin marks associated with transcriptional repression (DNA and Histone H3K9 methylation). Excess 2HG leads to impaired differentiation but very little is known about the underlying mechanisms. Here we use a well established model of cellular differentiation, the differentiation of 10T1/2 fibroblasts into myofibers by the lineage-specifying transcription factor MyoD to study the mechanisms by which IDH mutations impair differentiation. We show that 5-azacytidine induced differentiation of 10T1/2 cells is impaired when mutant IDH2 is expressed and that IDH2 mutations impair the ability of MyoD expression to reprogram 10T1/2 cells into myofibers. We propose that the metabolic landscape of undifferentiated cells determines the ability of the lineage determining factor MyoD to trigger differentiation and that the undifferentiated state of cancer cells is dependent on their unique metabolic profile. Further work aims to a) define the effects of mutant IDH1/2 on the ability of MyoD to program muscle differentiation, b) determine the nature of the tumorigenic effects of IDH1/2 mutations in 10T1/2 cells and c) identify molecular pathways that can overcome differentiation blocks upon activation. Insight from these experiments will outline the mechanism(s) by which metabolic alterations, in the form of 2HG, impair differentiation and drive tumorigenesis. They will also serve as a platform for the identification of metabolic alterations that trigger differentiation. These mechanisms could prove to be novel and readily targetable processes in an array of poorly differentiated and aggressive cancer subtypes where other pharmacological approaches have failed. Citation Format: Juan Manuel Schvartzman, Craig B. Thompson. Effects of metabolic stressors on cellular differentiation. [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 2877.
Blood pressure variability and cardiovascular risk
Authors: Jeff Whittle
Journal: BMJ (2016)

Would intensifying treatment for higher risk patients improve outcomes?

Although elevated mean blood pressure increases the risk of untoward vascular outcomes, that risk is markedly affected by a range of patient characteristics beyond mean blood pressure. In this issue, Stevens and colleagues (doi:10.1136/bmj.i4098) use meta-analysis to synthesise evidence on the affect of variability in blood pressure on this risk.1 They find consistent evidence that increased variability across clinic visits over months to years is associated with an increased cardiovascular risk. They convincingly exclude confounding by several other known risk factors, such as age, sex, mean blood pressure, and established cardiovascular disease.2 3 Although they found fewer studies of variability measured over shorter time frames, the evidence suggested a similar effect of variability measured over hours and weeks.

How should this new information affect clinical practice? Firstly, we should accept that variability in blood pressure across clinic visits does not tell us much about drug adherence. Previous research has shown that variation in adherence makes only a small contribution to variability in blood pressure.4 Furthermore, the study reminds us of …
Persistence of circulating endothelial microparticles in COPD despite smoking cessation
Authors: Yael Strulovici-Barel, Michelle R Staudt, Anja Krause, Cynthia Gordon, Ann E Tilley, Ben-Gary Harvey, Robert J Kaner, Charleen Hollmann, Jason G Mezey, Hans Bitter, Sreekumar G Pillai, Holly Hilton, Gerhard Wolff, Christopher S Stevenson, Sudha Visvanathan, Jay S Fine, Ronald G Crystal
Journal: Thorax (2016)

<h3>Introduction</h3> Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation. <h3>Methods</h3> Pulmonary function and high-resolution CT (HRCT) were assessed in 28 non-smokers, 61 healthy smokers and 49 COPD smokers; 17 healthy smokers and 18 COPD smokers quit smoking for 12 months following the baseline visit. Total EMP (CD42b<sup>−</sup>CD31<sup>+</sup>), pulmonary capillary EMP (CD42b<sup>−</sup>CD31<sup>+</sup>ACE<sup>+</sup>) and apoptotic EMP (CD42b<sup>−</sup>CD62E<sup>+</sup>/CD42b<sup>−</sup>CD31<sup>+</sup>) levels were quantified by flow cytometry. <h3>Results</h3> Compared with non-smokers, healthy smokers and COPD smokers had elevated levels of circulating EMPs due to active pulmonary capillary endothelial apoptosis. Levels remained elevated over 12 months in healthy smokers and COPD smokers who continued smoking, but returned to non-smoker levels in healthy smokers who quit. In contrast, levels remained significantly abnormal in COPD smokers who quit. <h3>Conclusions</h3> Pulmonary capillary apoptosis is reversible in healthy smokers who quit, but continues to play a role in COPD pathogenesis in smokers who progressed to airflow obstruction despite smoking cessation. <h3>Trial registration number</h3> NCT00974064; NCT01776398.
Abstract 4238: Multispectral optoacoustic tomography detects orthotopic pancreatic tumorsin vivousing a nano-contrast agent
Authors: Phillip Chuong, Matthew Zeiderman, William E. Grizzle, Lacey R. McNally
Journal: Cancer Research (2016)

