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chemo genetics

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
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
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...
March 1, 2018: Japanese Journal of Clinical Oncology
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
Maria Matos, Bruno Oliveira, Nuria Martínez-Sáez, Ana Guerreiro, Pedro M S D Cal, Jean Bertoldo, Maria Maneiro, Elizabeth Perkins, Julie Howard, Michael 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 both 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...
February 23, 2018: Journal of the American Chemical Society
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
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
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Velickovic, Amanda Rush, Shiloh Middlemiss, Yu-Wooi Ching, Ian Edward Alexander, Geoffrey B McCowage
Gene transfer targeting haematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in the severe combined immuno-deficiencies 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. The HSC is 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...
January 31, 2018: Human Gene Therapy
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
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
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
Madhuram Khandelwal, Vivek Anand, Sandeep Appunni, Amlesh Seth, Prabhjot Singh, Sandeep Mathur, Alpana Sharma
Genetic abnormalities and epigenetic alterations both play vital role in initiation as well as progression of cancer. Whereas genetic mutations cannot be reversed, epigenetic alterations such as DNA methylation can be reversed by the application of DNA methyltransferase inhibitor decitabine. Epigenetic silencing of RASSF1A and involvement of hippo pathway both have been shown to involve in chemo-resistance. Purpose of this study was to observe the effect of combination treatment of decitabine with cisplatin or doxorubicin on bladder cancer cells involving hippo pathway through RASSF1A...
January 24, 2018: Molecular and Cellular Biochemistry
Mikkel Staberg, Rikke Darling Rasmussen, Signe Regner Michaelsen, Henriette Pedersen, Kamilla Ellermann Jensen, Mette Villingshøj, Jane Skjoth-Rasmussen, Jannick Brennum, Kristoffer Vitting-Seerup, Hans Skovgaard Poulsen, Petra Hamerlik
Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter- and intra-patient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem-like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain...
January 23, 2018: Molecular Oncology
Andrea Mari, David D'Andrea, Mohammad Abufaraj, Beat Foerster, Shoji Kimura, Shahrokh F Shariat
Bladder cancer (BCa) is burdened by high rates of chemo- and radio-resistance. We reviewed and summarized the current evidence regarding the genetic determinants of resistance in patients treated with chemotherapy and/or radiotherapy (RT) for BCa. Genetic heterogeneity may preexist to treatment arising with tumorigenesis or increasing progressively during the treatment. Several biological pathways seem to be involved in the cellular response to treatment. These pathways comprehend mechanisms leading to modify the intracellular concentration of the drug, mechanisms leading to increase the repair of DNA damage caused by the treatment, mechanisms leading to increase cell survival, despite DNA damage, acting on the signaling pathways affecting apoptosis, mechanisms promoting autophagy...
December 2017: Translational Andrology and Urology
Bradford E Hall, Michaela Prochazkova, Matthew R Sapio, Paul Minetos, Natalya Kurochkina, B K Binukumar, Niranjana D Amin, Anita Terse, John Joseph, Stephen J Raithel, Andrew J Mannes, Harish C Pant, Man-Kyo Chung, Michael J Iadarola, Ashok B Kulkarni
Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and this interaction was blocked by TFP5, an inhibitor that prevents activation of Cdk5...
January 19, 2018: Scientific Reports
Michael Tøstesen, Lene S G Østergård, Eigil Kjeldsen, Jesper Stentoft, Jan M Nørgaard
Acute promyelocytic leukaemia has changed from being a highly fatal to a highly curable disease. Over time, key discoveries have identified the genetic and molecular abnormalities, which cause the disease. First choice of treatment has now changed from all-trans retinoic acid (ATRA) and chemotherapy to a chemo-free combination of arsenic trixoide and ATRA. This new regimen has shown equal responses and overall cure rates compared with the previous standard of care containing conventional chemotherapy, but with much lower toxicity...
January 15, 2018: Ugeskrift for Laeger
Nikica Šutalo, Snježana Tomić, Milenko Bevanda, Vedran Dragišić, Inga Marijanović, Joško Petričević, Ivanka Mikulić
BACKGROUND: Chemo preventive and antitumor role of vitamin D is manifested through genetic and non genetic ways with a powerful antproliferatory and proapopoptic effect, which is proven by numerous epidemiologic studies. The genetic activity of vitamin D is determined through vitamin D receptors (VDR), a member of stero-thyreoidal family of nuclear receptors, which with vitamin D form a cell nucleus complex responsible for the chemo preventive and antitumor effect. VDR in tissue cells is present in the cytoplasm and the nucleus and manifests its genetic activity after transfer from the cytoplasm to the nucleus...
December 2017: Psychiatria Danubina
Kazuharu Kai, Rachel L Dittmar, Subrata Sen
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression predominantly by inhibiting transcription and/or promoting degradation of target mRNAs also in addition to being involved in non-canonical mechanisms regulating transcription, translation and cell signaling processes. Extracellular secretory miRNAs, either in complex with specific proteins or encapsulated in microvesicles called exosomes, are transported between cells as means of intercellular communication. Secretory miRNAs in circulation remain functional after delivery to recipient cells, regulating target genes and their corresponding signaling pathways...
December 19, 2017: Seminars in Cell & Developmental Biology
Bryone J Kuss, Constantine S Tam
BACKGROUND: Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high-risk forms are known to be chemo-resistant and associated with early relapse. AIMS: To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants. RESULTS: A 'watch and wait' approach is recommended for all patients who are asymptomatic...
December 2017: Internal Medicine Journal
Daniel Andrade, Meghna Mehta, James Griffith, Janani Panneerselvam, Akhil Srivastava, Tae-Dong Kim, Ralf Janknecht, Terence Herman, Rajagopal Ramesh, Anupama Munshi
The Hippo pathway is an evolutionarily conserved signaling pathway that regulates proliferation and apoptosis to control organ size during developmental growth. Yes-associated protein 1 (YAP1), the terminal effector of the Hippo pathway, is a transcriptional co-activator and a potent growth promoter that has emerged as a critical oncogene. Overexpression of YAP1 has been implicated in promoting resistance to chemo-, radiation and targeted therapy in various cancers. However, the role of YAP1 in radioresistance in triple-negative breast cancer (TNBC) is currently unknown...
November 17, 2017: Oncotarget
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