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chemo genetics

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https://www.readbyqxmd.com/read/29735551/novel-richter-s-syndrome-xenograft-models-to-study-genetic-architecture-biology-and-therapy-responses
#1
Tiziana Vaisitti, Esteban Braggio, John N Allan, Francesca Arruga, Sara Serra, Alberto Zamò, Wayne Tam, Amy Chadburn, Richard R Furman, Silvia Deaglio
Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29721631/multiple-chemo-genetic-interactions-between-a-toxic-metabolite-and-the-ubiquitin-pathway-in-yeast
#2
Delphine Albrecht, Hans C Hürlimann, Johanna Ceschin, Christelle Saint-Marc, Benoît Pinson, Bertrand Daignan-Fornier
AICAR is the precursor of ZMP, a metabolite with antiproliferative properties in yeast and human. We aim at understanding how AICAR (and its active form ZMP) affects essential cellular processes. In this work, we found that ZMP accumulation is synthetic lethal with a hypomorphic allele of the ubiquitin-activating enzyme Uba1. A search for gene-dosage suppressors revealed that ubiquitin overexpression was sufficient to restore growth of the uba1 mutant upon AICAR treatment, suggesting that the ubiquitin pool is critical for cells to cope with AICAR...
May 2, 2018: Current Genetics
https://www.readbyqxmd.com/read/29713268/lateral-hypothalamus-as-a-motivation-cognition-interface-in-the-control-of-feeding-behavior
#3
REVIEW
Gorica D Petrovich
Converging evidence for an essential function of the lateral hypothalamus (LHA) in the control of feeding behavior has been accumulating since the classic work conducted almost 80 years ago. The LHA is also important in reward and reinforcement processes and behavioral state control. A unifying function for the LHA across these processes has not been fully established. Nonetheless, it is considered to integrate motivation with behavior. More recent work has demonstrated that the LHA is also required when cognitive processes, such as associative learning and memory control feeding behavior, suggesting it may serve as a motivation-cognition interface...
2018: Frontiers in Systems Neuroscience
https://www.readbyqxmd.com/read/29676221/prognostic-biomarkers-for-cholangiocarcinoma-and-their-clinical-implications
#4
Charupong Saengboonmee, Kanlayanee Sawanyawisuth, Yaovalux Chamgramol, Sopit Wongkham
Cholangiocarcinoma (CCA) is a poorly prognostic cancer with limited treatment options. Most patients have unresectable tumors when they are diagnosed and the chemotherapies provided are of limited benefit. Prognostic markers are therefore necessary to predict the disease outcome, risk of relapse, or to suggest the best treatment option. Areas covered: This article provides an up-to-date review of biomarkers with promising characteristics to be prognostic markers for CCA reported in the past 5 years. The biomarkers are sub-classified into tissue and serum markers...
April 26, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29670134/detection-of-functional-protein-domains-by-unbiased-genome-wide-forward-genetic-screening
#5
Mareike Herzog, Fabio Puddu, Julia Coates, Nicola Geisler, Josep V Forment, Stephen P Jackson
Establishing genetic and chemo-genetic interactions has played key roles in elucidating mechanisms by which certain chemicals perturb cellular functions. In contrast to gene disruption/depletion strategies to identify mechanisms of drug resistance, searching for point-mutational genetic suppressors that can identify separation- or gain-of-function mutations has been limited. Here, by demonstrating its utility in identifying chemical-genetic suppressors of sensitivity to the DNA topoisomerase I poison camptothecin or the poly(ADP-ribose) polymerase inhibitor olaparib, we detail an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast or haploid mammalian cells in a short timeframe, and with potential applications in other haploid systems...
April 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29643973/epigenetic-versus-genetic-deregulation-of-the-keap1-nrf2-axis-in-solid-tumors-focus-on-methylation-and-noncoding-rnas
#6
REVIEW
F P Fabrizio, A Sparaneo, D Trombetta, L A Muscarella
Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch-like erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo- and radiotherapy resistance of cancer cells...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29628790/heme-oxygenase-inhibition-in-cancers-possible-tools-and-targets
#7
REVIEW
Paulina Podkalicka, Olga Mucha, Alicja Józkowicz, Józef Dulak, Agnieszka Łoboda
Heme oxygenase-1 (HO-1, encoded by HMOX1 ) through degradation of pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe2+ ) and biliverdin, exhibits cytoprotective, anti-apoptotic and anti-inflammatory properties. All of these potentially beneficial functions of HO-1 may play an important role in tumors' development and progression. Moreover, HO-1 is very often upregulated in tumors in comparison to healthy tissues, and its expression is further induced upon chemo-, radio- and photodynamic therapy, what results in decreased effectiveness of the treatment...
