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https://www.readbyqxmd.com/read/29328656/design-and-synthesis-of-novel-reactive-oxygen-species-inducers-for-the-treatment-of-pancreatic-ductal-adenocarcinoma
#1
Yuting Kuang, Mario Sechi, Salvatore Nurra, Mats Ljungman, Nouri Neamati
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29138302/disruption-of-the-opal-stop-codon-attenuates-chikungunya-virus-induced-arthritis-and-pathology
#2
Jennifer E Jones, Kristin M Long, Alan C Whitmore, Wes Sanders, Lance R Thurlow, Julia A Brown, Clayton R Morrison, Heather Vincent, Kayla M Peck, Christian Browning, Nathaniel Moorman, Jean K Lim, Mark T Heise
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene...
November 14, 2017: MBio
https://www.readbyqxmd.com/read/28926599/experimental-colitis-delays-and-reduces-the-severity-of-collagen-induced-arthritis-in-mice
#3
Julie Hablot, Laurent Peyrin-Biroulet, Tunay Kokten, Reine El Omar, Patrick Netter, Claire Bastien, Jean-Yves Jouzeau, Harry Sokol, David Moulin
Amongst extraintestinal manifestations (EIM) occurring in IBD patients, rheumatologic manifestations are the most frequent. Understanding the relationships between arthritis and colitis is a prerequisite to improving the management of these patients. Microbiota of patients with IBD or rheumatologic diseases, like spondyloarthritis (SpA) is modified compared to healthy individual. Thus, we have evaluated the impact of colitis in the development of arthritis in mice and we have analyzed microbiota changes. Collagen-induced arthritis (CIA) was induced at day 0 in DBA1 mice exposed or not to Dextran Sodium Sulfate (DSS) to induce colitis between day 14 and day 21...
2017: PloS One
https://www.readbyqxmd.com/read/28756174/the-potent-anti-cancer-activity-of-dioclea-lasiocarpa-lectin
#4
Ana C S Gondim, Isolda Romero-Canelón, Eduardo H S Sousa, Claudia A Blindauer, Jennifer S Butler, María J Romero, Carlos Sanchez-Cano, Bruno L Sousa, Renata P Chaves, Celso S Nagano, Benildo S Cavada, Peter J Sadler
The lectin DLasiL was isolated from seeds of the Dioclea lasiocarpa collected from the northeast coast of Brazil and characterized for the first time by mass spectrometry, DNA sequencing, inductively coupled plasma-mass spectrometry, electron paramagnetic resonance, and fluorescence spectroscopy. The structure of DLasiL lectin obtained by homology modelling suggested strong conservation of the dinuclear Ca/Mn and sugar-binding sites, and dependence of the solvent accessibility of tryptophan-88 on the oligomerisation state of the protein...
July 16, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28751801/drought-tolerant-brassica-rapa-shows-rapid-expression-of-gene-networks-for-general-stress-responses-and-programmed-cell-death-under-simulated-drought-stress
#5
Yi Ming Guo, Birgit Samans, Sheng Chen, Kidist B Kibret, Sarah Hatzig, Neil C Turner, Matthew N Nelson, Wallace A Cowling, Rod J Snowdon
Production of oilseed rape/canola (Brassica napus) is increasingly threatened by dry conditions while the demand for vegetable oil is increasing. Brassica rapa is a genetically diverse ancestor of B. napus, and is readily crossed with B. napus. Recently, we reported promising levels of drought tolerance in a wild type of B. rapa which could be a source of drought tolerance for B. napus. We analysed global gene expression by messenger RNA sequencing in seedlings of the drought-tolerant and a drought-sensitive genotype of B...
2017: Plant Molecular Biology Reporter
https://www.readbyqxmd.com/read/28571721/transcriptome-analysis-revealed-impaired-camp-responsiveness-in-phf21a-deficient-human-cells
#6
Robert S Porter, Yumie Murata-Nakamura, Hajime Nagasu, Hyung-Goo Kim, Shigeki Iwase
Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. However, the molecular consequences of reduced PHF21A expression remain elusive. In this study, we analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated...
