tbuckley/cabot-search huggingface dataset:
54. Prevention of Sensory Ataxia in a Novel Mouse Model of Friedreich Ataxia Using Gene Therapy Approach
Authors: Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Hélène Puccio
Journal: Molecular Therapy (2016)

Friedreich's ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by a sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy and increase incidence of diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in individuals with FRDA. Proprioceptive neurons within the dorsal root ganglia (DRG) and cardiomyocytes are the most affected tissues in FRDA patients. To date there are not effective treatment for FRDA. We have previously established the primary proof-of-concept for developing gene therapy of FRDA cardiomyopathy and showed that adeno-associated virus (AAV) rh. 10 vector expressing human FXN injected intravenously not only prevented the onset of the cardiac disease in a faithful FRDA cardiac mouse model, but also, when administered at the time of heart failure, rapidly and completely reversed the cardiac disease. To date, there were unfortunately no adequate neuronal mouse model to address the possibility of gene therapy for the neuronal aspects of FRDA. We therefore recently generated a novel mouse model that recapitulates faithfully the sensory ataxia associated to FRDA using the conditional approach to delete frataxin specifically in the proprioceptive neurons of the DRG. By behavioural analysis, the mice exhibit an ataxic phenotype beginning at 3 weeks of age, which is rapidly progressive. Electrophysiological studies reveal a significant decrease of sensory wave already at 4.5 weeks and almost a complete loss at 8 weeks of age. A significant loss of sensory neurons within dorsal root ganglia is observed at 17.5 weeks of age compare to age matched controls. Ultrastructural analysis of sciatic and saphenous nerves showed abnormalities at early time points. Using this mouse model, we have developed an AAV gene therapy approach based on an intravenous delivery of AAV9-CAG-hFXN-HA vector at an early symptomatic stage of the disease. Mice displayed a complete prevention of the ataxic phenotype and electrophysiological analysis showed maintenance of the sensory wave in the treated animals. Histological studies revealed a complete prevention of neuronal loss in the DRG as well as a normal ultrastructure of saphenous and sciatic nerve. As results are encouraging, we plan to evaluate the potential therapeutical effect at a more advanced stage of the disease.
Abstract 1824: Predictive value of neutrophil-lymphocyte ratio for the efficacy of preoperative chemotherapy in triple-negative breast cancer
Authors: Yuka Asano, Shinichiro Kashiwagi, Tamami Morisaki, Satoru Noda, Hidemi Kawajiri, Tsutomu Takashima, Naoyoshi Onoda, Kosei Hirakawa
Journal: Cancer Research (2015)

Abstract Purpose: Abnormalities in the subpopulations in white blood cells, such as neutrophilia and lymphopenia, have been reported in tumor-bearing patients, and the neutrophil/ lymphocyte ratio (NLR) has been found to associate with prognosis in patients following radical surgery. The NLR was reported to associate with prognosis in cancer patients by influencing both cancer progression and chemosensitivity. The correlation between NLR and the outcome of neoadjuvant chemotherapy (NAC) in breast cancer patients has not been elucidated yet. The aim of this study is to evaluate NLR as one of the possible markers to predict the outcome of NAC in patients with TNBC by a retrospective investigation of the consecutive patient series treated with a standardized single protocol in our institute. Experimental Design: NLR was evaluated in a total of 177 patients with early-stage breast cancer treated with NAC consisting FEC (5-fluorouracil, epirubicin, and cyclophosphamide) followed by weekly paclitaxel followed by curative surgery. The correlation between NLR and the prognosis including the efficacy of the NAC was evaluated retrospectively. NLR was calculated from the preoperative blood sample by dividing the absolute neutrophil count by the absolute lymphocyte count. On the basis of previous studies, an NLR value of 3.0 was used as the cut-off value to discriminate between high-NLR (3.0 and over) and low-NLR (less than 3.0) groups. Results: NLR distributed from 0.5 to 10.6 with a median of 2.0. Fifty-eight patients with low NLR (less than 3) had a higher pCR rate (p&amp;lt;0.001), and more frequently diagnosed to have TNBC (p&amp;lt;0.001) compared with those with high NLR (3 and over). Among TNBC patients who achieved pCR, DFS (p = 0.006) and OS (p&amp;lt;0.001) were significantly longer in patients with low NLR than that with high NLR. Low NLR was associated with a significantly favorable prognosis in TNBC patients who achieved pCR, according to univariate analysis (p = 0.044, HR = 0.06). Conclusions: Low NLR in patients with TNBC could be expected to show high efficacy, and favorable outcome after NAC. Citation Format: Yuka Asano, Shinichiro Kashiwagi, Tamami Morisaki, Satoru Noda, Hidemi Kawajiri, Tsutomu Takashima, Naoyoshi Onoda, Kosei Hirakawa. Predictive value of neutrophil-lymphocyte ratio for the efficacy of preoperative chemotherapy in triple-negative breast 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 1824. doi:10.1158/1538-7445.AM2015-1824
Phase I trial of TPI 287 as a single agent and in combination with temozolomide (TMZ) in patients with refractory or recurrent neuroblastoma (NB) or medulloblastoma (MB).
Authors: G. L. Saulnier Sholler, D. Eslin, W. D. Roberts, J. Kaplan, G. Bergendahl, T. Ashikaga, T. Higgins, S. Lenox, S. Silberman, W. Ferguson
Journal: Journal of Clinical Oncology (2011)

