tbuckley/cabot-search huggingface dataset:
Erratum: Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice (Journal of Clinical Investigation (2012) 122, 1 (91-106) DOI: 10.1172/JCI59466)
Authors: Jae Hyuck Shim, Matthew B. Greenblatt, Anju Singh, Nicholas Brady, Dorothy Hu, Rebecca Drapp, Wataru Ogawa, Masato Kasuga, Tetsuo Noda, Sang Hwa Yang, Sang Kyou Lee, Vivienne I. Rebel, Laurie H. Glimcher
Journal: Journal of Clinical Investigation (2012)
488. In Vitro and In Vivo Genome Editing of the RHO Gene to Downregulate Dominant Mutations
Authors: Maria C. Latella, Maria T. Di Salvo, Fabienne Cocchiarella, Daniela Benati, Valeria Marigo, Alessandra Recchia
Journal: Molecular Therapy (2016)

Although progresses have been made in the understanding of the genetic basis for Retinitis Pigmentosa (RP), the development of therapeutic intervention is still lagging behind. Gene therapy was successfully applied to retina degeneration but only to recessive mutations. Rhodopsin (RHO) mutations represent a common cause of RP, accounting for 25% of adRP and 8 to 10% of all RP (Hartong et al., 2006) with more that 100 different mutations identified so far. RHO is a G-protein coupled receptor with localization restricted to rod outer segments where the phototransduction cascade initiates. Data on the pathogenic mechanism of mutant RHO are still controversial. Accumulation of mutant RHO in different subcellular compartments, and among those the ER, may trigger unfolded protein response (UPR) devoted to cytoprotective outputs to permit cells to reduce protein synthesis and up-regulate chaperons to cope with stress (Lin et al., 2007). In the autosomal dominant RP the mutation in only one allele is sufficient to the onset of retinal degeneration. To treat this kind of disorder a gene addition therapy is not suitable, as the mutant allele, mRNA, or protein product must be silenced beforehand. We aimed at developing genome editing tools to knock out the RHO defective alleles by introducing a double strand breaks (DSB) into the target gene. Two gRNAs were designed in the first exon on the RHO gene encompassing the P23H mutation. The two gRNAs were tested singularly or together in vitro on HeLa clones stably expressing P23H RHO. We demonstrated insertions or deletions (indels) in the genomic DNA specifically in the RHO gene by Cel I assay, TIDE and sequencing. Indels caused strong reduction of the RHO mRNA and of RHO protein up to 90%. The higher effect was obtained with the two gRNAs together. The two gRNAs were then in vivo expressed with Cas9 in photoreceptors of transgenic mice expressing the human P23H Rho gene by electroporation. Targeted cells were tracked by co-expression of EGFP. EGFP+ cells were FACS-sorted and indels in the human P23H RHO gene were analyzed by sequencing. We were able to detect up to 30% of genome editing in vivo. No editing was scored on murine Rho allele. We also detected reduction of RHO mRNA expression as well as RHO protein. Finally, we developed new tools to downregulate mutant RHO in dominant forms of RP. The CRISPR/Cas9 system reveled a high efficiency and should be tested for knock-down followed by gene replacement approaches.
Molecular analysis of KRAS polymorphism mutation using a high-resolution melting system in a large mCRC patients sample in Mexico.
Authors: H. Astudillo, E. B. Ruiz-Garcia, V. M. Vazquez, J. Bastarrachea, P. Romero-Garcia, A. J. Silva, H. Ruiz-Calzada, A. Lopez-Yañez, P. Cortes Esteban
Journal: Journal of Clinical Oncology (2011)

