tbuckley/cabot-search huggingface dataset:
DRES-03. PARP INHIBITOR, INHIBITION OF HOMOLOGOUS RECOMBINATION, OR DIANHYDRODULCITOL CAN OVERCOME TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS
Authors: Shigeo Ohba, Yuichi Hirose
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The acquisition of resistance to TMZ and the heterogeneity of the tumor are considered to be associated with poor prognosis. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 were obtained and analyzed. A clone showed high homologous recombination (HR), and inhibition of HR resensitized the clone to TMZ. MMR system was suppressed in the other clones. Inhibition of BER by PARP inhibitor resensitized them to TMZ. PARP inhibitor enhanced the TMZ-induced cytotoxicity in glioma cells with high expression of MGMT. Dianhydrodulcitol, alkylating agent, suppressed the proliferation in U251 and even U251-derived resistant clones. These effects were shown in U87MG-dereived resistant clones and MGMT-proficient cell lines. Moreover, inhibition of HR enhanced the cytotoxicity of dianhydrodulcitol. To select the appropriate treatment according to the mechanisms of resistance to TMZ can overcome the resistance in glioma cells.
RARE-47. CHARACTERIZATION OF ADULT MEDULLOBLASTOMA; A RETROSPECTIVE REVIEW OF 200 PATIENTS AT MD ANDERSON CANCER CENTER
Authors: Nazanin Majd, Max Mastall, Kenneth Hess, Greg Fuller, Kristin Alfaro-Munoz, Maria Gule-Monroe, Jason Huse, Soumen Khatua, Ganesh Rao, David I Sandberg, Jeffrey Wefel, Debra Yeboa, Wafik Zaky, Anita Mahajan, Vinay Puduvalli, Dima Suki, Shiao-Pei Weathers, Rebecca Harrison, John DeGroot, Marta Penas-Prado
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p&lt; 0.0001 and 2.33, p&lt; 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.
Cognitive Impairment Is Associated with Inferior Survival and Increased Non-Relapse Mortality in Older Allogeneic Hematopoietic Cell Transplant (alloHCT) Recipients: A Multicenter Retrospective Study
Authors: Rebecca L. Olin, Caitrin Fretham, Marcelo C. Pasquini, Mukta Arora, Vijaya R. Bhatt, Benjamin Derman, Sergio A Giralt, Li-Wen Huang, Thuy T. Koll, Sang Mee Lee, Richard J Lin, Linda Pang, Uday Popat, Daniel J. Weisdorf, Andrew S. Artz
Journal: Blood (2019)
Superiority of IFN Versus HU Using a Novel Biomarker-Based Tool for Assessment of Disease Burden in MPNs
Authors: Vibe Skov, Marc JB Dam, Rasmus K Pedersen, Morten Andersen, Trine Alma Knudsen, Zamra Sajid, Lasse Kjær, Christina Ellervik, Hans Hasselbalch, Johnny T Ottesen
Journal: Blood (2019)
Mutational Landscape of Pediatric Acute Myeloid Leukemia: A Report of the AML-BFM Study Group with a Targeted NGS Approach in 525 Patients Integrating De Novo, Relapsed and Secondary AML
Authors: Christiane Walter, Markus Schneider, Nils Von Neuhoff, Helmut Hanenberg, Dirk Reinhardt, Mareike Rasche
Journal: Blood (2019)
Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA
Authors: Brian J Ball, Christopher Famulare, Eytan M. Stein, Martin S. Tallman, Saar I. Gill, Benjamin M Manning, Jamie Koprivnikar, James McCloskey, Rebecca Testi, Najla Al Ali, David A Sallman, Eric Padron, Aaron D Goldberg, Rami S. Komrokji
Journal: Blood (2019)
Adrenalectomy for Breast Cancer
Authors: O. H. Pearson
Journal: BMJ (1955)

<h3>ABSTRACT</h3> Neuronal homeostasis depends on the proper functioning of different quality control systems. The accurate degradation of dysfunctional mitochondria by mitophagy is essential for maintaining mitochondrial quality and quantity in neurons. Huntingting protein (Htt) can interact with numerous other proteins and thereby perform multiple biological functions in the cell. We investigated the role of Htt during neuronal mitophagy in post-mitotic differentiated striatal neurons avoiding artificial overexpression of mitophagy-related proteins. Our study shows that Htt promotes the physical proximity of different protein complexes during initiation of the mitophagy process. Htt is needed to promote the ULK1 complex activation, the recruitment of the essential receptors of mitophagy –optineurin and NDP52- and the interaction of these receptors with LC3-II. Mutant Htt also causes a gain of toxic function avoiding the formation of the Beclin1-Vps34 initiation complex. We report that the presence of the expanded polyQ tract can affect the efficiency of neuronal mitophagy and consequently promote the accumulation of damaged mitochondria and increase oxidative stress, leading to mitochondrial dysfunction and contributing to neurodegeneration in Huntington’s disease.