9554 Background: Survival for children diagnosed with NB after age 18 months is <40% despite aggressive multimodal therapy. Similarly, <15% survive relapse of MB, with often severe long-term toxicity. A novel anti-microtubule agent, TPI 287, has very high potency against several NB and MB cell lines and xenograft models, prompting a phase I study to determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287 in patients with refractory or recurrent NB or MB. Secondary objectives were to evaluate the pharmacokinetics (PK) and anti-tumor activity of TPI 287 in these patient populations, both as a single agent and in combination with temozolomide. Methods: Patients with relapsed or refractory NB or MB were enrolled in a multicenter, dose escalation 3+3 design study and received intravenous TPI 287 on days 1, 8 and 15 of each 28-day cycle. After 2 cycles, TMZ 100 mg/m2 was added on days 1-5 of each cycle. The MTD of single agent TPI 287 was the dose below which DLTs were seen in ≥ 2 of 6 patients. Anti-tumor activity was measured by CT/MRI and MIBG scans. Results: 15 patients have been enrolled, 13 with NB, 2 with MB. Dosing with TPI-287 started at 90 mg/m2 and was increased in successive cohorts until DLTs were seen at 135 mg/m2. The MTD of TPI 287 in children with NB and MB was determined to be 125 mg/m2 and additional patients are being enrolled at this dose. The addition of TMZ caused no additional toxicity. The most frequent adverse events included peripheral neuropathy (36%), anemia (43%) and pain (43%). The DLT’s observed were Grade 3 peripheral neuropathy and Grade 3 hemorrhagic cystitis. All toxicities were reversible. To date 11 patients are evaluable for response with stable disease in 7 patients (range 3-12+ months). Conclusions: TPI-287 was safe and well tolerated in patients with NB and MB with many patients showing prolonged stabilization of disease. The MTD was 125 mg/m2. Based on these results in this heavily pretreated population with refractory disease, a phase II trial to evaluate efficacy is warranted.
PR-924, a Selective Inhibitor of the Immunoproteasome Subunit LMP-7 Blocks Multiple Myeloma Cell Growth Both in Vitro and In Vivo.
Authors: Ajita V. Singh, Madhavi Bandi, Monette Aujay, Susan Demo, Teru Hideshima, Nikhil C. Munshi, Paul G. Richardson, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2009)
Abstract 4951: Expression analysis of the LOT1 gene in head and neck cancer
Authors: SEDA EKIZOGLU ERATAK, Emin Karaman, NUR A. BUYRU
Journal: Cancer Research (2015)