March 2018: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/29578688/unprecedented-role-of-hybrid-n-glycans-as-ligands-for-hiv-1-broadly-neutralizing-antibodies
#8
Vidya S Shivatare, Sachin S Shivatare, Chang-Chun David Lee, Chi-Hui Liang, Kuo-Shiang Liao, Yang-Yu Cheng, Gannerla Saidachary, Chung-Yi Wu, Nan-Horng Lin, Peter D Kwong, Dennis R Burton, Chung-Yi Wu, Chi-Huey Wong
The development of HIV vaccine has been hampered by the extraordinary mutability and genetic diversity of the virus, particularly the substantial sequence diversity of gp120 and gp 41 envelope glycoproteins existing in more than 2,000 HIV variants. The highly diverse glycans on HIV spikes are commonly considered as immunologically silent self-antigens; however, the discovery of highly potent broadly neutralizing antibodies (bNAbs) from HIV patients targeting the viral surface glycans has raised a major question about the origin of their antigens...
March 26, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29562639/new-insights-into-protein-kinase-b-akt-signaling-role-of-localized-akt-activation-and-compartment-specific-target-proteins-for-the-cellular-radiation-response
#9
REVIEW
Klaudia Szymonowicz, Sebastian Oeck, Nathalie M Malewicz, Verena Jendrossek
Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors...
March 18, 2018: Cancers
https://www.readbyqxmd.com/read/29549912/%C3%AE-glutamylcysteine-synthetase-%C3%AE-gcs-as-a-target-for-overcoming-chemo-and-radio-resistance-of-human-hepatocellular-carcinoma-cells
#10
Li-Ching Lin, Chi-Fen Chen, Chun-Te Ho, Jun-Jen Liu, Tsan-Zon Liu, Chi-Liang Chern
AIMS: This study uncovered that the genetically endowed intracellular glutathione contents (iGSH) regulated by the catalytic subunit of γ‑glutamylcysteine synthetase heavy chain (γ‑GCSh) as a prime target for overcoming both the inherited and stimuli-activated chemo- and radio-resistance of hepatocellular carcinoma (HCC) cells. MAIN METHODS: Reactive oxygen species (ROS) production and mitochondrial membrane potential (Δψm) were determined by the probe-based flow cytometry...
April 1, 2018: Life Sciences
https://www.readbyqxmd.com/read/29521233/parp-inhibitors-for-the-treatment-of-ovarian-cancer
#11
Laura Cortesi, Angela Toss, Iole Cucinotto
The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer...
March 7, 2018: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29506214/predictive-value-of-genetic-analysis-for-pathological-complete-response-to-preoperative-treatment-in-her2-positive-hr-negative-early-breast-cancer-passion-trial
#12
Takeshi Yamaguchi, Hirofumi Mukai, Masato Takahashi, Fumikata Hara, Chikako Yamauchi, Satoshi Yamashita, Toshikazu Ushijima
We previously reported a potential predictive value of HSD17B4 hypermethylation for pathological complete response after preoperative trastuzumab plus chemotherapy in HER2-positive breast cancer. We will prospectively evaluate the predictive performance of HSD17B4 hypermethylation in patients with HER2-positive/HR-negative breast cancer treated with sequential chemo-radiotherapy. The primary endpoint is the rate of pathological complete response, defined as the absence of invasive and intraductal tumor cells in the breast at surgery, in breast cancer with HSD17B4 hypermethylation...
