tbuckley/cabot-search huggingface dataset:
TMIC-61. ROLE OF CX3CR1 SIGNALING IN MALIGNANT TRANSFORMATION OF GLIOMAS
Authors: Sungho Lee, Khatri Latha, Ganesh Rao
Journal: Neuro-Oncology (2019)

Abstract High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating data suggest that chemokine signaling directly contributes to malignant transformation of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in the malignant transformation of LGGs. First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, a genetically-engineered murine model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. Our data demonstrate that heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism was associated with significantly better median overall survival in patients with LGGs that have transformed to HGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204 positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival. Taken together, our results show that CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated M2 macrophages and microglia and increased angiogenesis.
Characterization of Complete Lncrnas Transcriptome Reveals Expression of Lncrnas As a Prognostic Factor and Linc-Smilo As a Potential Therapeutic Target in Multiple Myeloma
Authors: Arantxa Carrasco, Teresa Ezponda, Cem Meydan, Luis Vitores Valcárcel, Raquel Ordoñez, Marta Kulis, Leire Garate, Estíbaliz Miranda, Victor Segura, Elizabeth Guruceaga, Amaia Vilas-Zornoza, Diego Alignani, Laura Castro, Marien Pascual, Ane Amundarain, Halima El Omri, Ruba Yasin, Maria Jose Calasanz, Francisco J Planes, Bruno Paiva, Christopher Mason, Jesús San-Miguel, Inaki Martin Subero, Ari M Melnick, Felipe Prosper, Xabier Agirre
Journal: Blood (2019)
Eight novel loci implicate shared genetic etiology in multiple myeloma, AL amyloidosis, and monoclonal gammopathy of unknown significance
Authors: Subhayan Chattopadhyay, Hauke Thomsen, Niels Weinhold, Iman Meziane, Stefanie Huhn, Miguel Inacio da Silva Filho, Pavel Vodicka, Ludmila Vodickova, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Börge Schmidt, Stefano Landi, Roman Hajek, Göran Hallmans, Ulrika Pettersson-Kymmer, Claes Ohlsson, Paolo Milani, Giampaolo Merlini, Dorota Rowcieno, Philip Hawkins, Ute Hegenbart, Giovanni Palladini, Ashutosh Wechalekar, Stefan O. Schönland, Richard Houlston, Hartmut Goldschmidt, Kari Hemminki, Asta Försti
Journal: Leukemia (2019)
Predicting the Outcome in Egyptian Patients with Severe Aplastic Anemia Following Allogeneic Hematopoietic Stem Cell Transplantation Using Matched Sibling Donors
Authors: Mai Aly, Hassan Awada, Douaa Sayed, Esam ElBeih, Raafat Abdel El Fattah, Refat Fathy Abdel-Aal Naseer, Reem Alagooz, Rania Hafez, Almetwaly M. Sultan, Nahla El-Sharkawy, Valeria Visconte, Reda Z. Mahfouz
Journal: Blood (2019)
Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation with Venetoclax, Hypomethylating Agents and DLI - a Retrospective Multi Center Study
Authors: Esther Schuler, Eva-Maria Wagner-Drouet, Salem Ajib, Gesine Bug, Martina Crysandt, Sabine Dressler, Andreas Hausmann, Daniela Heidenreich, Klaus Hirschbühl, Matthias Hoepting, Edgar Jost, Jennifer Kaivers, Stefan A Klein, Lambros Kordelas, Oliver Kriege, Lutz Peter Mueller, Christina Rautenberg, Judith Schaffrath, Christoph Schmid, Daniel Wolff, Martin Bornhaeuser, Thomas Schroeder, Guido Kobbe
Journal: Blood (2019)
HOX Genes - Candidate Tumor Suppressor Genes in Adult and Childhood Leukemia.
Authors: Gordon R. Strathdee, Tessa L. Holyoake, Alyson Sim, Anton Parker, David G. Oscier, Junia V. Melo, Stefan Meyer, Tim Eden, Anne M. Dickinson, Joanne Mountford, Heather G. Jorgensen, Richard Soutar, Robert Brown
Journal: Blood (2007)
Clinical implications of incidental venous thromboembolism in cancer patients
Authors: Frits I. Mulder, Marcello Di Nisio, Cihan Ay, Marc Carrier, Floris T.M. Bosch, Annelise Segers, Noémie Kraaijpoel, Michael A. Grosso, George Zhang, Peter Verhamme, Tzu-Fei Wang, Jeffrey I. Weitz, Saskia Middeldorp, Gary Raskob, Ludo F.M. Beenen, Harry R. Büller, Nick van Es
Journal: European Respiratory Journal (2019)