e14132 Background: The KRAS-MAPK, PI(3)K signaling pathways form a network that play a central role in tumorigenesis. Mutations in codons 12, 13 and also 61 cause an activation of the KRAS protein. These mutations are frequently found in human tumors. The presence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC). Methods: We retrospectively collected paraffin embedded tumors from 807 patients with mCRC diagnosis from different Hospitals in Mexico. Mutation detection in KRAS codons 12 and 13 were determined. The tests were performed in a LightCycler 2.0 system using the LightMix Kit KRAS mutation (TIB-Molbiol). Results: Patients with KRAS wild-type tumors (n = 495; 61%) and patients with KRAS mutated (n=312; 39%) shown the following polymorphism: Gly12Ser (GGT>AGT) (148/312, 47%); Gly12Asp (GGT>GAT) (50/312, 16%); Gly12Val (GGT>GTT) (22/312, 7%); Gly13Asp (GGT>GAC) (20/312, 6%); Gly13Cys (GGT>TGT) (16/312, 5%); Gly12Arg (GGT>CGT) (13/312, 4%); Gly12Cys (GGT>TGT) (12/312, 4%); Gly12Ala (GGT>GCT) (11/312, 4%). Conclusions: KRAS mutation status was according with international previous reports (n=312; 39%), and it was more associated with the mutation polymorphism Gly12Ser (GGT>AGT; 148/312; 47%). Outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen was not evaluated because of the early treatment stage.
OP23A CONSENSUS WORKSHOP TO DEVELOP RISK-BASED SELECTION CRITERIA FOR THE NEXT SIOP TRIAL OF “SIGHT-SAVING THERAPY” FOR CHILDREN WITH NF1-ASSOCIATED OPTIC PATHWAY GLIOMA (NF1-OPG)
Authors: Enrico Opocher, Jo-Fen Liu, Rory Deasy, Amedeo A. Azizi, Rosalie Ferner, Tim Jaspan, Ian Simmons, Astrid Marie Sehested, David A. Walker
Journal: Neuro-Oncology (2015)

INTRODUCTION: The natural history of children with NF1-OPG is unpredictable, indications for therapy to save vision, using patient, imaging and visual factors have not been studied in Europe. The aim of this multi-disciplinary workshop was to promote a revised and standardised approach for the next SIOP LGG trial. METHOD: Eight SIOP-LGG2004 centres contributed 83 NF1-OPG cases with complete imaging, visual and clinical datasets (age at diagnosis: median 4.8 yrs range 1.1-13.1; m:F 37:46, median follow-up 19.2 months range 1.8-121 months). Severe visual impairment/blindness (LogMAR >= 1.0) at diagnosis and last follow up, respectively: unilateral 16,21; bilateral 3,7. Anatomical distribution at diagnosis: Dodge Stage A (nerves) 35; Stage B (chiasm) 16; Stage C (nearby structures) 32. Imaging evidence of: response 31: no change:46; progression 6. Analysis of this dataset informed consensus discussion and voting of representative cases for proposed trial criteria for observation, treatment and randomisation. RESULTS: Consensus on imaging and visual classification was achieved, including a schematic for recording patient, visual and imaging details. Criteria for case selection were: age, history of visual decline, presence of severe visual symptoms, unreliable visual assessment, proptosis and post-chiasmatic tumour involvement. A subsequent 19 case web-based questionnaire was completed by 15 workshop participants. The respondents allocated 8 cases to observation; 8 to immediate treatment and 3 for consideration for randomisation. CONCLUSION: A new consensus on selection criteria using a contemporary trial cohort was reached. We have piloted a web-based questionnaire to assess feasibility of a randomised trial.
641. Highly Efficient, ZFN-Driven Knockout of Surface Expression of the T-Cell Receptor and HLA Class I Proteins in Human T-Cells for Enhancing Allogeneic Adoptive Cell Therapies
Authors: Gary K. Lee, Pei-qi Liu, Nimisha Gandhi, Lynn Truong, Andreas Reik, Stephen Lam, Sarah J. Hinkley, Jeffrey C. Miller, David E. Paschon, Lei Zhang, Edward J. Rebar, Michael C. Holmes
Journal: Molecular Therapy (2016)

