tbuckley/cabot-search huggingface dataset:
Abstract 4059: Crosstalk between CD8+ T and NK cells: fine-tuning of antitumor immune response
Authors: Roman V. Uzhachenko, J Shawn Goodwin, Lino Costa, Alexander Terekhov, Menaka C. Thounaojam, William H. Hofmeister, Anil Shanker
Journal: Cancer Research (2015)

Abstract Local tumor antigen-specific T cell-NK cell collaboration is indispensable for the elimination of tumor cells, including antigen-deficient tumor escape variants before metastasis. While mechanistic details are available for the innate instruction of the T cell responses, little is known for the adaptive control of NK cell activity. We observed in a mouse model of mastocytoma expressing a self tumor antigen P1A that effector CD8+ T cells provided a necessary “help” to dormant NK cells in eliciting their antitumor effector function. Bioluminescence imaging of mastocytoma tumors following adoptive transfer of P1A-specific T cells in RAG-/- and RAG-/-γc-/- mice showed that NK cell anti-tumor activity requires cytolytic T cells, whereas T cells can function independent of NK cells. In 2D and 3D co-culture systems, we observed that PMA/ionomycin-stimulated CD8+ T cells form multiple contacts with naïve NK lymphocytes. Data show that NK cells interacting with activated CD8+ T cells show an up-regulation of CD25 and CD69 expression mediated by intercellular contacts, and activation of NKG2D receptors and Stat2, Stat6, Jak1, Jak3, Tyk2, and PTEN signaling molecules with a decrease in the phosphorylation of Stat1, PKB/Akt, SAPK/JNK, p38. On the other hand, interacting NK cells down-regulate CD25 molecule expression on CD8+ T cells and promote differentiation of central memory CD44+CD62L+ T cells. CD8+ T cells display an elevation in the phosphorylation of Stat1 and down-regulation of Stat5 with stimulated PKB/Akt, Lck, mTOR, and p42/p44. Moreover, significant changes in the cytosolic and mitochondrial Ca2+, production of mitochondrial ROS, mitochondrial membrane potential, mitochondrial permeability transition pore, and synthesis of nitric oxide and non-protein thiols (mostly, reduced glutathion) were observed in a reciprocal T cell-NK cell interaction. These results highlight the importance of mitochondrial activity in the re-modeling of activation signaling and memory differentiation of interacting CD8 T cells and NK cells. These results will help refine cancer immunotherapeutic strategies. Citation Format: Roman V. Uzhachenko, J Shawn Goodwin, Lino Costa, Alexander Terekhov, Menaka C. Thounaojam, William H. Hofmeister, Anil Shanker. Crosstalk between CD8+ T and NK cells: fine-tuning of antitumor immune response. [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 4059. doi:10.1158/1538-7445.AM2015-4059
Reduced-Intensity Unrelated Cord Blood Transplantation (RICBT) for Adults with Hematological Diseases.
Authors: Shigesaburo Miyakoshi, Koichiro Yuji, Eiji Kusumi, Daisuke Kato, Syouhei Koyama, Masayo Fujiwara, Takashi Maeda, Yuji Miura, Tomohiro Myoujo, Hiroto Narimatsu, Tomoko Matsumura, Kazuhiro Masuoka, Atsushi Wake, Shin-ichi Morinaga, Syuichi Taniguchi
Journal: Blood (2004)
Influence of Genetic Polymorphisms in CYP2C8 and ABCB1 on the Mobilization Ability and Toxicity of Paclitaxel,
Authors: María L. Lozano, Elkin A. Niño, Ana Isabel Anton, Jose Padilla, Jose Rivera, Juan José Cerezo, Cristina Castilla-Llorente, Vicente Garcia
Journal: Blood (2011)
Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease
Authors: Eunsil Hahm, Changli Wei, Isabel Fernandez, Jing Li, Nicholas J Tardi, Melissa Tracy, Shikha Wadhwani, Yanxia Cao, Vasil Peev, Andrew Zloza, Jevgenijs Lusciks, Salim S Hayek, Christopher O'Connor, Markus Bitzer, Vineet Gupta, Sanja Sever, David B Sykes, David T Scadden, Jochen Reiser
Journal: Nature Medicine (2016)
General Biomarker Recommendations for Lymphoma
Authors: Lisa Rimsza, Yuri Fedoriw, Louis M Staudt, Ari Melnick, Randy Gascoyne, Michael Crump, Lawrence Baizer, Kai Fu, Eric Hsi, John W C Chan, Lisa McShane, John P Leonard, Brad S Kahl, Richard F Little, Jonathan W Friedberg, Lale Kostakoglu
Journal: JNCI Journal of the National Cancer Institute (2016)

Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways. However, refinement in diagnostic evaluation is an evolving science. The ability to determine prognosis at diagnosis is variable, and for many of the lymphoid malignancies prognosis can only be made after initial treatment. Clinical trials that aim to evaluate specific features of these diseases are required in order to advance clinical practice that meaningfully addresses this important public health challenge. Herein, we describe the process and general recommendation from the National Cancer Institute (NCI) clinical trials planning meeting in November 2014 to address clinical trial design and biomarker proposals in the context of NCI-supported lymphoma clinical trials in the National Clinical Trials Network.
Abstract 1304: Identification of responders for Anti-CTLA4 in refractory colorectal cancers using CANScript™ platform
Authors: Biswanath Majumder, Baraneedharan Ulaganathan, Allen Thayakumar, Saravanan Thiyagarajan, Nilesh Brijwani, Biplab Tewari, Basavaraja U. Santhappa, Padhma Radhakrishnan, Pradip K. Majumder
Journal: Cancer Research (2015)

Abstract Predicting clinical response to anticancer drugs remains a major challenge in the treatment of cancer. Indeed, while biomarker-guided strategies for personalizing anticancer drugs have shown strong promise in certain cases, recent studies have shown that the tumor microenvironment and heterogeneity can limit the predictive power of biomarkers alone. Here we have engineered a personalized tumor ecosystems, termed CANScript™, that contextually conserve tumor heterogeneity and phenocopy the tumor ecosystem using thin tumor explants maintained in defined tumor grade-matched matrix support and autologous ligands from patients. We then demonstrated that the CANScript™ platform can be used to predict clinical response. Specifically, functional readouts obtained by exposing the CANScript™ ecosystems from more than 1100 patients to a panel of anticancer drugs, together with the corresponding clinical outcomes, were used to train a novel machine learning algorithm; the learned model was then applied to predict clinical response to anticancer drugs in a test group comprising of 900 new patients, where it achieved 100% sensitivity in its predictions while also keeping specificity in a desired high range. We have also observed that CANScript™ retains patient tumor immune environment which is important for clinical response of not only immunomodulators but other anti-cancer drugs. Here we report the effect of immunomodulators in refractory CRC tumors which remains difficult to treat. Data demonstrates that Anti-CTLA-4 has profound antitumor effect in refractory CRC tumors by increasing cytotoxic T-Cells. In this cohort of 16 patients’ tumors CANScript™ platform identifies 31% as responders (5/16) where conventional tumor sections culture model shows only 6% as (1/16) responders. Citation Format: Biswanath Majumder, Baraneedharan Ulaganathan, Allen Thayakumar, Saravanan Thiyagarajan, Nilesh Brijwani, Biplab Tewari, Basavaraja U. Santhappa, Padhma Radhakrishnan, Pradip K. Majumder. Identification of responders for Anti-CTLA4 in refractory colorectal cancers using CANScript™ platform. [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 1304. doi:10.1158/1538-7445.AM2015-1304
Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis of Lipoprotein(a)
Authors: Monika Sharma, Gregory M. Redpath, Michael J.A. Williams, Sally P.A. McCormick
Journal: Circulation Research (2016)

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown.Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells.Human hepatoma cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using Western blot analysis and intracellular localization of Lp(a) by confocal microscopy. Lp(a) was maximally internalized by 2 hours and was detected by an antiapo(a) antibody to be localized to Rab5-positive early endosomes, the trans-Golgi network, and subsequently Rab11-positive recycling endosomes. In human hepatoma cells, the apo(a) component from the internalized Lp(a) was resecreted back into the cellular media, whereas the low-density lipoprotein component was localized to the lysosomal compartment. Lp(a) internalization was reduced 0.35-fold in HAP1 and 0.33-fold in human hepatoma cells in which the plasminogen receptor (KT) was knocked out. Conversely, Lp(a) internalization was enhanced 2-fold in HAP1 and 1.6-fold in human hepatoma cells in which plasminogen receptor (KT) was overexpressed, showing for the first time the role of a specific plasminogen receptor in Lp(a) uptake.The novel findings that Lp(a) is internalized by the plasminogen receptor, plasminogen receptor (KT), and the apo(a) component is recycled may have important implications for the catabolism and function of Lp(a).
Abstract 1207: Nrf2 suppression results in growth inhibition and enhances response to chemotherapy and radiation therapy in triple-negative breast cancer cells
Authors: Yuzhe Yang, Douglas Yee
Journal: Cancer Research (2015)

