tbuckley/cabot-search huggingface dataset:
The human Achaete Scute Homolog 1 promoter - a candidate for transcriptionally regulated gene therapy of small cell lung cancer
Authors: Thomas T. Poulsen, Nina Pedersen, Mikkel W. Pedersen, Hans S. Poulsen
Journal: Cancer Research (2006)

2109  Small Cell Lung Cancer (SCLC) is an aggressive, highly metastatic disease, for which no satisfactory treatment is presently available. Due to the disseminated nature of SCLC, treatments must be systemically administered to target both the primary tumor and metastases. Transcriptionally targeted gene therapy constitutes such a systemic strategy, with a therapeutic potential for SCLC. We have identified a number of genes with high and specific mRNA-expression in many SCLC cell lines and xenografts and all patient tumors tested. One of these genes encode the transcription factor human Achaete-Scute Homolog 1 (hASH1). The hASH1 gene is known to be activated only transiently during embryonic neuroendocrine development; it is inactive in normal adult tissues, but reactivated in neuroendocrine malignancies such as SCLC. Furthermore, the hASH1 promoter has been characterized and hASH1-gene specificity has been reported to depend on two inhibitory regions - one proximal and one distal to the transcription start site. The purpose of this study is to evaluate the use of the hASH1-promoter for regulating suicide gene therapy of SCLC. A 0,7kb hASH1-proximal promoter region has been cloned and fused to the Luciferase gene and transfected into SCLC and non-neuroendocrine control cell lines. Results demonstrate high Luciferase activity in all tested classic SCLC cell lines (equivalent to or higher than expression from the SV40-promoter), whereas hASH1-promoter activity was low or absent (
Randomized multicenter phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy as first-line therapy in patients with translocation-related sarcoma (TRS).
Authors: Jean-Yves Blay, Michael Gordon Leahy, Binh Bui Nguyen, Shreyaskumar Patel, Armando Santoro, Peter Hohenberger, George D. Demetri, Pilar Lardelli, Iratxe Perez, Sant P. Chawla
Journal: Journal of Clinical Oncology (2012)

TPS10101 Background: One third of sarcoma histotypes have specific chromosomal translocations which result in abnormal transcription factors, integral to the change to a malignant phenotype. T is the first of a new class of anti-tumor agents with a transcription-targeted mechanism of action. In vitro evidence exists of the ability of T to interfere with the aberrant transcription factor’s binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round cell liposarcomas (MRCL) have benefited from long-lasting tumor control in response to T. Methods: A randomized, phase III study of T (1.5 mg/m 2 in 24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m 2 q3wk, or doxorubicin 60 mg/m 2 with ifosfamide 6-9 g/m 2 q3wk) as first line treatment in patients with advanced TRS. Primary aim: to determine the efficacy of T vs doxorubicin-based therapy by comparing progression-free survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six months, response rate (RR), PFS and RR by histological type (MRCL vs other subtypes), overall survival, safety, exploratory response evaluation by Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other subtypes) and randomized (1:1 ratio) to T or doxorubicin ± ifosfamide. Confirmation of the translocation by fluorescence in situ hybridization is compulsory for inclusion in the primary efficacy analysis. An adaptive design was chosen to test the reduction in relative risk of progression or death with T, an interim analysis will be conducted with 45 PFS events from 80 evaluable patients. To date 117 patients have been enrolled from six countries and 29 centers. An independent data monitoring committee met on 15 November 2011 and concluded that the trial should continue as planned.
Abstract #5215: Applying single molecule real time DNA sequencing
Authors: Stephen Turner
Journal: Cancer Research (2009)