Introduction In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE. Methods The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. Results 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. Conclusion Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.
Gall-bladder Dyspepsia
Authors: W. H. Price
Journal: BMJ (1963)

RMSH ~~~~~~~~MEDICAL JOURNALand there appears to be no clear distinction, either in the severity or in the duration of the attacks, which indicates the precise cause of the pain.Probably the pain may arise from one or more of several causes in a variety of sites in the biliary tract.Judging from the data from 50 case histories of renal colic, the pattern of pain is often similar, but it is also common to have severe background pain, upon which bouts of even greater intensity are superimposed.In renal colic, infection can usually be excluded as a factor by examination of the urine.It is probable, therefore, that high pressure in the renal tract or smooth-muscle spasm, or a combination of these two, is responsible for the pain.That obstruction is present is strongly suggested by the fact that an I.V.P. during the attacks shows increased density of the kidney on the affected side with delay in the pyelo- gram.Evidence that a high pressure occurs proximal to the obstruction is provided by a recent experience.A man aged 49 developed typical right renal colic: an intravenous pyelogram was made about 45 minutes after the onset, when the pain was at its height.The first films showed a normal left pyelogram, an increase in the density of the right kidney, with a small stone at the lower end of the ureter, and later a delayed normal right pyelogram.A radiograph taken a few minutes later showed that the dye had burst out of the renal pelvis as a large cloud in the peripelvic tissues.Thirty-six hours after this there was right shoulder-tip pain, made worse by breathing, which persisted for 24 hours and then subsided without further incident.Retrograde pyelography a few days after the onset showed a normal renal pelvis, and the stone passed uneventfully.SummaryA clinical study is made of the time/intensity pattern of pain in biliary and in renal colic.In biliary colic the pain rises to a plateau and does not usually show fluctuations in severity.Renal colic often has a similar pattern, but nearly half the patients noted some fluctuations in severity during an attack.Possible causes of these pains are discussed.Intermittent pain such as is implied by the word " colic" is rare.Our thanks are due to Professor J.
Quantification of drug uptake, efflux and modulation in MDR cells in vitro and in vivo
Authors: Fei Shen, Barbara Bailey, Aimee Bence, Xinjian Xue, Priscilla Erickson, William Beck, Leonard Erickson
Journal: Cancer Research (2008)

