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Metabolically Supported Chemotherapy

Jennifer H Shepherd, Daniel Howard, Amie K Waller, Holly Rebecca Foster, Annett Muller, Thomas Moreau, Amanda L Evans, Meera Arumugam, Guénaëlle Bouët Chalon, Eleonora Vriend, Natalia Davidenko, Cedric Ghevaert, Serena M Best, Ruth E Cameron
Platelet transfusions are a key treatment option for a range of life threatening conditions including cancer, chemotherapy and surgery. Efficient ex vivo systems to generate donor independent platelets in clinically relevant numbers could provide a useful substitute. Large quantities of megakaryocytes (MKs) can be produced from human pluripotent stem cells, but in 2D culture the ratio of platelets harvested from MK cells has been limited and restricts production rate. The development of biomaterial cell supports that replicate vital hematopoietic micro-environment cues are one strategy that may increase in vitro platelet production rates from iPS derived Megakaryocyte cells...
August 8, 2018: Biomaterials
Tiago Lobo Ferreira, Tiago Nunes da Silva, Dolores Canário, Maria Francisca Delerue
Ectopic adrenocorticotropic hormone (ACTH) secretion represents 5%-10% of cases of Cushing's syndrome (CS), and approximately 50%-60% of these arise from neuroendocrine lung tumours, including small-cell lung cancer (SCLC). We report a 42-year-old man admitted with hypertension, metabolic alkalosis and severe hypokalaemia. On physical examination, centripetal obesity with 'moon face' and 'buffalo's hump' were identified, and wheezing on left lung was heard. A markedly elevated serum cortisol, ACTH and urine free cortisol production supported the diagnosis of CS...
August 16, 2018: BMJ Case Reports
Lawrence Karsh, Neal Shore, Mark Soloway, Gajanan Bhat, Guru Reddy, Szu-Yun Leu, J Alfred Witjes
Background: Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk. Objective: To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo. Methods: Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT...
July 30, 2018: Bladder Cancer
Angelica Macauda, Eleonora Castelli, Gabriele Buda, Matteo Pelosini, Aleksandra Butrym, Marzena Watek, Marcin Kruszewski, Annette Juul Vangsted, Marcin Rymko, Krzysztof Jamroziak, Niels Abildgaard, Eva Kannik Haastrup, Grzegorz Mazur, Rafael Ríos, Artur Jurczyszyn, Daria Zawirska, Marek Dudziński, Małgorzata Raźny, Magdalena Dutka, Waldemar Tomczak, Anna Suska, Agnieszka Druzd-Sitek, Herlander Marques, Mario Petrini, Miroslaw Markiewicz, Joaquin Martinez-Lopez, Lene Hyldahl Ebbesen, Elżbieta Iskierka-Jażdżewska, Juan Sainz, Federico Canzian, Daniele Campa
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries...
August 6, 2018: British Journal of Haematology
Hae-In Kim, Hyesol Lim, Aree Moon
The incidence and mortality of various cancers are associated with sex-specific disparities. Sex differences in cancer epidemiology are one of the most significant findings. Men are more prone to die from cancer, particularly hematological malignancies. Sex difference in cancer incidence is attributed to regulation at the genetic/molecular level and sex hormones such as estrogen. At the genetic/molecular level, gene polymorphism and altered enzymes involving drug metabolism generate differences in cancer incidence between men and women...
July 1, 2018: Biomolecules & Therapeutics
Catharina Bartmann, Sudha R Janaki Raman, Jessica Flöter, Almut Schulze, Katrin Bahlke, Jana Willingstorfer, Maria Strunz, Achim Wöckel, Rainer J Klement, Michaela Kapp, Cholpon S Djuzenova, Christoph Otto, Ulrike Kämmerer
Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro...
2018: Cancer & Metabolism
Michael I Koukourakis, Alexandra Giatromanolaki
PURPOSE: The anaerobic metabolism of glucose by cancer cells, even under well oxygenated conditions, has been documented by Otto Warburg as early as 1927. Micro-environmental hypoxia and intracellular pathways activating the hypoxia-related gene response, shift cancer cell metabolism to anaerobic pathways. In the current review we focus on a major enzyme involved in anaerobic transformation of pyruvate to lactate, namely lactate dehydrogenase 5 (LDH5). CONCLUSIONS: The value of LDH5 as a marker of prognosis of cancer patients, as a predictor of response to radiotherapy and chemotherapy and, finally, as a major target for cancer treatment and radio-sensitization is reported and discussed...