Abstract There have been very modest developments in pancreatic cancer detection and treatment with mortality essentially remaining unchanged in the last four decades. The major challenge for both early detection and treatment of pancreatic tumors lies in overcoming various biological barriers, especially poor perfusion, insufficient contrast agents/drugs uptake by the tumor, and limitations of traditional imaging modalities. The combination of accurate real-time imaging with tumor-specific nano-contrast agents could mitigate these impediments. We constructed highly stable nano-contrast agents by encapsulating GNRs having aspect ratio 3:1 in PAA (1.5 ± 0.5 nm), and MS (6.25 ± 0.25 nm) shell, respectively and targeted to insulin growth factor 1 receptor (IGF1-R) positive pancreatic tumor cells via Syndecan-1 ligand. IGF1-R specific binding of Syndecan-MS GNRs and Syndecan-PAA-GNR was determined using in an IGF1-R negative cell line (MiaPaca-2) or a blocking antibody to IGF1-R in S2VP10L pancreatic cancer cells determined via flow cytometry. In vivo, mice bearing orthotopic pancreatic tumors were iv injected with 100 nM of Syndecan-MS GNRs and accumulation was determined four hours post injection via Multispectral Optoacoustic Tomography. Biodistribution was determined using a Region of Interest method. The cellular uptake of Syndecan-MS-GNRs significantly enhanced in the S2VP10L cells (503.4 counts) compared to MiaPaca-2 cells (64.1 counts), blocking agent (323.7counts) and untargeted MS GNRs (average 47 counts) revealing that Syndecan-MS-GNRs enhanced both tumor specificity and OA signals by binding with IGF1-R in S2VP10L cells. In vivo, Syndecan-MS-GNRs significantly accumulated in S2VP10L orthotopic pancreatic tumors (233.1 MSOT a.u.) with minimal accumulation in kidney(29.7 MSOT a.u.) and liver (31.4 MSOT a.u.). The Syndecan-MS-GNRs did not accumulate within the orthotopic MiaPaca-2 (IGF1-R negative) mouse model with the biodistribution of pancreas tumor (12.4 MSOT a.u.), kidney (114.3 MSOT a.u.), and liver (35.2 MSOT a.u.). Citation Format: Phillip Chuong, Matthew Zeiderman, William E. Grizzle, Lacey R. McNally. Multispectral optoacoustic tomography detects orthotopic pancreatic tumors in vivo using a nano-contrast agent. [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 4238.
Abstract 2941: Increased expression of ABCB1/MDR1 could be associated with alectinib resistance in ALK-rearranged lung cancer cells
Authors: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Yoshitaka Yagi, Hiroki Nagai, Young Hak Kim, Michiaki Mishima
Journal: Cancer Research (2016)

Abstract Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has shown promising activity in ALK-rearranged non-small cell lung cancer (NSCLC). The mechanisms of drug resistance to alectinib have been still unclear. To explore whether overexpression of ATP-binding cassette (ABC) transporters might provide a potential mechanism of alectinib resistance in lung cancer, we established alectinib-resistant cell lines from NCI-H2228 and primary ALK-rearranged cells and evaluated the expression of ABC transporters. We established ALK-rearranged NSCLC cell lines (KTOR 1, 2, and 3) from tumor cells in pleural effusion obtained from 3 patients with alectinib naïve ALK-rearranged NSCLC. In the 2 of 3 patients, tumor cells in pleural effusion were also obtained when disease progression was observed during alectinib treatment (KTOR1-RE and KTOR2-RE). Expression profiling of ABC transporters using quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the expression of ABCB1 was significantly increased in KTOR1-RE and KTOR2-RE compared with the parental cells (4.6 and 10.8 folds), but not other ABC transporters. Then, alectinib-resistant NCI-H2228 cell lines (H2228-AR) were established by exposing the parental cells to stepwise-increasing alectinib up to 5μM for 10 months. We found that the ABCB1/MDR1 expression in H2228-AR cells were significantly increased (2.09-16.6 folds) compared with the parental cells using qRT-PCR and immunoblotting. Then, we examined the alternation of alectinib cytotoxicity by inhibition of ABCB1. Knockdown of ABCB1 expression using small interfering RNA and inhibition of ABCB1 by verapamil enhanced alectinib cytotoxicity in H2228-AR cells. Next, the levels of ABCB1 expression after short-term alectinib exposure were examined in NCI-H2228 and the three alectinib naïve ALK-rearranged NSCLC primary cell lines (KTOR 1, 2, and 3). In all the four ALK-rearranged cell lines, exposure to 100 nM alectinib for 72 hours induced increased expression of ABCB1 compared with control medium. These data suggested that increased expression of ABCB1/MDR1 might be, in part, responsible acquired resistance and sensitivity to alectinib in ALK-rearranged NSCLC cells. Citation Format: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Yoshitaka Yagi, Hiroki Nagai, Young Hak Kim, Michiaki Mishima. Increased expression of ABCB1/MDR1 could be associated with alectinib resistance in ALK-rearranged lung 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 2941.
Abstract 4182: Statins induce apoptosis in osteosarcoma cells by activation of Ampk and p38-MAPK via suppression of mevalonate pathway
Authors: Walied Abd-Elghani Kamel, Eiji Sugihara, Sayaka Iwai Yamaguchi, Hiroyuki Nobusue, Kenta Maki, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu
Journal: Cancer Research (2016)