While adoptive transfer of T-cells modified to express a chimeric antigen receptor or tumor antigen specific T-cell receptor (TCR) has shown great promise for the treatment of malignant cancers, most current clinical applications are limited by the use of autologous T-cell products. Targeting of the TCR and HLA Class I genes in primary T-cells thus represent attractive targets for genome editing in order to produce universal T cells from allogeneic donors. Elimination of the native TCR and HLA class I proteins on T-cells would, respectively, reduce the risk of graft-versus-host disease and host-versus-graft clearance mediated by the adaptive immune system. We have developed clinical grade zinc finger nuclease (ZFN) reagents that can efficiently target the T-cell receptor alpha constant (TRAC) and beta-2-microglobulin (B2M) loci. ZFN encoding mRNAs were introduced into purified T-cells by electroporation. Without selection, T-cells treated with TRAC specific ZFNs showed modification of up to 89% of alleles as gauged by deep sequencing. Flow analysis showed 91% of treated cells were negative for CD3 expression. Results from ZFN mRNA dose titration studies showed that the level of TRAC gene modification by deep sequencing was highly correlated with the percentage of cells that stain negative for CD3 expression by FACS (Spearman rho = 0.96; p < 0.0001). B2M is a subunit in all HLA class I molecules, and represents a conserved target for eliminating HLA class I presentation in cells from different donors. Analysis of T-cells transfected with mRNAs encoding B2M specific ZFNs showed up to 94% of alleles were modified, as determined by deep sequencing. FACS analysis showed that 89% of treated cells were negative for expression of HLA-A, B, C. Similar to TRAC modified cells, a marked correlation was observed between the percentage of B2M alleles modified and percentage of cells lacking surface expression of HLA-A,B, and C (Spearman rho = 0.57; p < 0.0001). ZFN mediated genome editing was well tolerated. T-cells treated with TRAC or B2M specific ZFNs showed similar viability and growth characteristics as mock transfected cells. Together, these highly efficient ZFN reagents permit the highly efficient double knockout of TCR and HLA class I surface expression in primary human T-cells for potential use in the development of allogeneic cell therapies.
Comparing Outcomes for Robotic and Open Pancreatoduodenectomy
Authors: Shachar Laks, David A. Kooby, Hong Jin Kim
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
Drug-free sustained remission or spontaneous remission by natural history in rheumatoid arthritis? An unsolved question: comment on the article of Ajeganova<i>et al</i>
Authors: Henning Zeidler
Journal: Annals of the Rheumatic Diseases (2016)

Dear Editor, I read with interest the article by Ajeganova et al 1 reporting disease-modifying antirheumatic drug (DMARD) free sustained remission in rheumatoid arthritis (RA) as an increasingly achievable outcome with subsidence of disease symptoms. The conclusion of their study was that more intensive treatment strategies increased the chance for DMARD-free sustained remission, indicating that RA chronicity can be influenced. Of note, ‘Patients who achieved DMARD-free sustained remission, compared with those who did not, were less often anti-citrullinated protein antibodies (ACPA) or rheumatoid factor (RF) positive (18% vs 62%, and 31% vs 65%, both p≤0.001) and had shorter symptom duration …
A Pilot Study of Combined Escalated BEACOPP-ABVD Therapy for Advanced Hodgkin’s Lymphoma Patients with High IPS Score: The Israel Cooperative Lymphoma Group.
Authors: Abraham Avigdor, Shlomo Bulvik, Noga Shemtov, Itai Levi, Miriam Berkowicz, Dina Ben-Yehuda, Dorit Blickstein, Neta Goldschmidt, Alexander Gural, Abraham Kornberg, Dianna Libster, Drorit Merkel, Elizabeth Naparstek, Pia Raanani, Batia Roth, Yulia Volchek, Arnon Nagler, Isaac Ben-Bassat, Aaron Polliack
Journal: Blood (2004)
HBsAg Loss With TDF Plus PegIFN in Chronic Hepatitis B (CHB): Long-term Results of a Global Randomized Controlled Trial
Authors: Sang-hoon Ahn, Patrick Marcellin, Xiaoli Ma, Florin Caruntu, Won Young Tak, Magdy Elkhashab, Wan-Long Chuang, Fehmi Tabak, Rajiv Mehta, Joerg Petersen, Amoreena Corsa, Eduardo Martins, Leland Yee, Phillip Dinh, Mani Subramanian, Yiwei Lu, Maria Buti, Giovanni Gaeta, George Papatheodoridis, Robert Flisiak, Henry Lik-Yuen Chan
Journal: Clinical Gastroenterology and Hepatology (2016)
Abstract A05: Proteomic analysis of exosome content changes induced by gemcitabine in pancreatic cancer stromal cells
Authors: Wei Huang, Peter Feist, Amanda Hummon, Reginald Hill
Journal: Cancer Research (2016)

