tbuckley/cabot-search huggingface dataset:
Abstract 2999: DEC1 and DEC2 crosstalk between circadian rhythm and tumor progression
Authors: Fuyuki Sato, Yasuteru Muragaki
Journal: Cancer Research (2015)

Abstract Circadian rhythms are tightly regulated by clock genes. It has been reported that clock genes plays important roles in biological function of normal cells. However, it is not well understood the function of clock genes in tumor cells. We showed that basic helix-loop-helix (bHLH) transcription factors, differentiated embryonic chondrocyte gene 1 (DEC1/BHLHE40/Sharp2/Stra13) and DEC2 (BHLHE41/Sharp1), are clock genes and play important roles in circadian rhythm, cell proliferation, apoptosis, hypoxia response, various stresses and epithelial-to-mesenchymal transition (EMT) in tumor cells. Various stresses, such as exposure to transforming growth factor-beta (TGF-β), hypoxia, cytokines, serum-free, and anti-tumor drugs affect DEC expression. The increased or decreased DEC expression by such stresses is involved in tumor progression. The evidence that DEC2 has circadian expression in implanted mouse sarcoma cells and negatively regulates VEGF expression under hypoxia. DEC1 has pro-apoptotic effects in human breast cancer cells, whereas DEC2 has anti-apoptotic effects. DEC1 induced EMT by TGF-β in human pancreatic cancer cells, whereas DEC2 suppressed EMT. Immunohistochemical analysis showed that DEC1 is highly expressed in tumor cells and the expression is involved in malignancy. On the other hand, DEC2 is little expressed in tumor cells compared with adjacent non-tumor cells. These findings suggest that DEC1 and DEC2 have different roles in tumor progression under circadian rhythm. DEC2 regulates the circadian rhythm and VEGF expression by negative feed-back system, and DEC1 and DEC2 regulates EMT by positive and negative feed-back system in tumor cells. So, DEC acts as “accelerator” and “brake” in tumor progression. In this study, we show current progress of the DEC genes in tumor progression. Citation Format: Fuyuki Sato, Yasuteru Muragaki. DEC1 and DEC2 crosstalk between circadian rhythm and tumor progression. [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 2999. doi:10.1158/1538-7445.AM2015-2999
578. microRNA Inhibition Through Gapmer Activated RNase H-Mediated Degradation
Authors: Elizabeth M. Munding, Mark A. Kay
Journal: Molecular Therapy (2015)

MicroRNAs (miRNAs) are a class of small (20-24 nucleotide) non-coding RNAs that regulate gene expression post-transcriptionally. miRNAs induce gene silencing through a conserved pathway requiring a complementary base pairing interaction between the miRNA and its target mRNA. This mode of post-transcriptional gene regulation is essential for processes such as cellular differentiation, development and metabolism. While the number of identified human miRNAs is greater than 1000, the function of most of these has yet to be characterized. A common method to assign function to a particular miRNA is to block its activity with antisense oligonucleotides (ASOs). These molecules contain nucleic acid modifications that in addition to enhancing their stability allow for increased affinity and specificity against their corresponding miRNA. The traditional and most commonly used inhibitory miRNA ASOs are 16-30 base pairs long, contain a phosphorothioate backbone and locked nucleic acids (LNAs) interspersed throughout the sequence to block RNase H-mediated cleavage. In this case, the LNA inhibits miRNA function by interfering with recognition of the target mRNA. Conversely, gapmer ASOs trigger degradation of the miRNA-ASO duplex by RNase H due to a longer stretch of DNA bases flanked by several LNAs on both ends. In recent studies, we compared miRNA inhibition through the use of different ASOs that function by either sequestration (mixmer ASOs) or degradation (gapmer-mediated RNase-H cleavage) while maintaining the identical sequence. Using these two types of iso-sequential ASOs we measured the dose response in cultured cells. We quantified the reduction in the miRNA using two independent methods— (1) directly by northern blot and (2) indirectly by monitoring the level of targeted mRNA. Surprisingly, our preliminary data shows that miRNA repression occurs at a lower IC50 with the gapmers compared to mixmers. We are currently investigating if the observed differences in ASO-mediated miRNA inhibition occur by differential activity against the mature miRNA species or miRNA processing and whether differential on- and off-targeting rates are associated with each. These results will have important implications for designing the most effective ASO strategies for inhibiting miRNAs for biologic discovery and therapeutics.
Abstract 1389: Study on cancer stem cell marker CD90 in liver cancer
Authors: Wei-Ching Chen, Ming-Derg Lai
Journal: Cancer Research (2015)