April 1, 2018: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29484684/clinical-pathological-and-biological-characterization-of-richter-syndrome-developing-after-ibrutinib-treatment-for-relapsed-chronic-lymphocytic-leukemia
#13
Idanna Innocenti, Davide Rossi, Giulio Trapè, Francesco Autore, Luigi Maria Larocca, Vincenzo Gomes, Michaela Cerri, Paolo Falcucci, Simona Sica, Gianluca Gaidano, Luca Laurenti
Richter syndrome, a transformation of chronic lymphocytic leukemia (CLL) into a diffuse large B-cell lymphoma, is a rare complication of patients treated with chemo-immunotherapy. Richter syndrome might be both clonally related or unrelated to the underlying CLL and often showed mutations of the TP53 and NOTCH1 genes. Recently, ibrutinib was approved for patients with relapsed/refractory CLL or for untreated CLL patients with del 17p or TP53 mutation. The clinical picture, pathology, and genetics of Richter transformation after IBR treatment are largely unknown...
February 27, 2018: Hematological Oncology
https://www.readbyqxmd.com/read/29473744/chemo-and-regioselective-lysine-modification-on-native-proteins
#14
Maria J Matos, Bruno L Oliveira, Nuria Martínez-Sáez, Ana Guerreiro, Pedro M S D Cal, Jean Bertoldo, María Maneiro, Elizabeth Perkins, Julie Howard, Michael J Deery, Justin M Chalker, Francisco Corzana, Gonzalo Jiménez-Osés, Gonçalo J L Bernardes
Site-selective chemical conjugation of synthetic molecules to proteins expands their functional and therapeutic capacity. Current protein modification methods, based on synthetic and biochemical technologies, can achieve site selectivity, but these techniques often require extensive sequence engineering or are restricted to the N- or C-terminus. Here we show the computer-assisted design of sulfonyl acrylate reagents for the modification of a single lysine residue on native protein sequences. This feature of the designed sulfonyl acrylates, together with the innate and subtle reactivity differences conferred by the unique local microenvironment surrounding each lysine, contribute to the observed regioselectivity of the reaction...
March 21, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29462900/next-generation-immunotherapy-for-pancreatic-cancer-dna-vaccination-is-seeking-new-combo-partners
#15
REVIEW
Paola Cappello, Claudia Curcio, Giorgia Mandili, Cecilia Roux, Sara Bulfamante, Francesco Novelli
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor...
February 16, 2018: Cancers
https://www.readbyqxmd.com/read/29416873/biomarker-discovery-for-renal-cancer-stem-cells
#16
REVIEW
Claudia Corrò, Holger Moch
Characterised by high intra- and inter-tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo- and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self-renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence...
January 2018: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/29385852/clinical-trial-of-mgmt-p140k-gene-therapy-in-the-treatment-of-pediatric-patients-with-brain-tumors
#17
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Dent, Amanda Rush, Shiloh Middlemiss, Yu Wooi Ching, Ian E Alexander, Geoffrey McCowage
Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T-cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit...
March 23, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29378860/dorsal-raphe-serotonin-neurons-mediate-co-2-induced-arousal-from-sleep
#18
Haleigh R Smith, Nicole K Leibold, Daniel A Rappoport, Callie M Ginapp, Benton S Purnell, Nicole M Bode, Stephanie L Alberico, Young-Cho Kim, Enrica Audero, Cornelius T Gross, Gordon F Buchanan
Arousal from sleep in response to CO2 is a critical protective phenomenon. Dysregulation of CO2 -induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO2 -induced arousal is unknown. Because CO2 is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO2 -induced arousal...
February 21, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29374850/pathological-bases-and-clinical-impact-of-intratumor-heterogeneity-in-clear-cell-renal-cell-carcinoma
#19
REVIEW
José I López, Javier C Angulo
PURPOSE OF REVIEW: Intratumor heterogeneity is an inherent event in tumor development that is receiving much attention in the last years since it is responsible for most failures of current targeted therapies. The purpose of this review is to offer clinicians an updated insight of the multiple manifestations of a complex event that impacts significantly patient's life. RECENT FINDINGS: Clear cell renal cell carcinoma is the most common renal tumor and a paradigmatic example of a heterogeneous neoplasm...
January 27, 2018: Current Urology Reports
https://www.readbyqxmd.com/read/29374563/does-the-use-of-melatonin-overcome-drug-resistance-in-cancer-chemotherapy
#20
REVIEW
Mohammad Hossein Asghari, Emad Ghobadi, Milad Moloudizargari, Marjan Fallah, Mohammad Abdollahi
Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound...
March 1, 2018: Life Sciences
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