Abstract Despite recent advances in multimodality therapy, pancreatic ductal adenocarcinoma (PDAC) remains the 3rd leading cause of cancer-related deaths in the United States with a 5-year survival rate of 8%. One hallmark of this disease is desmoplasia that consist largely of stromal cells and extracellular matrix (ECM) proteins. The abundant stromal cells provide a unique tumor microenvironment that aid tumorigenesis. Unfortunately, there is little data on the mechanism underlying the stromal cells’ ability to impact chemoresistance in neighboring cancer cells in response to drug treatment. Exosomes are small vesicles secreted into the extracellular environment from cells and evidence is accumulating that exosomes play a key role in intercellular signaling. Researchers have focused on exosomes secreted from cancer cells, but the function of stromal exosomes has not been investigated, especially in pancreatic cancer. As stromal cells comprise the majority of the pancreatic tumor bulk, we hypothesize that stromal cell-derived exosomes help pancreatic cancer cells resist chemotherapy. Thus, it is critical to characterize the complex composition of stromal exosomes. In this study, we analyzed the proteomic content of exosomes collected from stromal cell lines created from PDAC patients. Furthermore, we also determined the change in exosomal proteomic composition after the patient-derived stromal cells were treated with gemcitabine, the current standard of care chemotherapy for patients with PDAC. Our studies have identified possible diagnostic and prognostic biomarkers and suggest novel molecular mechanism responsible for the tumor microenvironment’s ability to regulate chemoresistance in neighboring pancreatic cancer cells. Citation Format: Wei Huang, Peter Feist, Amanda Hummon, Reginald Hill.{Authors}. Proteomic analysis of exosome content changes induced by gemcitabine in pancreatic cancer stromal cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A05.
Abstract 634: Novel antibody-drug conjugates targeting Axl show anti-tumor activity in solid cancer xenograft models
Authors: Esther C.W. Breij, Sandra Verploegen, Andreas Lingnau, Edward N. van den Brink, Maarten Janmaat, Mischa Houtkamp, Wim K. Bleeker, David Satijn, Paul W.H.I. Parren
Journal: Cancer Research (2015)

Abstract Axl is a receptor tyrosine kinase of the TAM family, which is structurally characterized by the presence of two extracellular immunoglobulin-like domains and two fibronectin type III domains, a single-pass transmembrane region and an intracellular tyrosine kinase domain. Axl is aberrantly expressed and activated in both solid and hematological malignancies and has been associated with poor clinical prognosis in a number of cancers, including non-small cell lung cancer, breast cancer, pancreatic cancer and acute myeloid lymphoma. Functionally, Axl has been implicated in multiple pathological processes, such as tumor cell motility, adherence and migration, epithelial-to-mesenchymal transition, metastasis, angiogenesis and resistance to tyrosine kinase inhibitors. With the aim to target Axl expressing cancers, a panel of Axl-specific antibody-drug conjugates (ADC) was generated. First, high affinity human Axl antibodies were generated in HuMAb mice. Binding studies using Axl mutants, in which specific human Axl domains had been replaced with their murine analogs, demonstrated that the Axl antibody panel consisted of antibodies against different Axl extracellular domains. Second, the Axl antibodies were conjugated with the microtubule disrupting agent monomethyl auristatin E (MMAE) using the protease cleavable valine citrulline linker. Axl ADCs showed cytotoxic activity in vitro, which was dependent on target expression and on conjugation with cytotoxic payload. The anti-tumor activity of Axl ADCs was confirmed in vivo. Axl ADCs induced tumor regression in cell line derived xenograft models for lung cancer and epidermoid carcinoma. Anti-tumor activity was especially efficient in the lung cancer xenograft model, in which inhibition of tumor growth was observed upon treatment with a single dose of 0.5 mg/kg Axl ADC. In the same model, 1 mg/kg Axl ADC was sufficient to induce complete tumor regression. Importantly, Axl ADCs also showed efficient anti-tumor activity in patient-derived xenograft (PDX) models that showed heterogeneous target expression. In summary, Axl is a novel target for antibody-mediated delivery of cytotoxic agents into tumor cells. The promising results obtained in preclinical tumor models support further development of Axl-specific ADCs. Citation Format: Esther C.W. Breij, Sandra Verploegen, Andreas Lingnau, Edward N. van den Brink, Maarten Janmaat, Mischa Houtkamp, Wim K. Bleeker, David Satijn, Paul W.H.I. Parren. Novel antibody-drug conjugates targeting Axl show anti-tumor activity in solid cancer xenograft models. [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 634. doi:10.1158/1538-7445.AM2015-634
The BCR-Associated Tyrosine Kinase SYK Is Linked to the Activation of AKT in Mantle Cell Lymphoma.
Authors: Martina Rudelius, Denise Sebasigari, Yoko Tabe, Theresa Davies-Hill, Falko Fend, Quintanilla-Martinez Leticia, Jaffe S. Elaine, Pittaluga Stefania, Raffeld Mark
Journal: Blood (2007)
Use of combination treatment with the investigational RAF kinase inhibitor MLN2480 and the investigational MEK kinase inhibitor TAK-733 on the growth of BRAF-mutant and RAS-mutant preclinical models of melanoma and CRC.
Authors: Elizabeth Grace Carideo Cunniff, Julie Zhang, Jouhara Chouitar, Jerome Mettetal, Kazuhide Nakamura, Takeo Arita, Akito Nakamura, Masanori Okaniwa, Tomoyasu Ishikawa, Sei Yoshida, Robyn Fabrey, Patrick Vincent, Kurt Eng, Khristofer Garcia, Deanna Borrelli, Teena Vagrhese, Steve Stroud, Saurabh Menon, Mike Kuranda, Katherine Galvin
Journal: Journal of Clinical Oncology (2013)

