tbuckley/cabot-search huggingface dataset:
Abstract 448: The role of the Nanog transcription factor in tumor immune escape
Authors: Emily Robitschek, Chih-Ping Mao, Shiwen Peng, Chien-Fu Hung, TC Wu
Journal: Cancer Research (2015)

Abstract The emergence of cancer stem cells and escape from immune surveillance play major roles in the progression of many cancer types. We recently established a link between these two “hallmarks” of cancer by demonstrating that they are both driven by overexpression of Nanog, a pivotal transcription factor in the self-renewal of pluripotent stem cells. In particular, we found that tumor cells acquire Nanog expression in the course of immune selection, and that Nanog confers a stem-like and immune-resistant phenotype to these cells. However, the way in which Nanog causes this to occur remains largely unknown. We reasoned that Nanog-driven immune escape may be in part due to the effect of this transcription factor on the tumor microenvironment. Therefore, here we investigated the relationship between Nanog, immune selection, and the properties of the tumor microenvironment. We found that mice bearing tumor cells that underwent immune selection, compared to those bearing parental tumor cells (without immune selection), had markedly elevated levels of the cytokine IL-6 as well as of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment; both IL-6 and MDSCs have been well-documented to promote cancer immune escape. We further investigated the role of Nanog in setting up this microenvironment. To this end, we have devised an in vivo system that enables us to examine the relationship between Nanog expression in the tumor microenvironment and tumor growth in real-time. Taken together, we infer from these data that not only is Nanog induction a consequence of immune selection, but Nanog also plays an essential role in tumor immune escape. In fact, we found in multiple mouse and human tumor models that Nanog is necessary and sufficient for immune escape. Additionally, these results suggest that Nanog mediates immune escape by converting the tumor microenvironment into an immune-inhibitory site, through the induction of IL-6 and MDSCs. These studies authenticate the role of Nanog in cancer progression as a central instigator of tumor immune escape, and demonstrate its potential both as an important diagnostic/prognostic index and as a therapeutic target. Citation Format: Emily Robitschek, Chih-Ping Mao, Shiwen Peng, Chien-Fu Hung, TC Wu. The role of the Nanog transcription factor in tumor immune escape. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2015-448
Abstract 2211: A comparative analysis of the cis-regulatory landscape between human and mouse
Authors: Feng Yue, Yin Shen, Zhen Ye, Bing Ren
Journal: Cancer Research (2015)

Abstract As the premier model organism in biomedical research, the laboratory mouse shares the vast majority of protein-coding genes with humans, but significant differences exist between the two mammals, posing considerable challenges in the study and modeling of human diseases. The mouse ENCODE consortium applied the same high throughput approaches as the human ENCODE studies and produced more than1000 coordinated datasets in over 100 mouse cell types and tissues and greatly expanded the annotation of the mouse genome. By comparative analysis with the human genome, we found that although the majority of gene expression and cis-regulatory elements are conserved between the two species, a large degree of gene regulatory elements appear to be species-specific and these species-specific elements are enriched for genes involved in immune system and metabolic process, suggesting that different gene pathways evolve at distinct rates. Moreover, we found that species-specific elements are also enriched for repetitive DNA elements such LTR and SINE, which we hypothesize to be responsible generating the species-specific elements. Finally, we developed a novel computational method to study the functional conservation between two species without requiring perfectly matched cell lines or tissues. The result confirms that cis-elements with different evolutionary rates are associated distinct biological pathways and reveals the complex driving forces in the evolution of cis-regulatory landscape in mammals. Note: This abstract was not presented at the meeting. Citation Format: Feng Yue, Yin Shen, Zhen Ye, Bing Ren. A comparative analysis of the cis-regulatory landscape between human and mouse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2211. doi:10.1158/1538-7445.AM2015-2211
Deregulated neddylation in liver fibrosis
Authors: Imanol Zubiete‐Franco, Pablo Fernández‐Tussy, Lucía Barbier‐Torres, Jorge Simon, David Fernández‐Ramos, Fernando Lopitz‐Otsoa, Virginia Gutiérrez‐de Juan, Sergio López de Davalillo, Antonio Martín Duce, Paula Iruzubieta, Daniel Taibo, Javier Crespo, Juan Caballeria, Erica Villa, Igor Aurrekoetxea, Patricia Aspichueta, Marta Varela‐Rey, Shelly C Lu, José M. Mato, Naiara Beraza, Teresa C. Delgado, María L Martínez‐Chantar
Journal: Hepatology (2016)

Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances.Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
Abstract 4379: MPT0B292 enhances acetylation of α-tubulin through up-regulation of acetyltransferase gene, MEC-17 and exhibits potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo
Authors: Jang-Yang Chang, Yun-Ching Cheng
Journal: Cancer Research (2015)

Abstract In recent years, epigenetic therapeutics is a new generation of chemotherapeutics for cancer. Microtubule-targeted agents constitute a type of anticancer drugs largely used in the clinics. Cells generate distinct microtubule subtypes through expression of different iso-types and through post-translational modifications, including acetylation, detyrosination, polyglutamination and polyglycylation. The acetylation of α-tubulin K-40 is controlled by the balance between acetyltransferase and de-acetylase expression. MEC-17, one of α-tubulin acetyltransferases, plays an important role in the regulation of acetylation of α-tubulin. Through screening of compounds that is able to selectively acetylate α-tubulin, MPT0B292 was identified. Our results show that MPT0B292 up-regulate MEC-17 gene and protein expression, which subsequently lead to enhancing α-tubulin acetylation. MPT0B292 exhibits potent anti-proliferative activities toward various human cancer cells with IC50 ranged from 75 to 200 nM. In addition, HUVEC and WI-38 cells were much less susceptibility to the anti-proliferative effect of MPT0B292 with IC50 4 and12 μM, respectively. In FACS analysis of cell cycle, MPT0B292 induces G2/M phase arrest with concomitantly losses from G0/G1 and S phases in a concentration-dependent manner. Furthermore, MPT0B292 induces ROS generation in a concentration-dependent manner by FACS analysis, which leads to damaging mitochondria and triggering cell apoptosis. The effects MPT0B292-induced ROS and cell apoptosis could be significantly rescued by pretreatment with N-acetylcysteine, Diphenyleneiodonium (DPI) and rotenone. Moreover, the amount of ROS induced by MPT0B292 was significantly reduced by knockdown of MEC-17 with siRNA and resulted in rescuing cell viability. In addition, MPT0B292 inhibits cell motility by an increase in cellular focal adhesion area. Moreover, MPT0B292 shows potent activity against the growth of xenograft tumor of lung cancer cell, A549, without significantly compromising the mice body weight. MPT0B292 also decreases lung metastasis in orthotopical breast cancer model. These data indicate MPT0B292 is a promising anticancer compound with unique action of mechanism that has potential for future development. Citation Format: Jang-Yang Chang, Yun-Ching Cheng. MPT0B292 enhances acetylation of α-tubulin through up-regulation of acetyltransferase gene, MEC-17 and exhibits potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4379. doi:10.1158/1538-7445.AM2015-4379
Prognostic Impact of the Plasma Cell Labeling Index (LI) in Newly Diagnosed Myeloma Patients Treated with Thalidomide-Dexamethasone (Thal/Dex) or Lenalidomide-Dexamethasone (Len/Dex).
Authors: Prashant Kapoor, Shaji Kumar, Philip R Greipp, Kristina M. Laumann, Sumithra Mandrekar, S. Vincent Rajkumar, Thomas E. Witzig
Journal: Blood (2008)
A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors
Authors: Ryan J Park, Tim Wang, Dylan Koundakjian, Judd F Hultquist, Pedro Lamothe-Molina, Blandine Monel, Kathrin Schumann, Haiyan Yu, Kevin M Krupzcak, Wilfredo Garcia-Beltran, Alicja Piechocka-Trocha, Nevan J Krogan, Alexander Marson, David M Sabatini, Eric S Lander, Nir Hacohen, Bruce D Walker
Journal: Nature Genetics (2016)
Excellent Long-Term Survival of Patients with Steroid-Refractory and Steroid-Dependent Acute Graft-Versus-Host Disease after Extracorporeal Photochemotherapy.
Authors: Hildegard T. Greinix, Robert M. Knobler, Nina Worel, Margit Mitterbauer, Axel Schulenburg, Armin Schneeberger, Franz Karlhofer, Paul Hoecker, Gerda Leitner, Agathe Rosenmayr, Peter Kalhs
Journal: Blood (2004)
A Novel Real-Time In Vivo Homing Model of Multiple Myeloma.
Authors: Judith M. Runnels, Costas Pitsillides, Joel A. Spencer, Joji Fujisaki, Hai Ngo, Evdoxia Hatjiharissi, Xavier Leleu, Anne-Sophie Moreau, Xiaoying Jia, Teru Hideshima, Nikhil Munshi, Kenneth C. Anderson, Charles P. Lin, Irene M. Ghobrial
Journal: Blood (2006)
Abstract 3408: Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis
Authors: Aiqin Sun, Guanzhen Yu, Xiaoyan Dou, Xiaowei Yan, Wannian Yang, Qiong Lin
Journal: Cancer Research (2015)