SMRT (single molecule real time) DNA sequencing is a third generation technique for sequencing DNA that has characteristics uniquely suited to cancer applications. By directly observing DNA polymerization at the single molecule level and in real time, fast cycle time and long readlength are possible. Single molecule observation is enabled by an advanced optical microscopy technology called the zero-mode waveguide. It enables observation of individual nucleotides as they are incorporated in real time. This will allow dissection of a DNA sample to the most basic level: the individual strand of DNA, enabling comprehensive characterization of the frequencies of point mutations and structural variations in complex mixtures. Pacific Biosciences\#8217; Phospholinked nucleotides substitute the natural nucleotides used to synthesize DNA without compromising the natural speed, accuracy or processivity of DNA synthesis. Because the fluorescent labels used to allow detection of incorporation are attached to the nucleotides\#8217; phosphate group, they are automatically cut away from the nascent strand during synthesis. Thus the synthesized product is natural DNA with no adducts. These innovations allow exploitation of the long readlengths intrinsic to polymerase replication, while keeping cycle times short through reaction rates 30,000 times faster than second generation sequencing systems. Here we present application of this technology to shotgun sequencing of trial organisms using a fast and simple sample prep concept that facilitates whole genome shotgun sequencing directly from genomic DNA. Using a strand-displacing DNA polymerase, we will demonstrate sequencing multiple times around a circular DNA fragment, allowing consensus sequencing on an individual molecule. This enables high confidence detection of low frequency variants even in heterogeneous samples, enabling new applications in biology and medicine.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5215.
FRI0257 Changes in skeletal muscles in patients with knee joint replacement
Authors: E Neuen-Jacob, M Meinhardt, M Egl, B Fink
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Knee joint replacement is used as a routine surgical procedure in the treatment of rheumatoid diseases or arthrosis. However, systematical studies on the affected muscles are rare. <h3>Objectives</h3> In the present systematic study we analysed the pathological changes in the vastus medialis muscles in 108 patients with rheumatoid arthritis and gonarthrosis who underwent knee joint replacement. The aim of the current study was to examine possible differences in both entities with respect to kind and degree of muscle changes and to the state of innervation/denervation which might be important for the therapeutic effect of the arthroplasty. <h3>Methods</h3> Serial cross-cut cryostat sections were stained by H&amp;E and Gomori’s trichrome and submitted to routine histochemical preparations including NADH/TR, ATPase after preincubation at pH 4.6 and 9.4, oil-red O, periodic acid Schiff and acid phosphatase. Immunohistochemistry was performed using commercially available monoclonal antibodies (Mab) against neonatal myosin and neural cell adhesion molecule CD56 for the identification of regenerating fibres. In addition, the Mab against HLA-ABC was applied in order to detect the up-regulation of MHC Class I antigen on the muscle fibres. <h3>Results</h3> Lipomatosis was striking in the majority of both groups. Regenerating fibres also were detectable in both entities. As a trend, patients with <b>gonarthrosis</b> mainly showed atrophy of type 2 fibres indicating inactivity due to muscle or joint pain. Patients with<b> rheumatoid</b><b>arthritis</b> commonly revealed atrophy of both type 1 and 2 fibres and fibre type grouping consistent with neurogenic muscular atrophy indicating a systemic disease. Vasculitis was only occasionally detected. In rheumatoid arthritis, however, up-regulation of MHC Class I antigen was regularly seen reflecting the underlying autoimmune disease. A small percentage of cases showed <b>corticoid myopathy </b>with atrophy of type 2 fibres in combination with increased lipid content of type 1 fibres. <h3>Conclusion</h3>
Medical Discharge Summary—“Disposition: To the Street”
Authors: Scott Goldberg
Journal: JAMA Internal Medicine (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Quantifying the impact of antiangiogenic therapy on hypoxia and implications for radiation therapy in glioblastoma multiforme with a biomathematical model.
Authors: Andrea Hawkins-Daarud, Russell Rockne, Paul Kinahan, Mark Muzi, Adam Alessio, Kenneth A. Krohn, Kristin Swanson
Journal: Journal of Clinical Oncology (2013)