e13529 Background: RAS mutant melanoma and colorectal cancer represent areas of significant unmet medical need. MLN2480 is an investigational class II RAF kinase inhibitor and TAK-733 is an investigational allosteric MEK kinase inhibitor; each of which is the subject of a single agent phase I clinical trial. The present studies have characterized the combination activity of these agents in BRAF mutant and RAS mutant preclinical models of melanoma and colorectal cancer. Methods: Combination effects of MLN2480 and TAK-733 on cell viability were studied using an ATP-based cell viability assay across a panel of BRAF and RAS mutant melanoma and CRC cell lines. Western blot analysis was used to compare effects on MAPK pathway signaling and response markers in cell lines showing a range of sensitivity to this combination. Pharmacodynamic responses and growth inhibitory effects of the combination were studied in xenografts of the same cell lines, as well as in primary human tumor xenografts, of RAS mutant melanoma and CRC. Results: MLN2480 inhibits MAPK pathway signaling in BRAF mutant and some RAS mutant preclinical cancer models at concentrations that are tolerated in vivo. MLN2480 is most potent in BRAF mutant melanoma models but also has single agent activity in some RAS mutant models. The combination of MLN2480 with TAK-733 inhibits the growth of a broader range of RAS mutant tumor models than single agent MLN2480, including primary human tumor xenograft models of melanoma and CRC. In vitroanalysis of this drug combination in cell proliferation assays demonstrates synergistic activity. Western blot analysis demonstrated the effect of MLN2480 in reversing feedback activation of MEK in response to TAK-733, leading to more concerted MAPK pathway inhibition. Conclusions: The activity of the RAF kinase inhibitor MLN2480 in preclinical models of BRAF and RAS mutant melanoma and CRC provides a rationale for clinical testing. The combination of MLN2480 with the MEK inhibitor TAK-733 represents an additional strategy for clinical research within these tumor types.
Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus
Authors: Qihui Wang, Huabing Yang, Xiaoqing Liu, Lianpan Dai, Tong Ma, Jianxun Qi, Gary Wong, Ruchao Peng, Sheng Liu, Junfu Li, Shihua Li, Jian Song, Jianying Liu, Jianhua He, Hui Yuan, Ying Xiong, Yong Liao, Jianhua Li, Jianping Yang, Zhou Tong, Bryan D. Griffin, Yuhai Bi, Mifang Liang, Xiaoning Xu, Chuan Qin, Gong Cheng, Xinzheng Zhang, Peiyi Wang, Xiangguo Qiu, Gary Kobinger, Yi Shi, Jinghua Yan, George F. Gao
Journal: Science Translational Medicine (2016)

Zika virus–specific antibodies isolated from a single infected patient show postexposure protection in mice and reveal targets for therapy.
Image Gallery: Syphilitic chancre of the palm
Authors: M. Nico, E. Rivitti
Journal: British Journal of Dermatology (2016)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 55‐year‐old man presented with a painless lesion on his left palm. It had persisted unaltered for 1 month despite several topical treatments. Examination revealed a 2‐cm shallow nonpurulent erosion with scaly borders located centrally on the palm. Proximally, a violaceous streak of lymphangitis could be observed. Further examination revealed a very subtle thoracic exanthema that went unnoticed by the patient, besides palpable left axillary lymph nodes. No anogenital lesions nor inguinal adenopathies were present, and the patient denied such changes previously. He was married and admitted being bisexual, with occasional extramarital intercourse with men. Investigations for syphilis revealed a rapid plasma reagin titre of 1 : 4, and positive Treponema pallidum particle agglutination test. HIV serology was negative. The palmar lesion was interpreted as a primary chancre, and the exanthema was interpreted as an initial manifestation of secondary syphilis. The patient was treated with intramuscular benzathine G penicillin, with complete clinical and serological cure. ...