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Nelson S Yee
Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented...
March 16, 2018: Biomedicines
Harriet C Fitzgerald, Jemma Evans, Nicholas Johnson, Giuseppe Infusini, Andrew Webb, Luk J R Rombauts, Beverley J Vollenhoven, Lois A Salamonsen, Tracey A Edgell
The regenerative, proliferative phase of a woman's menstrual cycle is a critical period which lays the foundation for the subsequent, receptive secretory phase. Although endometrial glands and their secretions are essential for embryo implantation and survival, the proliferative phase, when these glands form, has been rarely examined. We hypothesized that alterations in the secreted proteome of the endometrium of idiopathic infertile women would reflect a disturbance in proliferative phase endometrial regeneration...
March 13, 2018: Biology of Reproduction
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Han Yao, Jana Vandenbossche, Cari E Sänger-van de Griend, Yorick Janssens, Cristina Soto Fernández, Xiaolong Xu, Evelien Wynendaele, Govert Willem Somsen, Rob Haselberg, Bart De Spiegeleer
A capillary zone electrophoresis (CZE) method with UV detection was developed for the quantification of the E.colil-asparaginase (l-ASNase) and its acidic variants. During the initial method development, a variety of experimental conditions were screened. Subsequently, a Design of Experiments (DoE) was used to optimize the pH and concentration of the selected background electrolyte (BGE) containing both TRIS and boric acid. Optimization was performed taking into account both the separation efficiency of l-ASNase and its acidic variants as well as overall method robustness...
May 15, 2018: Talanta
Ebenezer Ajewole, Liliana Santamaria-Kisiel, Agnieszka Pajak, Mariusz Jaskolski, Frédéric Marsolais
L-asparaginases (EC play an important role in nitrogen mobilization in plants. Here, we investigated the biochemical and biophysical properties of potassium dependent (PvAspG1) and potassium independent (PvAspG-T2) L-asparaginases from Phaseolus vulgaris. Our previous studies revealed that PvAspG1 requires potassium for catalytic activation and its crystal structure suggested that Ser-118 in the activation loop plays a critical role in coordinating the metal cation. This amino acid residue is replaced by isoleucine in PvAspG-T2...
March 2, 2018: FEBS Journal
Kwangsoo Kim, Sa-Young Min, Ho-Dong Lim, Sung-Hwan You, Daejin Lim, Jae-Ho Jeong, Hyun-Ju Kim, Joon Haeng Rhee, Kyeongil Park, Minsang Shin, Geun-Joong Kim, Jung-Joon Min, Hyon E Choy
Bacterial cancer therapy relies on the properties of certain bacterial species capable of targeting and proliferating within solid malignancies. If these bacteria could be loaded with antitumor proteins, the efficacy of this approach could be greatly increased. However, because most antitumor proteins are also toxic to normal tissue, they must be expressed by bacteria that specifically target and exclusively localize to tumor tissue. As a strategy for treating solid malignancies, we recently evaluated L-asparaginase (L-ASNase) delivered by tumor-targeted Salmonella ...
February 2, 2018: Oncotarget
Abbie L Speas, Sarah E Lyles, Kimberly A Wirth, Christine E Fahey, Kelvin Kow, Amandine T Lejeune, Rowan J Milner
OBJECTIVES: To establish the occurrence of increased plasma ammonia concentration after L-asparaginase (L-asp) administration in dogs with high-grade lymphoma or leukemia; to identify risk factors for the development of hyperammonemia after L-asp administration; and to determine occurrence of adverse events related to hyperammonemia. DESIGN: Prospective case controlled study of sequentially enrolled dogs between May 2011 and March 2012. SETTING: A university veterinary teaching hospital...
February 22, 2018: Journal of Veterinary Emergency and Critical Care
Nivedita Patni, Xilong Li, Beverley Adams-Huet, Abhimanyu Garg
BACKGROUND: Extreme hypertriglyceridemia (eHTG; serum triglycerides ≥ 2000 mg/dL) poses a significant risk for acute pancreatitis. There is paucity of data regarding the prevalence and etiology of eHTG in children. OBJECTIVE: To determine the prevalence, clinical features and etiologies of patients with eHTG at a tertiary children's hospital in the United States and in the United States National Health and Nutrition Examination Survey (NHANES). METHODS: A retrospective analysis was conducted of the electronic medical records of the Children's Medical Center, Dallas, from 2000-2015, and the NHANES data from 2005-2014 for eHTG...
January 12, 2018: Journal of Clinical Lipidology
Stuart E Siegel, Wendy Stock, Rebecca H Johnson, Anjali Advani, Lori Muffly, Dan Douer, Damon Reed, Mark Lewis, David R Freyer, Bijal Shah, Selina Luger, Brandon Hayes-Lattin, Jerry J Jaboin, Peter F Coccia, Daniel J DeAngelo, Nita Seibel, Archie Bleyer
Importance: The incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adolescent and young adult (AYA) patients (age range, 15-39 years) in the United States is increasing at a greater rate than in younger or older persons. Their optimal treatment has been increasingly debated as pediatric regimens have become more widely used in the age group. This review compares the basic features of pediatric and adult chemotherapy regimens for ALL and LBL, recognizes and describes the challenges of the pediatric regimen, and suggests strategies to facilitate its adoption for AYAs with ALL and LBL...
