tbuckley/cabot-search huggingface dataset:
Single agent versus doublet chemotherapy as second-line therapy of metastatic urothelial carcinoma (UC): a meta-analysis
Authors: D. Raggi, R. Miceli, G. Sonpavde, P. Giannatempo, N. Nicolai, R. Salvioni, G. Procopio, F. De Braud, L. Mariani, A. Necchi
Journal: Annals of Oncology (2015)
Abstract 2102: Targeting mTOR downstream of LIN28 in atypical teratoid rhabdoid tumors promotes apoptosis and suppresses tumorigenicity
Authors: Jeffrey Rubens, Antoinette Price, Brent Orr, Charles Eberhart, Eric Raabe
Journal: Cancer Research (2016)

Abstract LIN28 is a somatic cell reprogramming and stem cell factor that binds to and regulates RNA involved in growth, invasion and metabolic genes. We have previously shown that LIN28 is upregulated in atypical teratoid rhabdoid tumors (AT/RT) and contributes to the aggressive nature of these tumors. One of the canonical downstream targets of LIN28 is the mTOR pathway. We hypothesized that AT/RT tumorgenicity is dependent on mTOR signaling downstream of LIN28 and inhibition of this pathway would disrupt tumor growth. We found that primary human AT/RT samples have high expression of the mTOR pathway as determined by immunohistochemistry staining for P-S6 and P-AKT Ser473 (21% of tumors with 2+ P-S6 staining; 87% with 2+ p-AKT staining). The dual TORC1/2 inhibitor MLN0128 has good brain penetration and is currently being tested in phase I clinical trials. Treatment of AT/RT cell lines with MLN0128 inhibits TORC1/2 targets in vitro and suppresses cell proliferation at 100nM concentration in multiple AT/RT cell lines (MTS assay for BT12 p&amp;lt;0.005 vs DMSO control; BT37 p = 0.006 vs DMSO control; and CHLA-06 p&amp;lt;0.005 vs DMSO control by t-test). MLN0128 also slows cell proliferation via BrdU assay (BT12 p&amp;lt;0.005 vs DMSO control; BT37 p&amp;lt;0.005 100nM vs DMSO control; CHLA-06 p&amp;lt;0.005 100nM vs DMSO control by t-test) and induces apoptosis measured by Western Blot for cleaved PARP and cleaved caspase 3 assay (BT12 p&amp;lt;0.005 100nM vs DMSO; BT37 p&amp;lt;0.005 100nM vs DMSO; CHLA-06 p = 0.007 100nM vs DMSO by t-test). MLN0128 induces apoptosis synergistically with cisplatin, which is the backbone of conventional AT/RT therapy (CC3 assay BT37 p&amp;lt;0.005 vs DMSO by t-test) and slows cell growth (MTS assay BT37 p&amp;lt;0.005 vs DMSO control by t-test). MLN0128 treatment of AT/RT xenograft mouse models extends overall survival from a median of 23 days to 39 days (Log-rank test p = 0.002). Targeting the mTOR pathway with MLN0128 leads to potent in vitro and in vivo activity against AT/RT and can be combined with conventional chemotherapy to provide an important survival benefit. MLN0128 may be a candidate for future clinical trials to treat this deadly tumor. Citation Format: Jeffrey Rubens, Antoinette Price, Brent Orr, Charles Eberhart, Eric Raabe. Targeting mTOR downstream of LIN28 in atypical teratoid rhabdoid tumors promotes apoptosis and suppresses tumorigenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2102.
Combination Of Kinase Inhibitors Overcomes B-Raf Inhibitor-Induced Paradoxical ERK Activation In CLL Cells In Vitro – Potential Implications For CLL Treatment
Authors: Niuscha Yaktapour, Christine Dierks, Dietmar Pfeifer, Hassan Jumaa, Hendrik Veelken, Tilman Brummer, Katja Zirlik
Journal: Blood (2013)
Abstract 2249: Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing
Authors: Ken Suzawa, Shuta Tomida, Takahiro Matsubara, Kadoaki Ohashi, Yuho Maki, Hiromasa Yamamoto, Mizuki Morita, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Katuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka
Journal: Cancer Research (2016)