Abstract Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional activator that specifically binds to the Antioxidant Response Element (ARE) to initiate expression of various anti-oxidative and anti-inflammation genes to protect cells from oxidative stress. Recently, Nrf2 has been shown to redirect glucose and glutamine into anabolic pathways to promote cell proliferation. Constitutive stabilization of Nrf2 has been observed in many human cancers and confers chemo- and radio-resistance of cancer cells. We examined Nrf2 expression and function in triple negative breast cancer cells (TNBC). mRNA and protein expression of Nrf2 were higher in the TNBC cell lines MDA-MB-231 and MDA-MB-436 compared to immortalized breast epithelial cell lines (MCF10A and MCF12A) and estrogen receptor positive breast cancer cell lines (MCF-7 and T47D). shRNA knock-down of Nrf2 in MDA-MB-231 and MDA-MB-436 TNBC cells showed decreased mRNA expression of multiple Nrf2 regulated anti-oxidant (SLC7A11, NQO-1, GCLC, GCLM, SLC7A5, etc) and pentose phosphate pathway genes (G6PD, PGD, ME-1, TKT, TALDO1, PPAT, etc), enhanced basal levels of cellular reactive oxygen species, impaired mitochondrial function as determined by measuring mitochondrial potentials in living cells, and reduced S phase entry. Cells with decreased Nrf2 had reduced cell growth in monolayer and anchorage independent growth assays. In addition, Nrf2 suppression reduced cell migration. Nrf2 down-regulated MDA-MB-231 cells also showed increased response towards ionizing radiation and mitomycin C treatment in clonogenic and soft agar assays. Furthermore, reduced Nrf2 expression decreased the number of stem-like (CD44+/CD24-) cells in MDA-MB-231 cell populations. Thus, Nrf2 regulated many aspects of the malignant phenotype in TNBC and suggest that inhibition of Nrf2 might be a therapeutic target for TNBC. Citation Format: Yuzhe Yang, Douglas Yee. Nrf2 suppression results in growth inhibition and enhances response to chemotherapy and radiation therapy in triple-negative breast cancer cells. [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 1207. doi:10.1158/1538-7445.AM2015-1207
A phase I b study of panobinostat and 5-azacitidine in Japanese patients with MDS, CMML, or AML
Authors: Kimikazu Yakushijin, Hironobu Minami, Toshiki Uchida, Michinori Ogura, Masafumi Taniwaki, Tsutomu Kobayashi, Asuka Mori, Masataka Yonemura, Wataru Munakata, Yukio Kobayashi
Journal: Annals of Oncology (2015)
MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma
Authors: Naoshi Nishida, Tadaaki Arizumi, Satoru Hagiwara, Hiroshi Ida, Toshiharu Sakurai, Masatoshi Kudo
Journal: Liver Cancer (2016)