3234  Multidrug Resistance (MDR) is one of the major reasons for anti-cancer chemotherapy failure. The molecular mechanisms of MDR in cancer cells are involved in the over-expression of ATP-Binding Cassette (ABC) transporters on cell membranes. These transporters mediate the efflux of the structurally and functionally unrelated anti-neoplastic drugs from cells and thereby decrease intracellular drug accumulation. Using confocal microscopy we have conducted in vitro and in vivo studies on the roles of P-glycoprotein (Pgp), one of the ABC transporters, in the uptake and efflux of doxorubicin (DOX) and mitoxantrone (MX), and on the effects of Pgp modulators in MDR transduced human cancer MDA-MB-435 cells (MDR). IC50s of DOX and MX in MDA-MB-435 wild type (WT) cells are 0.60 ± 0.04 µM and 0.13 ± 0.008 µM, respectively. The MDR cells were about 9- and 12-fold more resistant to DOX and MX than the WT cells. Intracellular accumulation of DOX and MX in the MDR cells was only 19% and 33% of that in the WT cells. Lower DOX net uptake in the nuclei and stronger DOX efflux in the cytoplasm were the main reasons for the decreased DOX intracellular accumulation in the MDR cells. Compared to the WT cells, MDR cells had lower net uptake of MX in both nuclei and cytoplasm, which was the major cause of the reduced MX intracellular accumulation in the cells. In MDA-MB-435 tumor xenografts in living mice, the accumulation of DOX and MX in MDR tumors was 68% and 42% of that in WT tumors. Pgp inhibitor, PSC833 increased the accumulation of DOX and MX in MDR cells to 65 % and 85% of that in the WT cells in vitro and reversed the fluorescent intensity of DOX and MX in MDR tumors to 94 % of that in the WT tumors in vivo. Taken together, Pgp causes reduced intracellular accumulation by decreasing drug net uptake and/or increasing drug efflux and the Pgp inhibitor PSC833 reverses the effects of Pgp in cancer cells. In addition, Pgp processes individual anticancer compounds differently, which may be related to the anti-neoplastic mechanisms of these drugs.
PDTM-35. MODELLING MEDULLOBLASTOMA WITH MOUSE MODELS AND HUMAN CEREBELLAR ORGANOIDS
Authors: Luca Tiberi
Journal: Neuro-Oncology (2019)

Abstract Malignant medulloblastoma (MB) is the most common brain tumor affecting children and it remains responsible for a high percentage of morbidity and mortality among cancer patients. During the past few years, studies on human MB and mouse models have uncovered the existence of four major MB groups, with specific pathological and molecular features: WNT, SHH, Group 3 and Group 4. Of the four groups, patients with Group 3 MB have the worst outcome with nearly 50% of the tumors metastatic at the time of diagnosis. Therefore, developing “humanized “ mouse model of Group3 Medulloblastoma would be of paramount importance for the identification and testing of new drugs for pediatric patients, tailored on the genetic condition of the patient itself. We performed an in-vivo screen to identify new cancer-inducing genes starting from the published genome-wide analyses of MB patients. This screen led to the identification of novel driver gene combinations required for tumorigenesis. To study Medulloblastoma in human cells, we generated human cerebellar organoids. Organoids are cellular structures that resemble whole organs and can be generated from pluripotent stem cells or isolated organ progenitors. We were able to induce cerebellar progenitors to self-form neuro-epithelial structures that mimic early human cerebellar plate, composed by cerebellar progenitors, cerebellar neurons (interneurons, Purkinje cells, and granule neurons) and glial cells. Notably, we have generated human putative iPSC-derived cancer organoids with gene combinations mimicking human Group3 MB. Indeed, organoids that mimic cancer can be used as an alternative system for drug testing that better recapitulate effects in human patients as compared to other in-vitro and in-vivo systems.
DNA-PK dependent versus independent nonhomologous end joining: Pathway selection as function of reaction conditions
Authors: Cynthia L. Hendrickson, Kamal Datta, Ronald D. Neumann, Thomas A. Winters
Journal: Cancer Research (2005)