Abstract [Background] Mutational analysis is essential for recent personalized therapeutic approaches of non-small cell lung cancer (NSCLC) patients. Circulating cell-free DNA (cfDNA) from plasma is an emerging topic as a tool for liquid biopsy and possibly enable repetitive genetic diagnosis or monitoring of cancer status. However, detection of cfDNA from the circulation still remains challenging because of its highly fragmented and low concentration nature. In this study, we analyzed cfDNA samples by targeted deep sequencing at high coverage. [Materials and Methods] Twenty matched DNA samples were collected from metastatic NSCLC patients with EGFR mutation, which was detected by a clinical EGFR mutant enriched PCR assay using PNA-LNA PCR clamp method. These samples were extracted from tissue samples of fresh tumor tissue except one formalin fixed paraffin embedded (FFPE) sample (tDNA), and plasma samples (cfDNA). Mutation hotspots were enriched by multiplex PCR using the GeneRead DNAseq Targeted Panels V2 Human Tumor Actionable Mutations panel (QIAGEN, Hilden, Germany), followed by library construction, and sequenced on the MiSeq sequencer. Resulting data was analyzed using CLC Genomics Workbench and Genomics Server and mapped to the full human genome. [Results and discussion] The mean read depth in target region was 59,000 reads. Matched EGFR driver mutations between cfDNA and tDNA were detected with an overall concordance of 25% (5 of 20 samples). The concordance rate of exon21 L858R point mutation, exon19 deletions and exon20 T790M point mutation were 32.5% (3 of 8 samples), 16.7% (2 of 12 samples), and 66.7% (2 of 3 samples), respectively. The mutant allele frequencies in cfDNA ranged from 0.1% to 44.5% (median, 0.3%). While further improvement is mandatory, these results suggest that targeted deep sequencing of cfDNA at high coverage may have a potential utility as a non-invasive mutational analysis. In addition, there seemed to be a tendency of better detection rate for point mutations (45.5%) than deletions (16.7%), while the difference didn't reach statistical significance (p = 0.19), which were corresponding to previous reports. Citation Format: Ken Suzawa, Shuta Tomida, Takahiro Matsubara, Kadoaki Ohashi, Yuho Maki, Hiromasa Yamamoto, Mizuki Morita, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Katuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka. Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2249.
Randomized Trial of Thymectomy in Myasthenia Gravis
Authors: Gil I. Wolfe, Henry J. Kaminski, Inmaculada B. Aban, Greg Minisman, Hui-Chien Kuo, Alexander Marx, Philipp Ströbel, Claudio Mazia, Joel Oger, J. Gabriel Cea, Jeannine M. Heckmann, Amelia Evoli, Wilfred Nix, Emma Ciafaloni, Giovanni Antonini, Rawiphan Witoonpanich, John O. King, Said R. Beydoun, Colin H. Chalk, Alexandru C. Barboi, Anthony A. Amato, Aziz I. Shaibani, Bashar Katirji, Bryan R.F. Lecky, Camilla Buckley, Angela Vincent, Elza Dias-Tosta, Hiroaki Yoshikawa, Márcia Waddington-Cruz, Michael T. Pulley, Michael H. Rivner, Anna Kostera-Pruszczyk, Robert M. Pascuzzi, Carlayne E. Jackson, Guillermo S. Garcia Ramos, Jan J.G.M. Verschuuren, Janice M. Massey, John T. Kissel, Lineu C. Werneck, Michael Benatar, Richard J. Barohn, Rup Tandan, Tahseen Mozaffar, Robin Conwit, Joanne Odenkirchen, Joshua R. Sonett, Alfred Jaretzki, John Newsom-Davis, Gary R. Cutter
Journal: New England Journal of Medicine (2016)

Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003).Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).
Use of Diffusion-Weighted Magnetic Resonance Imaging in Sporadic Creutzfeldt-Jakob Disease
Authors: Paolo Vitali, Marina Pan, Eduardo Caverzasi
Journal: JAMA Neurology (2016)

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 Neurology 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 Neurology journal
Spectrum of Movement Disorders in Mitochondrial Disorders
Authors: Josef Finsterer, Sinda Zarrouk-Mahjoub
Journal: JAMA Neurology (2016)

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 Neurology 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 Neurology journal
Abstract 2401: RD3-loss orchestrates GC-signaling independent evolution of progressive neuroblastoma
Authors: Singh Meghna, Wolansky Rachel, Terence S. Herman, Natarajan Aravindan
Journal: Cancer Research (2016)