e13028 Background: Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. As angiogenesis is a major hallmark of GBM, it can be inferred that hypoxia plays a prominent role in the progression of the disease. However, due to difficulty in assessing hypoxia, the development and evolution of hypoxia has not been well studied for GBM. 18F-Fluoromisonidazole (FMISO) PET indirectly measures hypoxia. It is known that hypoxia reduces the efficacy of radiation therapy, and one current strategy being explored is to combine anti-angiogenic therapy and radiation therapy. However, it is unclear whether anti-angiogenic therapy is ultimately reducing or increasing hypoxia nor is it clear how long the effects last. Methods: We have developed a spatio-temporal biomathematical model for glioma proliferation and invasion that incorporates the angiogenic cascade. In this context, we can simulate the action of anti-angiogenic treatment, such as bevacizumab, by modifying the availability of angiogenic factors. By applying a pharmacokinetic model for the uptake of FMISO to the simulation results, we can generate the corresponding FMISO-PET images during and after anti-angiogenic therapy to compare with what would be seen in the clinic. Results: Simulation results for a wide range of tumor kinetics demonstrated that hypoxia in general decreased during anti-angiogenic therapy. However, the rates at which it decreased and the time for the hypoxia to return to pre-treatment levels were not uniform. Conclusions: Dynamic understanding of anti-angiogenic therapy effects on vascular normalization and hypoxia suggest that optimal timing of radiation therapy and anti-angiogenic therapies would vary by patient. This biomathematical model can be tuned to individual patients’ tumors and provide similar information as a FMISO-PET image and also give insight into the dynamics of the hypoxia over time. Such insight could be invaluable to patient-specific treatment planning for combining radiation with antiangiogenics.
Efficacy of Lenalidomide As Salvage Therapy for Patients with AL Amyloidosis
Authors: Efstathios Kastritis, Maria Gavriatopoulou, Maria Roussou, Tina Bagratuni, Magdalini Migkou, Despina Fotiou, Dimitrios C. Ziogas, Ioannis Ntanasis-Stathopoulos, Ioannis Panagiotidis, Nikolaos Kanellias, Alexandra Papathoma, Erasmia Psimenou, Charikleia Gakiopoulou, Smaragdi Marinaki, Elektra Papadopoulou, Constantinos Pamboucas, Argyrios Ntalianis, Anna Tasidou, Evangelos Terpos, Meletios A. Dimopoulos
Journal: Blood (2017)
Abstract #5182: Genome wide assessment of epigenetic alterations in Ewing Sarcoma
Authors: Scott Borinstein, A Marcondes, H Deeg, William Grady
Journal: Cancer Research (2009)

Background: Epigenetic alterations are common in many cancer types and play an important role in their pathogenesis. However, the role of aberrant DNA methylation in Ewing Sarcoma (ES), a malignant neoplasm of bone and soft tissues in adolescents and young adults, is currently poorly understood. Aim: To determine the role of aberrant DNA methylation in the molecular pathology of ES Methods: We used a genome wide approach to identify genes hypermethylated in these neoplasms. Genomic DNA was isolated from formalin fixed, paraffin embedded primary ES tumors and cell lines. We compared the methylation signatures of 13 tumors and 3 ES cell lines with human mesenchymal stem cell primary cultures (hMSCs). Illumina Goldengate methylation analysis was used to determine the methylation status of 800 genes known to be altered in human cancer. Validation of the array results was performed with methylation specific PCR and sodium bisulfite sequencing. Results: The Illumina Goldengate arrays were found to be both sensitive and reproducible. After filtering out genes methylated in hMSCs, we determined that primary ES tumors and cell lines could be stratified into low and high methylator groups. In addition, we identified a group of genes that were methylated in >30% of ES primary tumors (range 30-100%) but not in hMSCs. Known tumor suppressor genes and genes methylated in other cancers were included in this group, including RASSF1A, a known tumor suppressor gene methylated in both adult and pediatric cancers. Methylation specific PCR and bisulfite sequencing analysis of RASSF1A confirmed the aberrant methylation detected by the methylation arrays in the ES cell lines. Furthermore, treatment of the cell lines with 5-aza-2\#8217;deoxycytidine induced RASSF1A expression in the cell lines with methylated RASSF1A demonstrating that RASSF1A is epigenetically silenced in ES cell lines due to DNA hypermethylation. Conclusions: Aberrant DNA methylation occurs in ES, demonstrating that epigenetic alterations play a role in pediatric tumors of mesenchymal origin. Determination of the genes affected by this process will provide further insights into the molecular pathology of ES.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5182.
Prevalence and Prognostic Significance of CD5 Immunohistochemistry in De-Novo DLBCL in a Western Population Cohort
Authors: Ajaz Bulbul, Kyaw Zin Thein, Emilio Paul Araujo-Mino, Sai-Ching J Yeung, Denice Tsao-Wei, Matney Huber, Siham Chouial, Sanjay Awasthi, Masoud Khorsand
Journal: Blood (2017)
Primary systemic chemotherapy for operable breast cancer with docetaxel followed by cyclophosphamide, epirubicin, and fluorauracil (DOC-CEF)
Authors: Y. Kikawa, Y. Masai, T. Hashimoto, Y. Nakamoto, H. Nishikawa, S. Takahara, H. Suwa, T. Tachibana
Journal: Journal of Clinical Oncology (2007)