Background: Several studies suggest the role of circulating microRNAs (miRNAs) as biomarkers of hepatocellular carcinoma (HCC). However, the serum miRNA profile associated with the response to sorafenib remains to be elucidated. The aim of this study was to clarify the specific miRNAs in serum that could predict the early response of HCC to sorafenib treatment. Summary: Analyzing the sera from 16 HCC patients, we selected five miRNAs that showed differences in serum levels between patients with and without tumor responses among 179 known secretory miRNAs by using locked nucleic acid probe-based quantitative PCR. Through further analysis using a validation cohort that included 53 HCC patients who underwent sorafenib treatment and 8 healthy control subjects, we found that miR-181a-5p and miR-339-5p showed significant differences in serum levels among patients with partial response (PR), stable disease (SD), and progressive disease (PD), where PR patients showed the highest and PD the lowest levels. We also analyzed the factors associated with disease control (DC; PR or SD) 3 months after the initiation of sorafenib treatment; patients with DC showed a significantly higher level of serum miR-181a-5p than non-DC patients or healthy control subjects (p = 0.0349 and 0.0180 for DC vs. non-DC and control vs. non-DC by Tukey-Kramer test, respectively). We further conducted multivariate analysis among HCC patients with Barcelona Clinic Liver Cancer stage C using extrahepatic metastasis, serum decarboxyprothrombin, and miR-181a-5p levels as covariables; serum miR-181a-5p was the only independent factor for achieving DC (p = 0.0092, odds ratio 0.139, and 95% confidence interval 0.011-0.658). In addition, miR-181a-5p level was also the only independent factor affecting overall survival (p = 0.0194, hazard ratio 0.267, and 95% confidence interval 0.070-0.818). Key Messages: A high serum level of miR-181a-5p before treatment is associated with DC after the initiation of sorafenib.
Single Versus Double Umbilical Cord Blood Transplantation (UCBT): Higher Risk of Acute Graft-Versus-Host Disease (GVHD) but Lower Transplant Related Mortality (TRM) in Recipients of Double UCBT.
Authors: Margaret L. MacMillan, Claudio Brunstein, Todd E. DeFor, Bruce R. Blazar, Daniel J. Weisdorf, John E. Wagner
Journal: Blood (2006)
Abstract 230: Do-It-Yourself expression microdissection (DIY xMD): A low-cost, high-throughput cell and organelle isolation system
Authors: Michael A. Tangrea, Avi Z. Rosenberg, Patricia A. Fetsch, Michael D. Armani, Liqiang Xi, Mark Raffeld, Tina Thu Pham, Yun Chen, Neil O'Flaherty, Rebecca Stussman, Adele R. Blackler, Qiang Du, Jeffrey C. Hanson, Mark J. Roth, Armando C. Filie, Michael H. Roh, Jason D. Hipp, Michael R. Emmert-Buck
Journal: Cancer Research (2015)

Abstract Laser-based microdissection technologies precisely recover histological regions or cells from cytology preparations and tissue sections. Yet, due to the high-cost and time-intensiveness of these methods, coarse manual microdissection is the most commonly used tool for laboratory-based studies and clinical applications, enabling rapid procurement but at the expense of reduced cell purity. We present a low-cost, do-it-yourself expression microdissection (DIY xMD) kit that combines the speed and ease-of-use of manual methods with the precision of laser-based instruments. Using DIY xMD, we isolated cell targets including ER+ nuclei and GMS-stained aspergillis fungi from clinical specimens. We also demonstrate the advantage of cellular enrichment in a cytology-based study where BRAF and KRAS mutations were masked by background cells in a manual dissection, yet identifiable after cells were recovered by DIY xMD. The new system makes high-throughput, efficient microdissection accessible to investigators and clinicians throughout the world. Citation Format: Michael A. Tangrea, Avi Z. Rosenberg, Patricia A. Fetsch, Michael D. Armani, Liqiang Xi, Mark Raffeld, Tina Thu Pham, Yun Chen, Neil O'Flaherty, Rebecca Stussman, Adele R. Blackler, Qiang Du, Jeffrey C. Hanson, Mark J. Roth, Armando C. Filie, Michael H. Roh, Jason D. Hipp, Michael R. Emmert-Buck. Do-It-Yourself expression microdissection (DIY xMD): A low-cost, high-throughput cell and organelle isolation system. [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 230. doi:10.1158/1538-7445.AM2015-230
Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC)
Authors: J. Bauman, R.L. Ferris, D.A. Clump, J. Ohr, W. Gooding, S. Kim, B. Karlovits, U. Duvvuri, J.T. Johnson, D. Petro, D. Heron
Journal: Annals of Oncology (2016)
GP performance tracker shows where costs could be saved
Authors: Nigel Hawkes
Journal: BMJ (2016)

A new analytical tool enables general practices to be compared with others with a similar patient population to discover how widely they vary in performance and how they might improve.

The tool uses data from many sources to compare measures of GP performance such as prescribing costs, cancer referrals, and emergency admissions—not against neighbouring practices but against 99 practices nationally that match the target practice’s size, demography, ethnic mix, geography, deprivation, and disease prevalence.

Michael von Bertele, former head of Army Medical Services and now chair of Trayned Insight, …
239. Preclinical Studies for the First Hematopoietic Stem Cell (HSC) Gene Editing Trial: Phase 1 Study of Beta-Thalassemia With Autologous Transplantation of Zinc Finger Nuclease-Treated HSC To Upregulate Fetal Hemoglobin
Authors: Dale Ando, Mark C. Walters, Kai-Hsin Chang, Andreas Reik, Fyodor D. Urnov, Gary Lee, Kaye S. Spratt, Edward J. Rebar, Philip D. Gregory, Winson Tang, Thalia Papayannopoulou, George Stamatoyannopoulos, Geoffrey Nichol
Journal: Molecular Therapy (2015)