Abstract Recently we recognized the transcriptional/translational loss of Retinal degeneration Protein 3 (RD3) in high-risk progressive neuroblastoma (HR-NB) and defined its novel tumor evolution stabilization function. Studies have shown that RD3 competitively binds to guanylate cyclases (GCs) and maintains GC expression, stability, as well as restores GC localization. Accordingly, we investigated the role of GCs, if any, in RD3-loss associated evolution of HR-NB. Utilizing an in vivo mouse model of spontaneous HR-NB coupled with ex vivo approaches using metastatic site derived aggressive cells (MSDACs), we examined the transcriptional and translational expression of GCs and validated with high-content confocal immunofluorescence. Further, utilizing a cGMP competitive enzyme immunoassay, we investigated both intracellular and soluble GC activity. Whole genome microarray analysis revealed a differential activation of GC signaling transcriptional machinery in three different clones of MSDACs (compared to parental SH-SY5Y cells) ex vivo. Immunoblotting identified a consistent translation of GCs (GC-1 and GC-2) in a manifold of metastatic tumors (compared to non-metastatic primary xenografts) in vivo and in MSDACs ex vivo. Confocal immunofluorescence analysis validated the near-identical expression of GC1 and GC2 both in SH-SY5Y cells and MSDACs. cGMP immunoassay recognized indistinguishable intracellular and soluble GC activity in clones of differentiated/undifferentiated MSDACs as opposed to the clones of SH-SY5Y. For the first time, the results of this study define the transcription and translation blueprint of GCs in HR-NB and, further imply that the RD3-loss may dictate GCs-signaling independent alternate molecular flow-through in the evolution of HR-NB. Acknowledgements: Stephenson Cancer Center, NIH COBRE 1P20GM103639-01, Broken Arrow Lady Elks Auxiliary, and Oklahoma TSET. Citation Format: Singh Meghna, Wolansky Rachel, Terence S. Herman, Natarajan Aravindan. RD3-loss orchestrates GC-signaling independent evolution of progressive neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2401.
Abstract LB-227: Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer
Authors: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew Nehs, Francis Moore, Amaro Taylor-Weiner, Jeremiah Wala, Travis Zack, Thomas Lee, Fiona Fennessy, Erik Alexander, Tom Thomas, Pasi Jäne, Levi Garraway, Scott Carter, Rameen Beroukhim, Jochen Lorch, Eliezer Van Allen
Journal: Cancer Research (2016)

Abstract Background: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors, with a uniformly fatal prognosis. No effective systemic therapies exist. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR or combined RAF/MEK inhibition, but experienced a dramatic response when both drug regimens were combined. Methods and Results: Nine biopsies of the tumor were obtained between diagnosis and autopsy. Multi-region whole-exome sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways respectively. We performed the largest meta-analysis of ATC to date and found a 7.4% co-occurrence of MAPK and PI3K pathway alterations in ATC. We analyzed 5,255 cancer exomes in the Cancer Genome Atlas (TCGA) to determine whether similar cancer genomes occurred outside of anaplastic thyroid carcinoma. We identified 11 tumors with BRAF V600E and non-silent PIK3CA mutations. These results indicate that this genotype occurs in other cancers and may predict response to combined therapy. Conclusions and future directions: We have identified a patient with ATC who had a dramatic response to combined inhibition of the MAPK and PI3K pathways, whereas neither MAPK inhibition nor PI3K inhibition alone was sufficient to produce tumor regression. These observations suggest that MAPK and PI3K/MTOR pathway blockade represents an effective dual therapy aimed at the founding oncogenic lesions in a subset of ATC. Citation Format: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew Nehs, Francis Moore, Amaro Taylor-Weiner, Jeremiah Wala, Travis Zack, Thomas Lee, Fiona Fennessy, Erik Alexander, Tom Thomas, Pasi Jäne, Levi Garraway, Scott Carter, Rameen Beroukhim, Jochen Lorch, Eliezer Van Allen. Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-227.
Abstract 2888: Identification of an NKX3.1-G9a-UTY regulatory network that controls proper prostate differentiation
Authors: Clementine Le Magnen, Aditya Dutta, Antonina Mitrofanova, Andrea Califano, Cory Abate-Shen
Journal: Cancer Research (2016)