Targeting B-Cell Maturation Antigen (BCMA) with CC-93269, a 2+1 T Cell Engager, Elicits Significant Apoptosis in Diffuse Large B-Cell Lymphoma Preclinical Models
Authors: Patrick R. Hagner, Michelle Waldman, Falon D. Gray, Renee Yura, Sarah Hersey, Henry Chan, Mingjun Zhang, Isaac Boss, Anita K Gandhi
Journal: Blood (2019)
Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance
Authors: Emely Verweyen, Dirk Holzinger, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Peter Pickkers, Sabrin Albeituni, Katherine Verbist, Kim E. Nichols, Grant Schulert, Alexei Grom, Dirk Foell, Christoph Kessel
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/β signaling. JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/β. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1β) production from human monocytes requires cooperative Toll-like receptor and IFNα/β signaling. Interference with IFNα/β expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.
Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study
Authors: Markus V. Heppt, Teresa Amaral, Katharina C. Kähler, Lucie Heinzerling, Jessica C. Hassel, Markus Meissner, Nicole Kreuzberg, Carmen Loquai, Lydia Reinhardt, Jochen Utikal, Evelyn Dabrowski, Anja Gesierich, Claudia Pföhler, Patrick Terheyden, Kai-Martin Thoms, Lisa Zimmer, Thomas K. Eigentler, Michael C. Kirchberger, Henner M. Stege, Friedegund Meier, Max Schlaak, Carola Berking
Journal: Journal for ImmunoTherapy of Cancer (2019)

Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
Tisagenlecleucel Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Children and Young Adults with Acute Lymphoblastic Leukemia (ALL): Real World Experience from the Center for International Blood and Marrow Transplant Research (CIBMTR) and Cellular Therapy (CT) Registry
Authors: Stephan Grupp, Zhen-Huan Hu, Yiyun Zhang, Amy Keating, Michael A. Pulsipher, Christine Philips, Steven P. Margossian, Joseph Rosenthal, Dana Salzberg, Deborah E. Schiff, Gregory Yanik, Kevin J. Curran, Andrew C. Harris, Peiman Hematti, Sarah Nikiforow, Patricia Steinert, Lan Yi, Raghav Chawla, Mary M. Horowitz, Eric Bleickardt, Marcelo C. Pasquini
Journal: Blood (2019)
Linear endoscopic ultrasound examination of portal biliopathy
Authors: Radhika Chavan, Zaheer Nabi, Sundeep Lakhtakia, Mohan Ramchandani, Jahangeer Basha, Rajesh Gupta, D. Nageshwar Reddy
Journal: Endoscopy (2019)

A 30-year-old man diagnosed 10 years ago with extrahepatic portal vein thrombosis underwent multiple sessions of endoscopic band ligation of esophageal varices. The last endoscopy session showed obliterated varices. Recently the patient complained of having had mild abdominal pain for 2 weeks. Laboratory evaluation showed mild anemia (Hb 11 g/dL) and normal bilirubin (total 1 mg/dl) with mildly elevated liver enzymes: alanine transaminase 68 U/L, aspartate transaminase 42 U/L, and alkaline phosphatase 168 U/L (normal < 120 U/L). Serum amylase and lipase were normal. Contrast-enhanced computed tomography showed diffuse thickening of the common bile duct (CBD) ([Fig. 1]), multiple peripancreatic collaterals, and a normal pancreas. Magnetic resonance cholangiography could not be done because of the patient's claustrophobia. For CBD evaluation he underwent endoscopic ultrasonography (EUS) with a linear echoendoscope. The EUS scope was passed into the duodenal bulb. From the duodenal bulb, multiple serpiginous linear structures were seen in the suprapancreatic region. On Doppler examination all these linear serpiginous structures showed a positive signal, and in the center a small, round, anechoic structure suggestive of the CBD was seen ([Video 1]). The CBD was then traced from the ampulla to the hilum and back and forth. These paracholedochal collaterals resulted in a diffusely decreased caliber of the CBD. On CT examination these paracholedochal collaterals gave a pseudo-appearance of thickened walls of the CBD. Further EUS examination showed a normal pancreas, splenomegaly, and multiple peripancreatic and splenic hilar collaterals ([Fig. 2]). The patient was managed symptomatically and asked to attend for regular follow-up.