June 18, 2018: International Journal of Radiation Biology
Matteo Allegretti, Beatrice Casini, Chiara Mandoj, Stefania Benini, Laurent Alberti, Mariangela Novello, Elisa Melucci, Laura Conti, Renato Covello, Edoardo Pescarmona, Giuseppe Maria Milano, Alessio Annovazzi, Vincenzo Anelli, Virginia Ferraresi, Roberto Biagini, Patrizio Giacomini
Background: Limited information is available on the applicative value of liquid biopsy (LB) in rare tumors, including Ewing's sarcoma (ES). The accepted precision diagnostics standards would greatly benefit from a non-invasive LB test monitoring pathognomonic gene rearrangements in the bloodstream. Methods: Tissue and blood samples were collected from six and four ES patients, respectively. Plasma was cleared by two successive rounds of centrifugation and stored frozen until RNA extraction by the QIAmp CNA kit...
2018: Therapeutic Advances in Medical Oncology
Julian Hlouschek, Christine Hansel, Verena Jendrossek, Johann Matschke
Pronounced resistance of lung cancer cells to radiotherapy and chemotherapy is a major barrier to successful treatment. Herein, both tumor hypoxia and the upregulation of the cellular antioxidant defense systems observed during malignant progression can contribute to radioresistance. We recently found that exposure to chronic cycling severe hypoxia/reoxygenation stress results in glutamine-dependent upregulation of cellular glutathione (GSH) levels and associated radiation resistance opening novel routes for tumor cell-specific radiosensitization...
2018: Frontiers in Oncology
Jennifer Ose, Akke Botma, Yesilda Balavarca, Katharina Buck, Dominique Scherer, Nina Habermann, Jolantha Beyerle, Katrin Pfütze, Petra Seibold, Elisabeth J Kap, Axel Benner, Lina Jansen, Katja Butterbach, Michael Hoffmeister, Hermann Brenner, Alexis Ulrich, Martin Schneider, Jenny Chang-Claude, Barbara Burwinkel, Cornelia M Ulrich
Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol)...
May 29, 2018: Cancer Medicine
Swatishree Sradhanjali, Mamatha M Reddy
Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate Dehydrogenase Kinase (PDK) is a gatekeeper enzyme involved in altered glucose metabolism in tumors. There are four isoforms of PDK (1 to 4) in humans. PDK phosphorylates E1α subunit of pyruvate dehydrogenase complex (PDC) and inactivates it...
2018: Current Topics in Medicinal Chemistry
Robert U Newton, Stacey A Kenfield, Nicolas H Hart, June M Chan, Kerry S Courneya, James Catto, Stephen P Finn, Rosemary Greenwood, Daniel C Hughes, Lorelei Mucci, Stephen R Plymate, Stephan F E Praet, Emer M Guinan, Erin L Van Blarigan, Orla Casey, Mark Buzza, Sam Gledhill, Li Zhang, Daniel A Galvão, Charles J Ryan, Fred Saad
INTRODUCTION: Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS AND ANALYSIS: Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC)...
May 14, 2018: BMJ Open
Abdul Razak, Bee See Goh, Jothi Raamahlingam Rajaran, Abd Jabar Nazimi
A 51-year-old woman a known case of stage 2 breast carcinoma in 2006 and underwent left mastectomy performed in the same year presented with bilateral lower limb pain suggestive of spinal pathology, and left chin numbness, both of 2 weeks' duration. Examination revealed left mandibular hypoesthesia without any other sign or symptoms. Orthopantomogram was unremarkable apart from mild alveolar bone expansion at tooth 36 area, which was extracted 3 months earlier. Subsequently, a full-body positron emission tomography contrast enhanced computer tomography revealed hypermetabolic lesions of her axial (excluding skull) and appendicular skeleton...