Abstract Background: Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients. Methods: Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays. Results: Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ2 = 21.885, p&amp;lt;0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p&amp;lt;0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion. Conclusions: Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis. Citation Format: Aiqin Sun, Guanzhen Yu, Xiaoyan Dou, Xiaowei Yan, Wannian Yang, Qiong Lin. Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2015-3408
382. Osteopetrosis: An Unusual Presentation of a Rare Disease as a Candidate for Gene Therapy
Authors: Alan O'Brien, Joerg Krueger, Lucie Dupuis, Irina Voronov, Peter Kannu, Ronald D. Cohn, Roberto Mendoza-Londono
Journal: Molecular Therapy (2015)

Osteopetrosis refers to a group of genetic disorders characterized by increased bone density due to failure of osteoclastic bone resorption. Infantile malignant osteopetrosis (IMO; MIM 259700) is the most severe form of the disease. It presents in early infancy and can lead to significant morbidity and death if untreated. Osteosclerotic changes lead to progressive blindness and hearing loss, bone marrow failure, hypocalcemic seizures and pathological fractures. The majority of cases of IMO are due to complete loss-of-function mutations in TCIRG1, which codes for a subunit of the osteoclast vacuolar proton pump (V-ATPase). Currently, hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but can be associated with significant morbidity and toxicity and has a varying success rate depending on the donor source. We present a 9 year old boy from Pakistan in whom increased bone mass and x-ray changes typical of osteopetrosis were found incidentally at age 7. His prior medical history was mostly unremarkable, except for strabismus and dentition problems. Sequence analysis of the TCIRG1 gene revealed a homozygous c.630G>A mutation that changes the last nucleotide of exon 6 and is predicted to result in aberrant splicing, possibly creating a hypomorphic allele and explaining his milder phenotype. Detailed phenotypic evaluation of the patient after diagnosis showed normal bone marrow function, but identified visual impairment with impingement of the optic nerves, and hearing loss. Given the patient's milder phenotype, the morbidity and mortality of HSCT and uncertainty about his speed of disease progression we decided to not pursue HSCT at this point. Thus, novel therapeutic options should be contemplated. Given that the mutation likely results in a splicing defect, this patient could potentially benefit from splicemodifying drugs that are under development. Moreover, we suggest that this patient's clinical presentation makes him an ideal candidate for a trial of gene therapy. Indeed, considering the mortality and morbidity of IMO as well as the established role of HSCT as curative treatment, a randomized clinical trial for the severe form of the disease is not ethically acceptable. There have been encouraging steps towards establishing lentiviral-mediated gene transfer of TCIRG1 as a potential treatment of osteopetrosis in humans. Furthermore, considering the point mutation found in our patient, gene editing technologies, such as CRISPR/Cas9 could allow us to correct this defect by ex-vivo editing of affected CD34+ cells and subsequent re-engraftment. Finally, we suggest that patients with a similarly mild phenotype and mutations in TCIRG1 would be ideal candidates for a clinical trial for gene therapy of osteopetrosis and could be gathered through an international consortium.
Doctors on film
Authors: Chris Holme
Journal: BMJ (2016)

Chris Holme explores some early portrayals of the medical profession

It may not be a huge cinematic genre but some historically interesting films of doctors can now be watched online through open access digital archives.