May 29, 2017: Neuroscience
https://www.readbyqxmd.com/read/28545349/exploring-different-mutations-at-a-single-amino-acid-position-of-cucumber-green-mottle-mosaic-virus-replicase-to-attain-stable-symptom-attenuation
#7
Liming Liu, Bin Peng, Zhenwei Zhang, Yang Wu, Manuel Miras, Miguel A Aranda, Qinsheng Gu
Cucumber green mottle mosaic virus (CGMMV) is a member of the genus Tobamovirus (family Virgaviridae) that causes serious economic losses in cucurbit crops. A possibility for CGMMV control is the use of cross-protection, for which stable attenuated isolates are required. In this study, an infectious clone was constructed for the hn isolate of CGMMV. Unexpectedly, this clone carried a nonconserved mutation involving a single nucleotide change resulting in the replacement of Arg by Cys at residue 284 of the replicase protein; this mutation correlated with delayed symptom induction and RNA accumulation, as shown in time-course experiments...
September 2017: Phytopathology
https://www.readbyqxmd.com/read/28472509/multicenter-phase-ii-study-of-temozolomide-and-myeloablative-chemotherapy-with-autologous-stem-cell-transplant-for-newly-diagnosed-anaplastic-oligodendroglioma
#8
Alissa A Thomas, Lauren E Abrey, Robert Terziev, Jeffrey Raizer, Nina L Martinez, Peter Forsyth, Nina Paleologos, Matthew Matasar, Craig S Sauter, Craig Moskowitz, Stephen D Nimer, Lisa M DeAngelis, Thomas Kaley, Sean Grimm, David N Louis, J Gregory Cairncross, Katherine S Panageas, Samuel Briggs, Geraldine Faivre, Nimish A Mohile, Jayesh Mehta, Philip Jonsson, Debyani Chakravarty, Jianjiong Gao, Nikolaus Schultz, Cameron W Brennan, Jason T Huse, Antonio Omuro
Background: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy. Methods: Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3...
October 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28422925/dynamics-of-b-cell-recovery-in-kidney-bone-marrow-transplant-recipients
#9
Baoshan Gao, Yiming Gu, Chunshu Rong, Carolina Moore, Fabrice Porcheray, Waichi Wong, Frederic Preffer, Susan L Saidman, Yaowen Fu, Benedict Cosimi, David H Sachs, Tatsuo Kawai, Megan Sykes, Emmanuel Zorn
BACKGROUND: Previous studies identified B cell gene signatures and predominance of specific B cell subsets as a marker of operational tolerance after kidney transplantation. These findings suggested a role for B cells in the establishment or maintenance of tolerance. Here we analyzed B cell recovery in 4 subjects, 3 of whom achieved tolerance after combined kidney/bone marrow transplantation. METHODS: Peripheral B cell subsets were examined longitudinally by flow cytometry...
November 2017: Transplantation
https://www.readbyqxmd.com/read/28281215/neoadjuvant-treatment-for-locally-advanced-rectal-cancer-new-concepts-in-clinical-trial-design
#10
REVIEW
Nitesh Rana, A Bapsi Chakravarthy, Lisa A Kachnic
Treatment for locally advanced rectal cancer has evolved from surgery alone to surgery plus adjuvant therapy. Preoperative 5-fluorouracil- or capecitabine-based chemoradiation with standard fractionated radiation, surgery utilizing total mesorectal excision, and further chemotherapy has become the standard of care in the USA. Preoperative adjuvant chemoradiation treatment sequencing has allowed for decreased toxicity, more sphincter-sparing surgery, and improved local control rates as compared to delivering the chemoradiation postoperatively...