Abstract Head and neck cancer (HNC) which is the sixth most common type of cancer worlwide, comprise a diverse group of tumors including neoplasias of the paranasal sinuses, the oral cavity, the trachea, the pharynx and the larynx. The most well known environmental risk factors for developing HNC are tobacca, alcohol and betel nut use and sexually transmitted viral pathogens such as human papilloma viruses (HPV). In addition to environmental factors, genetic factors may play a key role in the development of HNC. Therofore, genetic abnormalities have been studied extensively. The LOT1 (Lost-on-transformation 1) gene is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancer including squamous cell carcinomas of the head and neck. The product of the LOT1 gene is a 463 amino acid protein which contains 7 C2H2-type zinc-finger motifs at the amino terminal, as well as proline and glutamine rich areas at the carboxyl terminal. Functional analysis of LOT1 demonstrated that it may play a significant role as a transcription factor modulating growth suppression through mitogenic signaling pathways. To elucidate the role of the LOT1 gene in tumorigenesis, many studies analyzing alterations of the gene expression were performed. As a result of these studies, the absence or reduced expression of LOT1 gene was reported in many types of tumors including breast, ovarian, pituitary and lung tumors. In this study, we analyzed the role of the LOT1 gene in head and neck carcinogenesis. For this purpose, we investigated the expression level of LOT1 gene in tumor tissue and adjacent non-cancerous tissue samples from 81 patients with HNC by quantitative RT-PCR. We found that LOT1 gene expression was decreased in 64 of 81 tumor tissues (79%) when compared to normal tissue. Statistically, downregulation of the LOT1 gene mRNA expression was significant (p&amp;lt;0.001). No significant correlation was found between LOT1 gene expression and clinicopathological parameters including age, sex, stage, histological grade and tumor location (p&amp;gt;0.05). Our data indicate that loss of the LOT1 gene function may play a role in the etiology of head and neck carcinogenesis. Citation Format: SEDA EKIZOGLU ERATAK, Emin Karaman, NUR A. BUYRU. Expression analysis of the LOT1 gene in head and neck 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 4951. doi:10.1158/1538-7445.AM2015-4951
162. Crossing the Blood-Cerebrospinal Fluid Barrier in the Mouse Choroid Plexus With an Engineered Receptor/Ligand System
Authors: Hector R. Mendez-Gomez, Albert Galera-Prat, Craig Meyers, Weijun Chen, Mariano Carrion-Vazquez, Nicholas Muzyczka
Journal: Molecular Therapy (2015)

Crossing the blood-brain and the blood-cerebrospinal fluid barriers are one of the fundamental challenges in the development of new therapeutic molecules for brain disorders because they prevent entry of most drugs from the blood into the brain. However, some large molecules, like the protein transferrin, cross these barriers using a specific receptor that transports them into the brain. Mimicking nature, we engineered a receptor/ligand system to cross the brain barrier by combining the human transferrin receptor with the cohesin domain from Clostridium thermocellum, and we tested it in the choroid plexus of the mouse brain with a dockerin ligand. By expressing our receptor in choroidal ependymocytes, which are part of the blood-cerebrospinal fluid barrier, we found that our systemically administrated ligand was able to bind to the receptor and accumulate in ependymocytes, where some of the ligand was transported from the blood side to the brain side.
Eric William Taylor
Authors: John Williams, Peter Bull
Journal: BMJ (2016)

Eric William Taylor was a highly respected general surgeon. He spent 17 years in the Royal Navy before moving to the west of Scotland, where he worked in the NHS for 25 years. He was born on New Year’s Eve 1943 in Tunbridge Wells and educated at the Thomas Hardye School in Dorchester. He started his medical training in 1962, qualifying in 1967. In 1965 he applied to join the Royal Navy as a medical cadet, knowing that if successful he would serve for five years after qualifying.

Eric spent his early naval career in submarines before taking up surgical training, initially as a senior house officer in orthopaedics, before focusing on general surgery. At this time he applied for a full career commission, rather than leaving after his obligatory five years. He trained in general surgery at the Royal Naval Hospitals …
C-reactive protein levels are inversely correlated with the apolipoprotein B-48-containing triglyceride-rich lipoprotein production rate in insulin resistant men
Authors: Jean-Philippe Drouin-Chartier, André J. Tremblay, Jean-Charles Hogue, Myriam Leclerc, Marie-Ève Labonté, Johanne Marin, Benoît Lamarche, Patrick Couture
Journal: Metabolism (2016)
Abnormal Localization of Neutrophil Elastase in Patients with Severe Congenital Neutropenia.
Authors: Takashi Sato, Masakazu Habara, Hiroki Kihara, Hiroshi Kawaguchi, Mizuka Miki, Kazuhiro Nakamura, Satoshi Okada, Nobutsune Ishikawa, Norioki Ohno, Masao Kobayashi
Journal: Blood (2006)
Over 30% of Patients with Splenic Marginal Zone Lymphoma Express Distinctive Antigen Receptors Utilizing a Single Immunoglogulin Variable Gene: Implications for the Origin and Selection of the Neoplastic Cells
Authors: Vasilis Bikos, Nikos Darzentas, Anastasia Hadzidimitriou, Zadie Davis, Sarah Hockley, Alexandra Traverse-Glehen, Patricia Algara, Alessandra Santoro, David Gonzalez, Manuela Mollejo, Antonis Dagklis, George Bourikas, Achilles Anagnostopoulos, Athanasios Tsaftaris, Emilio Iannitto, Maurilio Ponzoni, Francoise Berger, Chrysoula Belessi, Paolo Ghia, Theodora Papadaki, Ahmet Dogan, Estella Matutes, Miguel Angel Piris, David Oscier, Kostas Stamatopoulos
Journal: Blood (2010)
361. Metallic Particles Generated During Electric Pulses Enhance Adenovirus-Mediated Gene Transfer
Authors: Thierry Ragot, Antoine Azan, Lluis M. Mir
Journal: Molecular Therapy (2015)