Beta-thalassemia (β-thal) and sickle cell disease (SCD) are monogenic diseases caused by mutations in the adult β-globin gene. Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment, but its application is limited by: (i) a paucity of HLA-matched donors and (ii) a fixed risk of graft vs host disease (GvHD) and transplant-related mortality. Sustained elevation of fetal hemoglobin (HbF) has a very strong clinical effect in both thalassemia and SCD with curative potential. HbF levels are under genetic control, and alleles of the transcription factor BCL11A that lower its expression result in elevation of HbF. BCL11A is thus an attractive target for gene editing of autologous hematopoietic stem cell (HSC) for HCT in β-hemoglobinopathies. We have designed zinc finger nucleases (ZFNs) that when transiently introduced into stem cells ex vivo can efficiently disrupt the BCL11A gene in hematopoietic stem cells (HSCs) by introduction of mutations following target site cleavage and non-homologous end joining. We have developed a clinical scale GMP process for mRNA electroporation of BC11A ZFNs into HSCs, and show that erythrocytes generated ex vivo from BCL11A-modified HSC have elevated fetal globin mRNA, and over 40% of all Hb is represented by HbF. A similar increase in HbF was seen in modified HSCs from subjects with β-thalassemia. Engraftment and differentiation potential of BCL11a modified and control HSCs in NSG mice were comparable. Furthermore, following engraftment into NSG mice, HSCs placed into erythropoiesis cultures maintained increased HbF levels. Preclinical safety studies included soft agar transformation, karyotyping, and double-strand break quantification following ZFN modification. Both bioinformatics guided and a novel, unbiased, oligonucleotide capture method were used to confirm low levels of off-target activity in BCL11A modified HSC as gauged by deep sequencing. In vivo carcinogenicity was evaluated by engraftment of HSC modified by BCL11A ZFNs in NSG mice. Engraftment and multilineage differentiation were comparable between groups and no evidence for carcinogenicity was found. The primary objective of the Phase I clinical study is to evaluate the safety of autologous BCL11A gene edited HSPC infusion after myeloablative (full dose busulfan) conditioning in subjects with transfusion dependent β-thalassemia major. The secondary objectives are to assess hematologic and immunological reconstitution, and to measure the treatment effects on anemia, RBC transfusion frequency, and iron burden.
Frailty and Subsequent Disability and Mortality among Patients with Critical Illness
Authors: Nathan E. Brummel, Susan P. Bell, Timothy D. Girard, Pratik P. Pandharipande, James C. Jackson, Alessandro Morandi, Jennifer L. Thompson, Rameela Chandrasekhar, Gordon R. Bernard, Robert S. Dittus, Thomas M. Gill, E. Wesley Ely
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The prevalence of frailty (diminished physiologic reserve) and its effect on outcomes for those aged 18 years and older with critical illness is unclear.We hypothesized greater frailty would be associated with subsequent mortality, disability, and cognitive impairment, regardless of age.At enrollment, we measured frailty using the Clinical Frailty Scale (range, 1 [very fit] to 7 [severely frail]). At 3 and 12 months post-discharge, we assessed vital status, instrumental activities of daily living, basic activities of daily living, and cognition. We used multivariable regression to analyze associations between Clinical Frailty Scale scores and outcomes, adjusting for age, sex, education, comorbidities, baseline disability, baseline cognition, severity of illness, delirium, coma, sepsis, mechanical ventilation, and sedatives/opiates.We enrolled 1,040 patients who were a median (interquartile range) of 62 (53-72) years old and who had a median Clinical Frailty Scale score of 3 (3-5). Half of those with clinical frailty (i.e., Clinical Frailty Scale score ≥5) were younger than 65 years old. Greater Clinical Frailty Scale scores were independently associated with greater mortality (P = 0.01 at 3 mo and P < 0.001 at 12 mo) and with greater odds of disability in instrumental activities of daily living (P = 0.04 at 3 mo and P = 0.002 at 12 mo). Clinical Frailty Scale scores were not associated with disability in basic activities of daily living or with cognition.Frailty is common in critically ill adults aged 18 years and older and is independently associated with increased mortality and greater disability. Future studies should explore routine screening for clinical frailty in critically ill patients of all ages. Interventions to reduce mortality and disability among patients with heightened vulnerability should be developed and tested. Clinical trial registered with www.clinicaltrials.gov (NCT 00392795 and NCT 00400062).