February 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28242623/type-i-interferon-enhanced-il-10-expression-in-human-cd4-t-cells-is-regulated-by-stat3-stat2-and-batf-transcription-factors
#11
Umeshree Govender, Béatrice Corre, Yasmine Bourdache, Sandra Pellegrini, Frédérique Michel
Type I IFN can exert pro- and anti-inflammatory activities in the immune system. Here, we have investigated the mechanism by which IFN-α enhances early expression of the anti-inflammatory cytokine IL-10 in human CD45RA(+)CD4(+) T cells. With the use of transcriptomic and biochemical approaches, we found distinct and combined contributions of the IFN and the TCR signaling pathways to the induction of STAT1/2/3 and the basic leucine zipper activating transcription factor-like (BATF) family members. Moreover, IFN-induced STAT3 phosphorylation was prolonged by the TCR response, whereas IFN-induced STAT2 phosphorylation was of long duration...
May 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28239415/coupling-gene-regulatory-patterns-to-bioprocess-conditions-to-optimize-synthetic-metabolic-modules-for-improved-sesquiterpene-production-in-yeast
#12
Bingyin Peng, Manuel R Plan, Alexander Carpenter, Lars K Nielsen, Claudia E Vickers
BACKGROUND: Assembly of heterologous metabolic pathways is commonly required to generate microbial cell factories for industrial production of both commodity chemicals (including biofuels) and high-value chemicals. Promoter-mediated transcriptional regulation coordinates the expression of the individual components of these heterologous pathways. Expression patterns vary during culture as conditions change, and this can influence yeast physiology and productivity in both positive and negative ways...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28116088/radiotherapy-and-mva-muc1-il-2-vaccine-act-synergistically-for-inducing-specific-immunity-to-muc-1-tumor-antigen
#13
Gilda G Hillman, Lyndsey A Reich, Shoshana E Rothstein, Lisa M Abernathy, Matthew D Fountain, Kali Hankerd, Christopher K Yunker, Joseph T Rakowski, Eric Quemeneur, Philippe Slos
BACKGROUND: We previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. To investigate whether tumor irradiation augments the immune response to MUC1 tumor antigen, we have tested the efficacy of tumor irradiation combined with an MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for murine renal adenocarcinoma (Renca) cells transfected with MUC1. METHODS: Established subcutaneous Renca-MUC1 tumors were treated with 8 Gy radiation on day 11 and peritumoral injections of MVA-MUC1-IL2 vector on day 12 and 17, or using a reverse sequence of vaccine followed by radiation...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28115216/myb-like-swirm-and-mpn-domains-1-mysm1-deficiency-genotoxic-stress-associated-bone-marrow-failure-and-developmental-aberrations
#14
Ehsan Bahrami, Maximilian Witzel, Tomas Racek, Jacek Puchałka, Sebastian Hollizeck, Naschla Greif-Kohistani, Daniel Kotlarz, Hans-Peter Horny, Regina Feederle, Heinrich Schmidt, Roya Sherkat, Doris Steinemann, Gudrun Göhring, Brigitte Schlegelbeger, Michael H Albert, Waleed Al-Herz, Christoph Klein
BACKGROUND: Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood. OBJECTIVES: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. METHODS: We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses...
October 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27933943/long-lived-intermediates-in-a-cooperative-two-state-folding-transition
#15
Tarick J El-Baba, Doyong Kim, Dylan B Rogers, Faizan A Khan, David A Hales, David H Russell, David E Clemmer
Biomolecular folding often occurs through a cooperative two-state reactant ↔ product transition; the term cooperative does not convey that intermediate structures are nonexistent but rather that these states are not observable by existing experimental techniques. Because of this, few intermediates have been studied and characterized. Recently, ion mobility spectrometry (IMS) measurements revealed that the oligomer polyproline-13 (Pro13, which in propanol (PrOH) favors the right-handed helical PPI structure having adjacent pyrrolidine rings in a cis configuration) folds through six sequential long-lived intermediates as it converts to the all-trans-configured PPII structure that is favored in aqueous solutions...