May 14, 2018: BMJ Case Reports
Sayyed K Zaidi, Andrew J Fritz, Kirsten M Tracy, Jonathan A Gordon, Coralee E Tye, Joseph Boyd, Andre J Van Wijnen, Jeffrey A Nickerson, Antony N Imbalzano, Jane B Lian, Janet L Stein, Gary S Stein
Nuclear organization is functionally linked to genetic and epigenetic regulation of gene expression for biological control and is modified in cancer. Nuclear organization supports cell growth and phenotypic properties of normal and cancer cells by facilitating physiologically responsive interactions of chromosomes, genes and regulatory complexes at dynamic three-dimensional microenvironments. We will review nuclear structure/function relationships that include: 1. Epigenetic bookmarking of genes by phenotypic transcription factors to control fidelity and plasticity of gene expression as cells enter and exit mitosis; 2...
May 9, 2018: Advances in Biological Regulation
Zongjing Chen, Liang Zhao, Keqing Shi, Bicheng Chen
BACKGROUND: Pancreatic cancer is one of the most lethal cancers with limited treatment options. Gemcitabine has been the standard drug for patients with advanced pancreatic cancer. Dasatinib is a competitive inhibitor of Src kinase, which has shown promise in treatment of pancreatic cancer. Several studies have revealed the drug resistant mechanism of gemcitabine or dasatinib in human cancers; however, few reports focused on the different mechanisms of gemcitabine and dasatinib resistance in pancreatic cancer...
May 1, 2018: Clinical Laboratory
Reishi Toshiyama, Masamitsu Konno, Hidetoshi Eguchi, Ayumu Asai, Takehiro Noda, Jun Koseki, Kei Asukai, Tomofumi Ohashi, Katsunori Matsushita, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Hiroshi Wada, Koichi Kawamoto, Kunihito Gotoh, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Hepcidin and ferroportin, which are known as key iron regulators, may be used in future treatments of pancreatic ductal adenocarcinoma. Iron is essential for life support; it helps oxygen molecules bind to hemoglobin and acts as an important catalytic enzyme center. However, iron overload is a risk factor for cancer, possibly through the generation of reactive oxygen species (ROS). Hepcidin, which is a peptide hormone mainly generated by the liver, inhibits iron absorption via enterocytes and iron release from macrophages...
May 2018: Oncology Letters
Ramit Singla, Kunal Prakash, Kunj Bihari Gupta, Shishir Upadhyay, Monisha Dhiman, Vikas Jaitak
In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells)...
September 2018: Bioorganic Chemistry
Isabel Tena, Garima Gupta, Marcos Tajahuerce, Marta Benavent, Manuel Cifrián, Alejandro Falcon, María Fonfria, Maribel Del Olmo, Rosa Reboll, Antonio Conde, Francisca Moreno, Julia Balaguer, Adela Cañete, Rosana Palasí, Pilar Bello, Alfredo Marco, José Luis Ponce, Juan Francisco Merino, Antonio Llombart, Alfredo Sanchez, Karel Pacak
Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B ( SDHB ) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB -related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide...
2018: Clinical Medicine Insights. Oncology
Akinori Nukui, Takahiro Narimatsu, Tsunehito Kambara, Hideyuki Abe, Setsu Sakamoto, Ken-Ichiro Yoshida, Takao Kamai
BACKGROUND: There is growing evidence that the transcription factor nuclear factor E2-related factor 2 (Nrf2) is the major participant in regulating antioxidants and pathways for detoxifying reactive oxygen species (ROS), as well as having a vital role in tumor proliferation, invasion, and chemoresistance. It was also recently reported that Nrf2 supports cell proliferation by promoting metabolic activity. Thus, Nrf2 is involved in progression of cancer. Upper urinary tract urothelial carcinoma (UTUC) is a biologically aggressive tumor with high rates of recurrence and progression, resulting in a poor prognosis...
May 2, 2018: BMC Cancer
Gigin Lin, Kun-Ju Lin, Frank Wang, Tse-Ching Chen, Tzu-Chen Yen, Ta-Sen Yeh
Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated in vitro using six cholangiocarcinoma cell lines. In vivo therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model...
May 14, 2018: Disease Models & Mechanisms
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