5681  DNA double-strand breaks (DSBs) are primarily repaired in mammalian cells by non-homologous end joining (NHEJ). Initially, the Ku 70/80 heterodimer and DNA-PKcs, the catalytic subunit of DNA-PK, were identified as critical components of the NHEJ pathway. It has been demonstrated that Ku binds to DSBs ends and recruits DNA-PKcs to form DNA-dependent protein kinase (DNA-PK), which has been proposed to be the first step in initiating NHEJ repair. This model is supported by experiments demonstrating that DNA end joining can be suppressed by wortmannin, an inhibitor of DNA-PK. Recent studies suggest that DNA-PKcs independent NHEJ pathways exist. Cells lacking DNA-PKcs, such as M059J, still have the capacity to repair DSBs. In addition, in vitro DNA end joining has been observed with human cell extracts after DNA-PKcs depletion. In this study, we provide further evidence of a DNA-PK-independent NHEJ pathway with activity that predominates dependent only upon the in vitro reaction conditions. We have assayed the DNA end joining activity of whole cell extracts (WCEs) from three cell lines (HeLa, M059J, and M059K) at 17°C with and without polyethylene glycol (PEG). DNA end joining activity was observed both in the presence and absence of PEG. However, Ku dependent end joining reactions in the presence of PEG were insensitive to inhibition by wortmannin. In contrast, end joining in the absence of PEG was strongly inhibited by wortmannin. The wortmannin insensitive end joining observed in the presence of PEG suggests a DNA-PK independent pathway, which is further supported by our observation of a loss of kinase activity in the presence of PEG. These data suggest that there are biochemically distinct end joining mechanisms that are a function of the repair complex architecture, which in turn is dependent upon the reaction conditions. This is supported by the observation that unique protein-DNA complexes form in the presence and absence of PEG, as detected by electrophoretic mobility shift assays. Supershift assays with antibodies to Ku and DNA-PKcs also indicated structural differences between the complexes formed in the presence and absence of PEG. Also, a comparison of DNA end joining rates with M059J WCE (lacking DNA-PKcs) and M059K WCE (with DNA-PKcs), showed that even in the presence of PEG, M059K WCE was far more efficient, suggesting that although the kinase is not active, DNA-PKcs may still have a role in DNA end joining. In conclusion, we have established conditions for observing both DNA-PK-dependent and DNA-PK-independent DNA end joining in vitro without removing DNA-PKcs. Furthermore, although the kinase activity of DNA-PK is inhibited in the presence of PEG at 17°C, and different protein complexes are formed on the DNA ends, DNA-PKcs still appears to play role in DNA end joining under these conditions.
Immunization Status at the Time of Liver Transplant in Children and Adolescents
Authors: Amy G. Feldman, Shikha S. Sundaram, Brenda L. Beaty, Richard Torres, Donna J. Curtis, Allison Kempe
Journal: JAMA (2019)

This study characterizes the percentage of pediatric patients undergoing liver transplant who were up to date for their age on immunizations at the time of transplant and risk factors for underimmunization.
Report of 5 Cases of Extramedullary Myeloma with Central Nervous System Involvement Treated with a Combination of Carfilzomib/Thalidomide/Dexamethasone As a First Line Treatment at a Single Institution in Mexico
Authors: Ramiro Espinoza, Diana Berenice Nolasco, Sosa Alejandro, Zapata Nidia, Cervera Eduardo, Myrna Candelaria, Alarcon Silvia, Espinoza Vicente, Vieyra Magnolia, Gutierrez Jorge, Luis Sosa, Escobedo Maria, Gonzalez Reynaldo, Oñate Luis, Lahuerta Juan, Labardini Juan
Journal: Blood (2016)
PATH-35. RETROSPECTIVE ANALYSIS OF 145 PATIENTS WITH GLIOBLASTOMA; CORRELATING MOLECULAR ALTERATION INCIDENCE WITH DEMOGRAPHICS, TUMOR LOCATION, AND PROGNOSIS
Authors: Mina Lobbous, ZacK Tucker, Elizabeth Coffee, Louis Nabors
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.
Immune Thrombocytopenia in Very Elderly Patients: Particularities in Presentation and Management. Results from the Multicenter Prospective Carmen-France Registry
Authors: Aurélien Sokal, Thomas de Nadaï, Thibault Comont, Nicolas Limal, Marc Michel, Odile Beyne-Rauzy, Bertrand Godeau, Daniel Adoue, Matthieu Mahévas, Guillaume Moulis, Carmen investigators Group
Journal: Blood (2019)
The Embryonic Program Activated during Blast Crisis of Chronic Myelogenous Leukemia (CML) Implicates a TCF7L2 and MYC Cooperative Chromatin Binding and Represents a Druggable Target
Authors: Christophe Desterke, Sarah Pagliaro, Patricia Hugues, Annelise Bennaceur-Griscelli, Ali G Turhan
Journal: Blood (2019)
Acute Influenza A Virus Infection Affects Cell Cycle and Lineage Output of Hematopoietic Stem Cells
Authors: Marcel E G Rommel, Lisa Walz, Saskia Kohlscheen, Franziska Schenk, Yvonne Krebs, Kevin Wittwer, Veronika von Messling, Ute Modlich
Journal: Blood (2019)
PDTM-04. EARLY DETECTION BY MRI OF MOUSE MODELS WITH DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Lincy Thomas, Rheal Towner, Rafal Gulej, Nataliya Smith, Michelle Zalles, Debra Saunders
Journal: Neuro-Oncology (2019)