Abstract CD90 is a glycophosphatidylinositol (GPI)-anchored glycoprotein, which is highly expressed in stem cells. CD90 involves in immunological function and nonimmunological functions, including cell adhesion, migration and cell death. The published data show that CD90 is a tumor suppressor gene in ovarian cancer and nasopharyngeal carcinoma. However, several studies indicate that CD90 is a potential marker for liver cancer stem cells (CSCs). It suggests that CD90 leads to different function in different tumors. In order to elucidate the role of CD90 in liver cancer progression, the HepG2 and Hep3B stable transfectants expressing exogenous CD90 were established and the tumorigenic ability was analyzed in vivo and in vitro. We further analyzed the stemness properties of the transfectants and found that CD90 increased the sphere formation ability and ALDH activity. We further analyzed the role of CD90 in ovarian cancer cell and found that there is a controversial phenotype in SKOV3 cell compared to liver cancer cell. Several cell surface markers have been used to identify liver cancer stem cells including CD90, EpCAM, CD133, CD44, and CD13. Among these markers, CD90 is particularly interesting since overexpression of CD90 inhibited the growth of another type of tumor. We analyzed the cross-talk interaction between CD90 and the other CSC markers and found that there was a cause-effect relationship. We further identified the signaling transduction pathway in mediating the processes of CD90-induced tumorigenic ability. Our findings provide a concept to target stemness-associated signaling axis as a strategy to treat cancer. Citation Format: Wei-Ching Chen, Ming-Derg Lai. Study on cancer stem cell marker CD90 in liver cancer. [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 1389. doi:10.1158/1538-7445.AM2015-1389
689. The Content of the More Immature Hematopoietic Stem Cells (HSCs) Is Dependent from the Underlying Genetic Diseases: Consequence on Transduction Efficiencies
Authors: Laure Caccavelli, Cécile Roudaut, Maeva Joigneaux, Johanna Blondeau, Fabien Touzot, Salima Hacein-Bey-Abina, Marina Cavazzana
Journal: Molecular Therapy (2016)

Ex vivo gene transfer into hematopoietic CD34+ cells provides therapeutic benefits in primary immunodeficiencies. However, the CD34+ cell population is heterogeneous and is mainly composed of progenitors (CD34+lin-CD38+) and multilineage progenitors (CD34+lin-CD38-). This latter population can be divided in 3 subtypes regarding to the CD45RA and CD90 expression. CD45RA+ define cells with lymphoid potential, CD45RA-CD90- defined cells with myeloid potential and CD45RA-CD90+ define cells with long term repopulating capability (HSCs) which constitutes the relevant target for gene correction. We found that in bone marrow (BM) CD34+linneg, addition of CD133 helps to delimitate CD38neg population and we have analysed HSC, MLP and MPP population in BM from SCID-X1 (n=4), Wiskott Aldrich Syndrome (WAS) (n=2), Artemis (n=2), Chronic Granulomatous Disease (CGD) patients (n=3), sickle cell disease (SCD) (n=3) and age matched healthy controls (n=6).As expected, mean percentage of HSC represent 1% of CD34+ in healthy donors and similar results are obtained in CD34+ from SCID-X1 (1.76% ± 0.72), Artemis (1.98% ± 0.15), and SCD (2.16% ± 0.6) patients. On the contrary HSC percentage are lower in CD34+ from WAS (0.35% ± 0.15) and nearly undetectable in CGD patients. Moreover in multilineage progenitors, proportion of HSC, MLP and MPP varies from one pathology to another as shown in table1.Table 1Mean percentage of HSC, MLP and MPP in the linnegCD133+CD38neg CD34+ cellsHSCsMLPMPPHealthy Donor42%33%24%SCIDX137%45%28%WAS35%35%30%Artemis30%48%20%SCD36%19%44% Open table in a new tab Our aim was then to determine the ability of vectors used for gene therapy to transduce these different progenitors. We first analysed transduction of bulk CD34+ and HSCs by SIN retroviral vector for IL2RG in 2 SCIDX-1 patients enrolled in the clinical trial. After transduction, the 3 cell types were purified by flow cytometry and transduction determined in CFU after 14 days of culture in methyl cellulose in order to avoid detection of non-integrated vector. We show that in both patients, transduction efficiency was lower in HSCs than in bulk CD34+ cells. We were not able to recover enough CFU to determine VCN from MPP fraction and as expected, no CFU were obtained from MLP fraction. These results will be extended to transduction of CD34+ from WAS and SCD patients and efforts will be concentrated on transduction protocols in order to improve transduction of HSCs. Nevertheless low HSCs contents observed in CD34+ from CGD patients also represents a major difficulty to obtain long term reconstitution after gene therapy.
Une nouvelle poudre hémostatique dans les hémorragies digestives hautes: un essai muticentrique (Le registre “Graphe”)
Authors: G. Lesur
Journal: Endoscopy (2016)