February 15, 2018: JAMA Oncology
Inna A Nikonorova, Emily T Mirek, Christina C Signore, Michael P Goudie, Ronald C Wek, Tracy G Anthony
Amino acid availability is sensed by general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal transduction events remains mysterious. In this study we utilized mouse genetic models to investigate the role of GCN2 in hepatic mTORC1 regulation upon amino acid stress induced by a single injection of asparaginase. We found that deletion of Gcn2 prevented hepatic phosphorylation of eukaryotic initiation factor 2 alpha (eIF2) to asparaginase and instead unleashed mTORC1 activity...
February 15, 2018: Journal of Biological Chemistry
Noeman Ardalan, Sako Mirzaie, Abbas Akhavan Sepahi, Ramazan Ali Khavari-Nejad
L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase has been used for the treatment of ALL. Glutaminase activity of enzyme causes some side effect and it is not essential for anticancer activity. The aim of this study was engineering of Escherichia coli asparaginase II to find a mutant with reduced glutaminase activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum mechanics molecular dynamics) simulations...
March 2018: Medical Hypotheses
Marta Mauro-Lizcano, Abelardo López-Rivas
Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation...
February 12, 2018: Cell Death & Disease
Rachael R Schulte, Manasi V Madiwale, Allyson Flower, Jessica Hochberg, Michael J Burke, Jennifer L McNeer, Adam DuVall, Archie Bleyer
Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy...
February 12, 2018: Leukemia & Lymphoma
Simon R V Knott, Elvin Wagenblast, Showkhin Khan, Sun Y Kim, Mar Soto, Michel Wagner, Marc-Olivier Turgeon, Lisa Fish, Nicolas Erard, Annika L Gable, Ashley R Maceli, Steffen Dickopf, Evangelia K Papachristou, Clive S D'Santos, Lisa A Carey, John E Wilkinson, J Chuck Harrell, Charles M Perou, Hani Goodarzi, George Poulogiannis, Gregory J Hannon
Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse...
February 7, 2018: Nature
Patrick W Burke, Ibrahim Aldoss, Matthew A Lunning, Sean M Devlin, Martin S Tallman, Vinod Pullarkat, Ann M Mohrbacher, Dan Douer
Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes. Preliminary results are promising, but hepatotoxicity rates with long-acting pegaspargase are greater in adults than children. However, adult pegaspargase-related hepatotoxicity is not as clearly defined despite being the commonest adult toxicity. We studied the frequency and characteristics of high-grade pegaspargase-related hepatotoxicity in newly diagnosed adults on a pediatric-inspired regimen that included six planned pegaspargase doses, 2000 IU/m2/dose intravenously, with doses given at least four weeks apart and not discontinued or dose-reduced for previous hepatotoxicity...
January 3, 2018: Leukemia Research
Akira Kojima, Kazunari Yamada, Koichi Kajiwara, Yuichi Takeuchi, Marina Matsui, Masao Tsukada, Kanichi Iwama, Yasuji Kozai, Hideki Kodo
A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence...
February 6, 2018: Journal of Adolescent and Young Adult Oncology
Alauldeen Mudhafar Zubair Alqasim, Raji Hussein Al-Hadithi, Aseel Nashaat Al-Khalidi
BACKGROUND: L - asparaginase is chemotherapeutic agent commonly used in treatment of Acute Lymphoblastic Leukemia. Thromboembolic and to a lesser extent bleeding events are serious complications associated with administration of this drug during the induction phase in ALL especially in children resulting from reduced synthesis of proteins such as Antithrombin & fibrinogen. OBJECTIVE: Evaluation of the coagulopathic side effect of L - asparaginase during the induction phase in treatment of ALL in children by measuring fibrinogen levels before & after administration of this drug...
February 1, 2018: Hematology/oncology and Stem Cell Therapy
Sunil S Raikar, James Felker, Kavita N Patel, Glen Lew, Robert F Sidonio
Coagulopathy in pediatric leukemia patients is typically associated with acute promyelocytic leukemia or after asparaginase use in acute lymphoblastic leukemia. Rarely seen in acute lymphoblastic leukemia, we report 2 patients who presented with normal coagulation markers, but subsequently developed severe hypofibrinogenemia and bleeding in induction before administration of asparaginase. In both cases, cryoprecipitate was administered as initial treatment for bleeding associated with the hypofibrinogenemia...
February 2, 2018: Journal of Pediatric Hematology/oncology
Anita Vallacha, Ghulam Haider, Wiky Raja, Dinesh Kumar
OBJECTIVE: To determine the remission rate in adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL). STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Oncology, Jinnah Postgraduate Medical Centre (JPMC), Karachi from January, 2016 to March, 2017. METHODOLOGY: Adolescent and young adult (AYA) patients aged 15-39 years, newly diagnosed with acute lymphoblastic leukemia from January, 2016 to March, 2017...
February 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Naoko Sogame, Rebecca Risbon, Kristine E Burgess
OBJECTIVE To describe signalment, clinicopathologic features, and outcomes of dogs with confirmed primary intestinal lymphoma and assess factors associated with survival times in these patients. DESIGN Retrospective case series. ANIMALS 84 client-owned dogs. PROCEDURES Medical records from 7 veterinary institutions were retrospectively reviewed to identify dogs with primary intestinal lymphoma. Data collected included signalment, clinical signs, anatomic location of tumors, diagnostic procedures, treatment, outcome, and dates of diagnosis and death...
February 15, 2018: Journal of the American Veterinary Medical Association
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