11085 Background: Primary systemic chemotherapy (PSC) for breast cancer has been considered to be useful controlling the micrometastasis and shown to increase the breast conserving surgery rate, result in similar survival rate as usual post-operative adjuvant chemotherapy. Recently, doxorubicin based regimen followed by taxan regimen in neoadjuvant chemotherapy has shown a high response rate and sequential administration is supposed to be important. However, taxan regimens sequentially followed by doxorubicin are not so common. The purpose of this study is to evaluate the efficacy of primary systemic chemotherapy with docetaxel followed by cyclophosphamide, epirubicin and fluoraouracil (DOC-CEF) in breast cancer. Methods: Since 2003, 80 women histologically proven as the primary breast cancer, measurable lesion &gt;= 2cm or inflammatory breast cancer, age 20–75, PS 0–1 were enrolled. The patients received 4 cycles of DOC (75mg/m2) every 3 weeks followed by CEF (500mg/m2, 75mg/m2, 500mg/m2) every 3 weeks as the primary systemic chemotherapy. After administrations, clinical responses and tumor vascularities were recorded by ultrasonography and pathological responses were examined after surgery for all patients. Results: 57 out of 80 patients (T2: 45, T3 6, T4 6) were analyzed at this time. Clinical response rate recorded by ultrasonography and pathological response rate were 82.4% (47/57) and 91.2% (52/57) respectively. Pathological CR rate was 26.3% (15/57). 8 pCR cases showed ER/PR-negative tumors of which 3 cases showed ER/PR-negative/Her2-negative (triple negative pattern). Breast conservative surgery was underwent in 51 patients (89.5%). Among the response group, the tumor vascularities were almost remarkably decreased in the early phase (mostly until 2–3 cycles) of the chemotherapy. Grade 4 neutropenia was observed in 16% (9/57) and 4% (2/57) had febrile neutropenia. Conclusion: This regimen is well tolerated and has good feasibility because most patients have experienced the early reduction of tumor by high response rate of docetaxel. No significant financial relationships to disclose.
Potential regulation of histone acetylation and DNA methylation by p12CDK2-AP1 through MBD3/NuRD complex
Authors: Yong Kim, Pei Wang, Jeffrey Kim, David Wong
Journal: Cancer Research (2007)

1164  Epigenetic regulation elicited by histone acetylation and DNA methylation through nucleosome remodeling (NuRD) complex has been implicated in cell proliferation, differentiation, development, and also in the pathogenesis of many cancers. p12CDK2-AP1 (p12), whose reduced or deleted expression is significantly correlated with oral/head and neck cancer, has recently been identified as a core subunit of MBD/NuRD complex (Guezennec et al., MCB 26:843-851, 2006). Furthermore, targeted disruption of p12 in murine embryonic stem (mES) cells has demonstrated alteration in the differentiation competency of mES cells and resulted in the early embryonic lethality of the knockout mice (manuscript submitted). We now demonstrate that p12 interacted with the methyl binding domain protein MBD3, a core subunit of NuRD complex, in vitro by using recombinant GST-MBD3 and p12-His proteins. In vivo interaction of these proteins was further confirmed by coimmunoprecipitation assay. The p12 interacting region of MBD3 has been mapped by employing deletion mutants of GST-MBD3 and p12-His proteins. To see if p12 plays any role in the epigenetic regulation through NuRD, we examined the effect of the disrupted expression of p12 on histone H3 acetylation and genomic DNA methylation in mES cells. The targeted disruption of p12 in mES cells resulted in an elevated acetylation of histone H3 compared to WT cells, indicating the downregulation of HDAC activity. Interestingly, the p12-/- mES cells showed an increased level of Dnmt3 expression along with an elevated level of genomic DNA methylation assessed by SssI methyl-accepting assay. These findings confirm p12 as a subunit of NuRD through interacting with MBD3 and suggest its role in the regulation of histone acetylation and DNA methylation.  [Supported by PHS grant T32 DE 007296-08 to Y.K. and R01 DE 14857 to D.T.W.]
Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation
Authors: W. Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P. Gondek, Dhanashree S. Kelkar, Abigail Read, Rachael Natrajan, Eric S. Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D. Leone, Daniel Shinn, Taylor Groginski, Anil K. Madugundu, Arun Patil, Daniel J. Zabransky, Arielle Medford, Justin Lee, Alex J. Cole, Marc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E. DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J. Hurley, Josh Lauring, Ben Ho Park
Journal: Journal of Clinical Investigation (2019)

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.