L’utilisation de la poudre hémostatique Hemospray® a fait la preuve de son intérêt dans le traitement endoscopique des hémorragies digestives. Le but de ce travail multicentrique était d’étudier sa faisabilité et son efficacité en pratique quotidienne.
Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes
Authors: Andre R. Brunoni, Anna Chaimani, Adriano H. Moffa, Lais B. Razza, Wagner F. Gattaz, Zafiris J. Daskalakis, Andre F. Carvalho
Journal: JAMA Psychiatry (2016)

Although several strategies of repetitive transcranial magnetic stimulation (rTMS) have been investigated as treatment of major depressive disorder (MDD), their comparative efficacy and acceptability is unknown.To establish the relative efficacy and acceptability of the different modalities of rTMS used for MDD by performing a network meta-analysis, obtaining a clinically meaningful treatment hierarchy.PubMed/MEDLINE, EMBASE, PsycInfo, and Web of Science were searched up until October 1, 2016.Randomized clinical trials that compared any rTMS intervention with sham or another rTMS intervention. Trials performing less than 10 sessions were excluded.Two independent reviewers used standard forms for data extraction and quality assessment. Random-effects, standard pairwise, and network meta-analyses were performed to synthesize data.Response rates and acceptability (dropout rate). Remission was the secondary outcome. Effect sizes were reported as odds ratios (ORs) with 95% CIs.Eighty-one studies (4233 patients, 59.1% women, mean age of 46 years) were included. The interventions more effective than sham were priming low-frequency (OR, 4.66; 95% CI, 1.70-12.77), bilateral (OR, 3.96; 95% CI, 2.37-6.60), high-frequency (OR, 3.07; 95% CI, 2.24-4.21), θ-burst stimulation (OR, 2.54; 95% CI, 1.07-6.05), and low-frequency (OR, 2.37; 95% CI, 1.52-3.68) rTMS. Novel rTMS interventions (accelerated, synchronized, and deep rTMS) were not more effective than sham. Except for θ-burst stimulation vs sham, similar results were obtained for remission. All interventions were at least as acceptable as sham. The estimated relative ranking of treatments suggested that priming low-frequency and bilateral rTMS might be the most efficacious and acceptable interventions among all rTMS strategies. However, results were imprecise and relatively few trials were available for interventions other than low-frequency, high-frequency, and bilateral rTMS.Few differences were found in clinical efficacy and acceptability between the different rTMS modalities, favoring to some extent bilateral rTMS and priming low-frequency rTMS. These findings warrant the design of larger RCTs investigating the potential of these approaches in the short-term treatment of MDD. Current evidence cannot support novel rTMS interventions as a treatment for MDD.clinicaltrials.gov Identifier: PROSPERO CRD42015019855.
Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report
Authors: Alexander Schulz, Franziska Wagner, Martin Ungelenk, Ingo Kurth, Christoph Redecker
Journal: Translational Neurodegeneration (2016)