Take Highland Doctor (http://movingimage.nls.uk/film/0033), filmed in 1943. Made for the Scottish Department of Health by Kay Mander to celebrate the first 30 years of the Highlands and Islands Medical Service (HIMS), it was shot on location in the Hebrides. As well as writing and directing, Mander played a brief cameo role as a cycling district nurse.

The focus is a pipe smoking consultant visiting an island GP who is wearing a loud tweed suit. The GP was modelled on Alex J Macleod of Uist, a celebrated family doctor …
We read spam a lot: prospective cohort study of unsolicited and unwanted academic invitations
Authors: Andrew Grey, Mark J Bolland, Nicola Dalbeth, Greg Gamble, Lynn Sadler
Journal: BMJ (2016)

To assess the amount, relevance, content, and suppressibility of academic electronic spam invitations to attend conferences or submit manuscripts. Prospective cohort study. Email accounts of participating academics. Five intrepid academics and a great many publishers, editors, and conference organisers. Unsubscribing from sender's distribution lists. Number of spam invitations received before, immediately after, and one year after unsubscribing from senders' distribution lists. The proportion of duplicate invitations was also assessed and the relevance of each invitation graded to the recipient's research interests. A qualitative assessment of the content of spam invitations was conducted. At baseline, recipients received an average of 312 spam invitations each month. Unsubscribing reduced the frequency of the invitations by 39% after one month but by only 19% after one year. Overall, 16% of spam invitations were duplicates and 83% had little or no relevance to the recipients' research interests. Spam invitations were characterised by inventive language, flattery, and exuberance, and they were sometimes baffling and amusing. Academic spam is common, repetitive, often irrelevant, and difficult to avoid or prevent.
Abstract 2214: Dynamic transcriptome analysis of DNA damage pathways under hypoxia
Authors: Winnie W. Lo, Gaetano Zafarana, Robert G. Bristow
Journal: Cancer Research (2015)

Abstract During the outgrowth of tumor, gradients of hypoxic regions develop due to reduced oxygen diffusion. Intratumoral hypoxia is a prognostic factor associated with decreased disease-free survival and increased resistance to radiotherapy and chemotherapy in different solid cancers. We have previously shown that chronic hypoxia suppresses DNA damage repair pathways partly through decreased protein translation efficiency. The RNA levels of repair pathway genes have also been shown to be downregulated in hypoxia; however, most of the RNA studies do not distinguish between RNA synthesis and degradation. Here, we use novel metabolic labeling of newly synthesized RNA to investigate the dynamic changes in transcription rates of DNA damage repair pathways under hypoxia. 4-thiouridine (4sU), a uridine analogue, was added to the media of DU145 cells (prostate cancer cell line) that have been cultured in 21% or 0.2% oxygen concentrations for 72 hours. Total RNA was extracted and 4sU-tagged RNA was biotinylated and separated from untagged pre-existing RNA using streptavidin coated magnetic beads. Real-time RT-PCR was used to quantify the expression of repair pathways in three RNA subsets (total, pre-existing, and newly synthesized). Parallel experiments were performed in RNA harvested from the cytoplasmic and nuclear factions of cells. We found that with 30-minute 4sU incubation, most 4sU-tagged RNA is still in the nucleus, and is subjected to little degradation, thus reflecting the average transcription rate. The percentage of newly synthesized RNA is lower in hypoxic than in normoxic cells. Importantly, the transcript levels of homologous recombination (HR) repair pathway regulators, RAD51, BRCA1 and BRCA2, are decreased in both total and newly-synthesized RNA of hypoxic cells. Our results demonstrate that in addition to translational regulation, hypoxia may also downregulate repair pathways through suppression of transcription. This 4sU assay provides opportunities for further analysis of differential RNA synthesis and decay of DNA damage repair pathways between hypoxia and normoxia. Citation Format: Winnie W. Lo, Gaetano Zafarana, Robert G. Bristow. Dynamic transcriptome analysis of DNA damage pathways under hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2214. doi:10.1158/1538-7445.AM2015-2214