Abstract Maintenance of cell differentiation is tightly coordinated by specific gene expression programs, which are often deregulated during tumorigenesis. While the homeodomain-containing transcription factor, NKX3.1, plays essential roles in both prostate differentiation and prostate cancer, the mechanisms governing these events are still unclear. Here, we aim to elucidate detailed mechanisms governing Nkx3.1-driven prostate epithelial differentiation and explain how deregulation of such can lead to prostate tumorigenesis. Using an Nkx3.1 mutant mouse model, we find that loss-of-function of Nkx3.1 in the prostate results in the down-regulation of genes associated with prostate differentiation as well as the up-regulation of genes that are not normally expressed in prostate. Interestingly, these mice also develop pre-malignant lesions resembling prostatic intraepithelial neoplasia (PIN). Conversely, gain of function of Nkx3.1 in a fully differentiated non-prostate epithelium is sufficient to induce prostate differentiation in renal grafts in vivo. Using a DNA binding mutant, we show that these activities are mediated via NKX3.1 homeodomain in vitro and in vivo. Exploiting mass spectrometry to identify NKX3.1-interacting proteins, we find that NKX3.1 interacts with the histone methyltransferase G9a and that this interaction is required for induction of prostate differentiation in vitro and in vivo. Finally, we show that these NKX3.1-driven activities are mediated, at least in part, by regulation of target genes such as the male-specific factor UTY (KDM6c). We propose that the NKX3.1-G9a-UTY network is essential for proper prostate differentiation whereas disruption of these activities predisposes to cancer. Citation Format: Clementine Le Magnen, Aditya Dutta, Antonina Mitrofanova, Andrea Califano, Cory Abate-Shen. Identification of an NKX3.1-G9a-UTY regulatory network that controls proper prostate differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2888.
Comparison Of Mutational Profiles Of Diagnosis and Relapsed Pediatric B-Acute Lymphoblastic Leukemia: A Report From The COG ALL Target Project
Authors: Jinghui Zhang, Mignon L. Loh, Xiaotu Ma, Michael Rusch, Gang Wu, Richard C. Harvey, David A. Wheeler, Oliver A. Hampton, William L. Carroll, I-Ming Chen, Daniela S. Gerhard, Julie M. Gastier-Foster, Mary V. Relling, Malcolm A. Smith, Meenakshi Devidas, Jaime M. Guidry Auvil, James R. Downing, Cheryl L. Willman, Charles G. Mullighan, Stephen P. Hunger
Journal: Blood (2013)
Abstract LB-194: AhR Arg554Lys impacts tumor ER expression and endocrine treatment response in breast cancer
Authors: Maria Simonsson, Andrea Markkula, Carsten Rose, Christian Ingvar, Helena C. Jernström
Journal: Cancer Research (2016)

Abstract Introduction: Markers for treatment resistance in breast cancer are needed. The Aryl hydrocarbon receptor (AhR) is involved in the regulation of estrogen metabolism. Previous studies have observed a crosstalk between AhR and the estrogen receptor (ER), indicating that the AhR may be of importance in the response of endocrine treatment. Materials and methods: A functional polymorphism in the AhR Arg554Lys (G&amp;gt;A) was analyzed in a cohort of 634 breast cancer patients included at their preoperative visits in Lund, Sweden between 2002 and 2008. AhR genotypes were studied in relation to ER status and risk for breast cancer events. Results: The frequencies of the AhR GG/ GA/ AA genotypes were 82.0%, 16.7%, and 1.3%, respectively. There was a trend towards increasing frequency of ER+ tumors with increasing number of A-alleles (P-trend = 0.03). Since few patients had the A/A genotype, patients with the G/A and A/A genotypes were combined in the survival analyses of the 576 patients with invasive tumors, no preoperative treatment, and no events detected on the postoperative metastases screen. Overall, AhR was not associated with event-free survival (LogRank P = 0.22). Among patients ever treated with chemotherapy or radiotherapy, AhR was not associated with event-free survival (LogRank P = 0.24 and P = 0.18, respectively). However, among tamoxifen-treated patients with ER+ tumors, AhR G/G carriers had a significantly lower risk for breast cancer events (LogRank P = 0.005), adjusted HR 0.53 (95% CI 0.29-0.94). This association was confined to patients who had received both tamoxifen and aromatase inhibitor (AI) switch treatment (LogRank P = 0.0002), adjusted HR 0.23 (0.09-055), while no association was seen in patients treated with tamoxifen only (LogRank P = 0.56). AI-treated patients with the G/G genotype had an even lower risk for breast cancer events than tamoxifen-treated patients (LogRank P = 0.005), adjusted HR 0.39 (0.19-0.81). Again this was only seen in patients who had received both AI and tamoxifen, but not in patients who had received AI but no tamoxifen treatment. Adjustments were made for age at inclusion, axillary lymph node involvement, invasive tumor size, and histological grade. Further adjustment for smoking status did not materially change the results. Conclusion: The functional AhR Arg554Lys polymorphism may impact tumor ER expression and response to endocrine switch treatment with both AI and tamoxifen in breast cancer patients. Citation Format: Maria Simonsson, Andrea Markkula, Carsten Rose, Christian Ingvar, Helena C. Jernström. AhR Arg554Lys impacts tumor ER expression and endocrine treatment response in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-194.