Acute-onset neurodegenerative diseases in older patients are rare clinical cases, especially when the degeneration only affects specific regions of the nervous system. Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem. Clinical diagnosis in these patients, however, is often complicated due to a poor understanding of these diseases and their underlying mechanisms.In this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years. Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis. The combination of patient's medical history, clinical examination and exceptional pattern of brain stem degeneration presenting as "kissing swan sign" in MR imaging was strongly suggestive of acute onset of Alexander's disease. This leukoencephalopathy is caused by GFAP (glial fibrilary acidic protein) gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals. However, a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing.After an extended differential diagnosis and exclusion of other diseases, a definite diagnosis of the patient's condition presently remains elusive. However, whole-exome sequencing performed from patient's blood revealed 12 potentially disease-causative heterozygous variants, amongst which several have been associated with neurological disorders in vitro and in vivo - in particular the axon degeneration-related NMNAT2 gene.
Mismatches in Low Expression HLA Class II Loci and MIC-A in Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Poliana Patah, Marcelo Fernandez-Vina, Peter Stastny, Ping Liu, Pedro Cano, Susana Pesoa, Elizabeth J. Shpall, Sergio Giralt, Issa Khouri, Paolo Anderlini, Amin Alousi, Leandro Padua, Carlos Ramos, Gabriela Rondon, Yago Nieto, Richard Champlin, Marcos de Lima
Journal: Blood (2007)
Mutations That Cooperate with Nf1 Inactivation in Leukemogenesis Influence Therapeutic Response to MEK Inhibition.
Authors: Jennifer O. Lauchle, Doan T. Le, Doris Kim, Keiko Akagi, Matthew F. Gorman, Mary Tran, Judith Sebolt-Leopold, Linda Wolff, Luis F. Parada, Nancy Jenkins, Neal Copeland, Kevin M. Shannon
Journal: Blood (2007)
Abstract 3786: Novel regulation of cyclin D1 stability and the DNA damage response
Authors: Fadila Guessous, Jinho Heo, Naga Vaddadi, Tarek Abbas
Journal: Cancer Research (2015)

Abstract Deregulation of the cell division cycle is critical for cancer development. Transition from G1 to S phase of the cell cycle is promoted by D-type cyclins (D1, D2 and D3). Cyclin D1 is a critical regulator of cell cycle progression due to its ability to activate cyclin dependent kinases (CDK) 4 and 6, which phosphorylate and inactivate the retinoblastoma protein (pRb) and activates the transcription factor E2F1 to promote the expression of genes essential for G1/S progression. Importantly, mutations in the tumor suppressor gene RB1 or inactivation of the RB tumor suppressor pathway occurs in almost all human malignancies and one such mechanism involves cyclin D1 overexpression. Even in cancer cells with amplified or elevated cyclin D1 mRNA, the Cyclin D1 protein rapidly declines as cells progress through the G1 phase of the cell cycle to reach undetectable levels in S-phase, and this is thought to be dependent on the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex. The identity of the E3 ubiquitin ligase that is specifically involved in downregulating cyclin D1 during S-phase of the cell cycle or the functional significance of cyclin D1 downregulation however, remains unknown, as recent genetic studies in mice demonstrated that the steady state levels or stability of cyclin D1 protein, are not altered following the inactivation of the known regulators of cyclin D1 stability. Using a genetic si-RNA-based screen, we have identified a novel E3 ubiquitin ligase; SCF-FBXW5, which specifically interacts with and downregulates cyclin D1 protein, both in unperturbed proliferating cancer cells and following DNA damage. Importantly, inactivation of this E3 ubiquitin ligase inhibits the proliferation of cancer cells primarily through cyclin D1-dependent inhibition of S-phase progression and sensitizes cancer cells to DNA damage induced by UV or ionizing radiation. These findings identify a novel axis of regulating cyclin D1 stability in cancer cells with implications for targeting this axis to inhibit cyclin D1-driven cancers. Citation Format: Fadila Guessous, Jinho Heo, Naga Vaddadi, Tarek Abbas. Novel regulation of cyclin D1 stability and the DNA damage response. [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 3786. doi:10.1158/1538-7445.AM2015-3786
Abstract 3804: Disruption of spindle microtubules by TTFields result in abnormal chromosomes segregation and subsequent caspase-dependent cell death
Authors: Tali Voloshin Sela, Rosa S. Schneiderman, Moshe Giladi, Yaara Porat, Mijal Munster, Roni Blat, Shay Sherbo, Zeev Bomzon, Noa Urman, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2015)