Abstract Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor in childhood with a very devastating prognosis and no curative treatment options as of yet. Approximately 300 children in the U.S. are diagnosed with DIPG each year. Our project hopes to assess the effectiveness of OKlahoma Nitrone-007 (OKN-007) as a therapeutic agent for DIPG. This agent has shown promise in prior studies involving pediatric glioma mouse models by decreasing growth of blood vessels, which is essential for any tumor progression, and by decreasing temozolomide (TMZ) resistance when used as adjunct therapy in adult GBM. We have successfully created an in vivo DIPG model using post-mortem patient-derived neurospheres, harboring the H3 K27M mutation, injected into the pontine region of immunocompromised mouse (SCID) brainstems via a stereotaxic device. After surgical implantation, mice are imaged every week using a 7.0 Tesla 30-cm bore Bruker Biospec Magnetic Resonance Imaging (MRI) system to assess tumor growth and progression of disease. We describe to you the first pre-clinical DIPG mouse model that shows evidence of tumor growth as early as 42 days, as detected on T2-weighted MR images. Another characteristic feature is that the blood-brain barrier (BBB) is intact in this DIPG model, as assessed by contrast-enhanced MRI. Additional MRI methods, including diffusion-weighted imaging (DWI), and perfusion imaging (arterial spin labeling) are also evaluated. Prior pre-clinical DIPG mouse models only had tumor detection by MRI 78 days after implantation. Once the tumors are large enough for treatment (clinically relevant), we separate the mice into a control group (no treatment), OKN-007 treatment alone, as well as combination therapy with OKN-007 and TMZ. With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies to help clinicians better understand and treat pediatric DIPG patients.
Abortion and the Psychiatrist
Authors: D. W. Kay
Journal: BMJ (1965)

BouxiiL later note by McClure' stating, " . . . it has recently been learned that at autopsy the neoplasms evidenced in the bladder and in the breast were indistinguishable histologically.It is impossible, therefore, to conclude that there was a positive relationship between estrogen therapy and the breast tumours...."(2) The editorial also states that " the only cases of breast cancer in men with prostatic cancer have been in patients receiving oestrogen therapy."Gaspari in correspondence with Gardini' mentioned three patients with carcinomas in the breast and prostate without oestrogen therapy.Guthorn,' Hertz,5 and Treves and Holleb6 reported single cases of such associations.If, as Liebegott7 suggested, tissues from the breasts and prostates of patients with car- cinoma of the prostate were examined at necropsy, a better understanding of this relationship may be obtained.-Iam, etc.,
Mitochondrial Oxphos As Survival Mechanism of Minimal Residual AML Cells after Induction Chemotherapy : Survival Benefit By Complex I Inhibition with Iacs-010759
Authors: Lina Han, Antonio Cavazos, Natalia Baran, Qi Zhang, Vinitha Mary Kuruvilla, Jason P Gay, Ningping Feng, Venkata Lokesh Battula, Hagop M. Kantarjian, Naval G. Daver, Joseph R Marszalek, Michael Andreeff, Marina Y Konopleva
Journal: Blood (2019)