Deregulated CXCR4-CXCL12 Signaling Impacts on the Pathogenesis of DLBCL
Authors: Katrin Pansy, Julia Feichtinger, Barbara Ehall, Barbara Uhl, Hildegard T. Greinix, Katharina Prochazka, Christine Beham-Schmid, Peter Neumeister, Tanja Wrodnigg, Karoline Fechter, Alexander Deutsch
Journal: Blood (2019)
Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial
Authors: Alex C. Spyropoulos, Gary E. Raskob, Alexander T Cohen, Walter Ageno, Jeffrey I. Weitz, Theodore E. Spiro, Wentao Lu, Concetta Lipardi, Elliot S. Barnathan
Journal: Blood (2019)
Comparison of Outcomes after Early Hospital Discharge (EHD) Following Intensive Induction Vs. Post-Remission Chemotherapy for Adults with Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms
Authors: Anna B. Halpern, Nicholas P Howard, Megan Othus, Paul C. Hendrie, Nikita Vashi Baclig, Sarah A Buckley, Mary-Elizabeth M. Percival, Pamela S. Becker, Bart L. Scott, Vivian G. Oehler, Terry B. Gernsheimer, Sioban B. Keel, Johnnie Orozco, Ryan D. Cassaday, Andrei R Shustov, Garrett Hartley, Verna L Welch, Elihu H. Estey, Roland B. Walter
Journal: Blood (2019)
Methotrexate and Area Under the Curve Exposure in Patients Receiving MT-R for Primary CNS Lymphoma: A Single Institution Retrospective Study
Authors: Alex G Sieg, Christopher Strouse, Sarah L Mott, Joshua Reeder, Sergei Syrbu, Guohua An, Grerk Sutamtewagul, Brian K. Link, Umar Farooq
Journal: Blood (2019)
Active DNA Demethylation Mediated By GADD45β Is Essential during G-CSF Triggered Granulocytic Differentiation
Authors: Perihan Mir, Maksim Klimiankou, Narges Aghaallaei, Betuel Findik, Frederic Thalheimer, Susanne Wingert, Michael A. Rieger, Thomas Thumberger, Cornelia Zeidler, Baubak Bajoghli, Karl Welte, Julia Skokowa
Journal: Blood (2019)
Enestpath Leukemic Stem Cell (LSC) Sub-Study: Analyzing Characteristics of LSC-Positive Patients and Impact of Switch from Imatinib to Nilotinib Therapy on LSCs in Patients with Chronic Myeloid Leukemia
Authors: Fermin Sanchez-Guijo, Sergio Matarraz, Eleni Plata, Miguel Sagüés, Montserrat Cortes, Irena Preloznik Zupan, Monica Crugnola, Giovanni Caocci, Heather Oakervee, Tobias Gedde-Dahl, Krzysztof Warzocha, Wieslaw W. Jedrzejczak, Slawomira Kyrcz-Krzemien, Alexander Kiani, Sharon Supekar, AnaRita Ferreira, Seema Shah, Juan Luis Steegmann, Michele Baccarani
Journal: Blood (2019)
Retrospective Non-Interventional Assessment of the Use of Idelalisib in Relapsed/Refractory Chronic Lymphocytic Leukemia Patients in Spain
Authors: Christelle M Ferra, Manuel Perez Encinas, Javier Lopez Jimenez, Macarena Ortiz, Santiago Osorio-Prendes, Raul Cordoba, Angel Ramirez Payer, Eva González-Barca, Guillermo Martín Sánchez, Marcos Gonzalez Diaz, Maria Jose Sanchez, Margarita Fernandez, Patricia Baltasar Tello, Elena Amutio, María-Dolores García-Malo, Maria Jesus Vidal Maceñido, Pascual Fernandez, Javier Loscertales, Juan Nicolás Rodríguez, Concha Alaez, Heribert Ramroth, Margarida Palla
Journal: Blood (2019)
18F-FDG PET Imaging Features of Patients With Autoimmune Lymphoproliferative Syndrome
Authors: Jorge A. Carrasquillo, Clara C. Chen, Susan Price, Millie Whatley, Nilo A. Avila, Stefania Pittaluga, Elaine S. Jaffe, V. Koneti Rao
Journal: Clinical Nuclear Medicine (2019)