Abstract Tumor Treating Fields (TTFields) are low intensity, intermediate frequency alternating electric fields. TTFields efficacy was demonstrated in vitro, in vivo and in clinical trials. The Optune device, designated to deliver TTFields to the tumor region, was approved by the FDA for the treatment of recurrent Glioblastoma multiforme (GBM). While there is a growing body of evidence demonstrating TTFields effect on mitotic cells, little is known about the mechanisms by which TTFields act to induce cancer cell death. The aim of the present study was to provide a mechanistic insight into the mode of action of TTFields. Cancerous cell lines were treated with TTFields using the inovitro system. Disruption of spindle microtubules was demonstrated by confocal microscopy. Divergence from normal chromosome number was evaluated using SKY analysis and chromosome spreads. Induction of apoptosis was examined using flow cytometry based on Annexin V and Propidium Iodide staining. Detection of caspase activity was carried using poly caspase assay kit. Broad-spectrum caspase inhibitor was used in combination with TTFields to evaluate to what extent caspase dependent apoptosis was accountable for treatment efficacy. Our results demonstrate that TTFields application prevents proper mitotic spindle assembly by interfering with microtubule polymerization. We also show that the outcomes of mitosis under TTFields application include abnormal chromosome segregation and caspase dependent apoptosis of daughter cells. Addition of caspase inhibitor completely abrogated apoptosis confirming that TTFields induced cell death is caspase dependent manner. Taken together, our results demonstrate that TTFields treatment interfere with normal mitotic spindle formation thereby promoting mitotic catastrophe which result in caspase dependent apoptosis. Citation Format: Tali Voloshin Sela, Rosa S. Schneiderman, Moshe Giladi, Yaara Porat, Mijal Munster, Roni Blat, Shay Sherbo, Zeev Bomzon, Noa Urman, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Disruption of spindle microtubules by TTFields result in abnormal chromosomes segregation and subsequent caspase-dependent cell death. [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 3804. doi:10.1158/1538-7445.AM2015-3804
Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX).
Authors: L. Dahan, B. Chibaudel, F. Di Fiore, P. Artru, L. Mineur, M. Galais, O. Dupuis, V. Blondin, S. Abdiche, M. Attia, A. De Gramont, G. Lledo
Journal: Journal of Clinical Oncology (2011)

4072 Background: Chemoradiotherapy (CRT) for locally advanced cardia and esophageal cancer is based on 5-FU combined with cisplatin, which could be favourably replaced by oxaliplatin (Ox). Cetuximab (C) has demonstrated synergism with both radiotherapy (RT) and platinum-based chemotherapy. ERaFOX trial was evaluating the safety and efficacy of the addition of C to CRT with FOLFOX. Methods: Main inclusion criteria were: stage III squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction; WHO PS 0-1; age 18-80 years; weight loss <15% in the last 6 months. Patients (pts) received 2 cycles of FOLFOX induction therapy (Ox 85 mg/m2/d1, folinic acid 400 mg/m2/d1, 5-FU 2,400 mg/m2/d1-2, q2w) plus C (first infusion 400 mg/m2 then 250 mg/m2, q1w), then RT 50.4 Gy (1.8Gy/d x 28 fractions) with FOLFOX plus C (same doses, except 5-FU 1,800mg/m2/d1-2). Tumor evaluation was performed at the end of CRT (RECIST and endoscopic ultrasonography). The primary endpoint was overall response rate (ORR), with a 50.0% threshold for efficacy (Simon Minimax two-stage design). Results: From Nov 2007 to Feb 2010, 80 pts were enrolled in 12 centers. The characteristics of the 79 eligible pts were (1 ineligible pt for stage IV disease): male/female 60/19, median age 63 (23-79), PS 0/1/ND 47/31/1, squamous/adenocarcinoma/undifferentiated 53/25/1; esophagus/cardia 74/5; median daily caloric intake 1720 Kcal (550-3160). 74 pts were treated by CRT (5 pts experienced anaphylaxis during the first cetuximab infusion). ORR (ITT) was achieved in 61 pts (77.2%; 95% CI 67.9-86.5). After a median follow-up of 19.4 months, median PFS/OS were 13.8/21.6 months. Nineteen (24.0%) pts experienced primitive resection. Pathological CR rate will be presented at the meeting. Most frequent grade 3-4 toxicities were: neutropenia (28.4%), dysphagia-esophagitis (13.5%), rash (10.8%) and allergy (8.9%). One toxic death (1.3%) occurred after CRT related to esophagitis with GI bleeding. Conclusions: Threshold for efficacy was reached with an ORR of 77.2%. Chemoradiotherapy with FOLFOX plus cetuximab should be compared to the same strategy without cetuximab in pts with locally advanced cardia or esophageal cancer.