Abstract Osteosarcoma (OS) is the most common, non-hematopoietic, primary malignant bone tumor. OS is characterized by its aggressive local growth and systemic dissemination. Although combination of surgical operation and adjuvant chemotherapy greatly improved the prognosis, more than 20% of patients still cannot get long-term survival. Therefore, novel therapeutic approaches should be expected to be developed. Previously, we developed an OS mouse model by overexpressing c-MYC in bone marrow stromal cells derived from Ink4a/Arf knockout mice. We isolated highly tumorigenic cells (designated AXT cells) from tumors after serial transplantation. Inoculation of AXT cells into syngeneic C57BL/6 mice results in the development of lethal OS with metastatic lesions including lung, which pathologically and clinically mimics human osteoblastic osteosarcoma. To obtain the novel therapeutic agents for OS, we performed drug screening using existing drug collections and found that statins strongly suppressed AXT cell growth and migration in vitro. Simvastatin induces caspase dependent apoptosis, which can be completely rescued by the supplement of mevalonate and geranylgeranyl pyrophosphate but not by farnesyl pyrophosphate, suggesting that OS cells are susceptible to the inhibition of the mevalonate pathway. As the responsible effectors, we found treatment of simvastatin drives RhoA-GTP translocation from cell membrane to cytosol as well as the disruption of interaction between RhoA and Rho-GDI, indicating that, in spite of the accumulation of RhoA-GTP in OS cells, RhoA cannot work properly, which appears to affect cell motility and anchorage dependent survival. As downstream signaling of RhoA, p38-MAPK and AMPK are strongly activated by simvastatin treatment. Activation of p38-MAPK is not accompanied by the ROS production. The specific inhibitor for p38-MAPK or AMPK can rescue this activation as well as the simvastatin-induced cell death, respectively, suggesting that activation of both kinases is responsible for the anti-tumor effect of simvastatin. A single treatment of statins attenuated OS tumor growth in vivo. These findings suggest that the activation of p38-MAPK and AMPK by statins become a potential therapeutic option for OS. Citation Format: Walied Abd-Elghani Kamel, Eiji Sugihara, Sayaka Iwai Yamaguchi, Hiroyuki Nobusue, Kenta Maki, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu. Statins induce apoptosis in osteosarcoma cells by activation of Ampk and p38-MAPK via suppression of mevalonate pathway. [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 4182.
Abstract 3497: Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells
Authors: Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Sun Il Lee, Bo Ram Kim, Yoo Jin Na, Suk Young Lee, Hong-Jun Kim, Sung Yup Joung, Sanghee Kang, Sang Cheul Oh
Journal: Cancer Research (2016)

Abstract Recent studies have reported that metformin is an anti-diabetic drug, and is the potential a promising anti-cancer agent. The purpose of this study is to evaluate whether metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL activated the intrinsic and extrinsic pathways of caspase activation. To elucidate the underlying mechanism, we found that metformin significantly reduced the protein levels of Mcl-1 (Myeloid cell leukemia 1) in CRC cells, and overexpression of Mcl-1 attenuated the cell death by metformin alone, or in combination with TRAIL. Further experiments revealed that metformin did not affect the mRNA level, but proteasomal degradation and protein stability of Mcl-1. The metformin-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Taken together, our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through the degradation of Mcl-1 by the proteasome machinery. Citation Format: Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Sun Il Lee, Bo Ram Kim, Yoo Jin Na, Suk Young Lee, Hong-Jun Kim, Sung Yup Joung, Sanghee Kang, Sang Cheul Oh. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal 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 3497.