Introduction Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory condition, usually presenting in childhood with massive lymphadenopathy, splenomegaly, and an increased incidence of lymphoma. Methods to differentiate between benign ALPS adenopathy and lymphoma are needed. To this end, we evaluated the usefulness of FDG PET. Methods We prospectively evaluated 76 ALPS/ALPS-like patients including F S-7– a ssociated s urface antigen ( FAS ) germline mutation with (n = 4) and without lymphoma (n = 50), FAS -somatic (n = 6), ALPS-unknown (n = 6), and others (n = 10) who underwent FDG PET. Uptakes in 14 nodal sites, liver, and spleen were determined. Results In 76 ALPS patients, FDG PET showed uptake in multiple nodal sites in all but 1 patient. The highest SUVmax values in FAS mutation without lymphoma, FAS mutation with lymphoma, FAS somatic, ALPS-unknown, and other genetic mutations were a median (range) 9.2 (4.3–25), 16.2 (10.7–37.2), 7.6 (4.6–18.1), 11.5 (4.8–17.2), and 5.5 (0–15.3), respectively. Differences between uptake in the FAS group with and without lymphoma were statistically significant, but overlapped, making discrimination between individuals with/without lymphoma impossible. The spleen:liver uptake ratio was greater than 1 in 82% of patients. Conclusions While statistically significant differences were observed in FAS mutation ALPS with and without lymphoma, the significant overlap in FDG uptake and visual appearance in many patients prevents discrimination between patients with and without lymphoma. Similar patterns of FDG biodistribution were noted between the various ALPS subgroups.
Oral delivery of novel human IGF-1 bioencapsulated in lettuce cells promotes musculoskeletal cell proliferation, differentiation and diabetic fracture healing
Authors: J. Park, G. Yan, K.-C. Kwon, M. Liu, P.A. Gonnella, S. Yang, H. Daniell
Journal: Biomaterials (2019)

Human insulin-like growth factor-1 (IGF-1) plays important roles in development and regeneration of skeletal muscles and bones but requires daily injections or surgical implantation. Current clinical IGF-1 lacks e-peptide and is glycosylated, reducing functional efficacy. In this study, codon-optimized Pro-IGF-1 with e-peptide (fused to GM1 receptor binding protein CTB or cell penetrating peptide PTD) was expressed in lettuce chloroplasts to facilitate oral delivery. Pro-IGF-1 was expressed at high levels in the absence of the antibiotic resistance gene in lettuce chloroplasts and was maintained in subsequent generations. In lyophilized plant cells, Pro-IGF-1 maintained folding, assembly, stability and functionality up to 31 months, when stored at ambient temperature. CTB-Pro-IGF-1 stimulated proliferation of human oral keratinocytes, gingiva-derived mesenchymal stromal cells and mouse osteoblasts in a dose-dependent manner and promoted osteoblast differentiation through upregulation of ALP, OSX and RUNX2 genes. Mice orally gavaged with the lyophilized plant cells significantly increased IGF-1 levels in sera, skeletal muscles and was stable for several hours. When bioencapsulated CTB-Pro-IGF-1 was gavaged to femoral fractured diabetic mice, bone regeneration was significantly promoted with increase in bone volume, density and area. This novel delivery system should increase affordability and patient compliance, especially for treatment of musculoskeletal diseases.
Deficiency of Either Carboxypeptidase B2 or Carboxypeptidase N Exacerbated Disease Activity in a Mouse Model of Hemolytic Uremic Syndrome
Authors: Lawrence L. Leung, Zhifei Shao, Toshihiko Nishimura, Qin Zhou, Laura Gigliello, Peter Castro, John Higgins, John Morser
Journal: Blood (2016)
Smoking and Pregnancy
Authors: Jonathan E. Fielding
Journal: New England Journal of Medicine (1978)

In 1957 Simpson published her original finding that babies born to women who smoke during their pregnancy are on the average 200 g lighter than neonates born to nonsmokers.1 More than 100 articles on this relation have led to general acceptance that, on the average, smokers' babies weigh 150 to 250 g less than nonsmokers' babies, and twice as many of the former weigh less than 2500 g. Differences in weight are in direct proportion to the number of cigarettes smoked and are independent of other infant and maternal factors known to influence birth weight.2 Until recently, however, it had . . .