December 1, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27876864/identification-of-an-infectious-bronchitis-coronavirus-strain-exhibiting-a-classical-genotype-but-altered-antigenicity-pathogenicity-and-innate-immunity-profile
#16
Shu-Yi Lin, Yao-Tsun Li, You-Ting Chen, Ting-Chih Chen, Che-Ming J Hu, Hui-Wen Chen
Avian coronavirus infectious bronchitis virus (IBV) poses economic threat to the poultry industry worldwide. Pathogenic IBV 3575/08 was isolated from broilers vaccinated with the attenuated viral vaccine derived from a Taiwan strain 2575/98. In this study, extensive investigations were conducted on the genome sequences, antigenicity, pathogenicity, and host immune responses of several IBV strains in specific-pathogen-free chickens. Sequence analyses revealed that 3575/08 and 2575/98 shared high homology in their structural genes, but not in non-structural accessory proteins such as 3a, 3b and 5b...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27873472/perfect-timing-splicing-and-transcription-rates-in-living-cells
#17
REVIEW
Tara Alpert, Lydia Herzel, Karla M Neugebauer
An important step toward understanding gene regulation is the elucidation of the time necessary for the completion of individual steps. Measurement of reaction rates can reveal potential nodes for regulation. For example, measurements of in vivo transcription elongation rates reveal regulation by DNA sequence, gene architecture, and chromatin. Pre-mRNA splicing is regulated by transcription elongation rates and vice versa, yet the rates of RNA processing reactions remain largely elusive. Since the 1980s, numerous model systems and approaches have been used to determine the precise timing of splicing in vivo...
March 2017: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27664238/cap-independent-translation-by-dap5-controls-cell-fate-decisions-in-human-embryonic-stem-cells
#18
Yael Yoffe, Maya David, Rinat Kalaora, Lital Povodovski, Gilgi Friedlander, Ester Feldmesser, Elena Ainbinder, Ann Saada, Shani Bialik, Adi Kimchi
Multiple transcriptional and epigenetic changes drive differentiation of embryonic stem cells (ESCs). This study unveils an additional level of gene expression regulation involving noncanonical, cap-independent translation of a select group of mRNAs. This is driven by death-associated protein 5 (DAP5/eIF4G2/NAT1), a translation initiation factor mediating IRES-dependent translation. We found that the DAP5 knockdown from human ESCs (hESCs) resulted in persistence of pluripotent gene expression, delayed induction of differentiation-associated genes in different cell lineages, and defective embryoid body formation...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27595037/an-intrabody-drug-raav6-int41-reduces-the-binding-of-n-terminal-huntingtin-fragment-s-to-dna-to-basal-levels-in-pc12-cells-and-delays-cognitive-loss-in-the-r6-2-animal-model
#19
I Alexandra Amaro, Lee A Henderson
Huntington's disease (HD) is a fatal progressive disease linked to expansion of glutamine repeats in the huntingtin protein and characterized by the progressive loss of cognitive and motor function. We show that expression of a mutant human huntingtin exon-1-GFP fusion construct results in nonspecific gene dysregulation that is significantly reduced by 50% due to coexpression of INT41, an intrabody specific for the proline-rich region of the huntingtin protein. Using stable PC12 cell lines expressing either inducible human mutant huntingtin (mHtt, Q73) or normal huntingtin (nHtt, Q23), we investigated the effect of rAAV6-INT41, an adeno-associated virus vector with the INT41 coding sequence, on the subcellular distribution of Htt...
2016: Journal of Neurodegenerative Diseases
https://www.readbyqxmd.com/read/27592554/targeting-odc1-inhibits-tumor-growth-through-reduction-of-lipid-metabolism-in-human-hepatocellular-carcinoma
#20
Yunseon Choi, Sang Taek Oh, Min-Ah Won, Kyung Mi Choi, Min Ji Ko, Daekwan Seo, Tae-Won Jeon, In Hye Baik, Sang-Kyu Ye, Keon Uk Park, In-Chul Park, Byeong-Churl Jang, Jun-Young Seo, Yun-Han Lee
Ornithine decarboxylase 1 (ODC1), a metabolic enzyme critically involved in the polyamine biosynthesis, is commonly upregulated in hepatocellular carcinoma (HCC). Despite its altered expression in human HCC tissues, the molecular mechanism by which ODC1 alters the course of HCC progression and functions in HCC cell survival is unknown. Here we identified that silencing of ODC1 expression with small interfering (si) RNA causes inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis...
September 30, 2016: Biochemical and Biophysical Research Communications
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