In vitro and in vivo gene transfer into cells and tissues using electric pulse application is more and more attractive due to its safety, versatility and efficiency improvement of protocols. However, the DNA penetration across the plasmic membrane during electrotransfer is not fully understood, and even large uncertainties remain about which mechanism(s) are actually involved. To learn more about the process(es) implicated for another large molecular object, we have applied electric pulses during recombinant adenovirus infection of cells in suspension. We observed an important increase of recombinant adenovirus-mediated GFP gene transfer when low voltage millisecond pulses were applied on poorly adenovirus-infectable cells. High quantities of metallic particles generated from the electrodes during this type of electropulsation were probably responsible of the observed effect. Indeed, if infection solution is pulsed separately and later on added to the cells, the same increase in adenovirus-mediated transfer is observed. Moreover, at a given multiplicity of infection of the virus, the effect is proportional to the quantities of metallic particles generated. After centrifugation of the pulsed infection solution, the virus was found mainly associated with metallic particles in the pellet. We are currently investigating the structure of adenovirus/metallic particle complex and the process involved in the enhancement of adenovirus entry into cells.
Identification of Previously Uncharacterized Delta 4-Positive Inflammatory Plasmacytoid Dendritic Cells That Play Important Roles in Eliciting Graft-Versus-Host Disease in Mice
Authors: Kazuhiro Mochizuki, Fang Xie, Shan He, Qing Tong, Yongnian Liu, Yajun Guo, Koji Kato, Hideo Yagita, Shin Mineishi, Yi Zhang
Journal: Blood (2012)
Abstract 402: Selective Protein Secretion Upon Endoplasmic Reticulum Stress Protects Cardiac Myocytes
Authors: Shirin Doroudgar, Donna J Thuerauf, Mirka Stastna, Mirko Voelkers, Jennifer E Van Eyk, Christopher C Glembotski
Journal: Circulation Research (2015)

Protein secretion is important for proper cardiac myocyte function. Many secreted proteins are synthesized and folded in the sarco- endo-plasmic reticulum (SR/ER). A number of diseases, including heart disease, alter the ER in ways that impair ER protein folding, causing ER stress, which can result in cardiac myocyte dysfunction and decreased viability. In studies aimed at assessing the effects of ER stress on cardiac myocyte viability, heart disease-related ER stress was mimicked by treating neonatal rat ventricular myocytes (NRVM) with either tunicamycin (TM) or thapsigargin (TG), which inhibit SR/ER protein glycosylation or decrease SR/ER calcium, respectively. When treated in high culture media volumes, both TM and TG caused cardiac myocyte death; however, in low culture media volumes, while TM still caused death, remarkably, TG was protective, suggesting that potentially protective factors were secreted in response to TG but not TM. To characterize these factors, the identities of proteins in control-, TM-, and TG-conditioned medium from NRVM were determined by proteomic approaches using high performance liquid chromatography and mass spectrometry. Twenty-four different proteins, known to be synthesized in the ER, were identified in control-conditioned medium. The levels of eighteen of these proteins, including extracellular matrix proteins, hormones, and growth factors were decreased in TM- and TG-conditioned medium. However, the levels of three SR/ER-resident, calcium-binding chaperones, glucose regulated protein 78 (GRP78), glucose regulated protein 94 (GRP94), and calreticulin were increased in TG-conditioned medium but not in TM-conditioned medium. Furthermore, we found that ischemia/reperfusion, which decreases SR/ER calcium, upregulated secretion of the proteins selectively secreted in response to TG. Thus, while ER stress mediated by TM or TG decreases the movement of most proteins through the secretory pathway, TG, which mimics the effects of heart disease on SR/ER calcium in cardiac myocytes, selectively enhances the secretion of a subset of proteins, which confer protection. Therefore, proteins once thought to be permanent residents of the SR/ER may have novel, extracellular, protective roles in the diseased heart.
Abstract 5325: A c-Kit targeting antibody-drug conjugate is efficiently metabolized and activated inside cancer cell lines and xenograft tumors
Authors: Erica Hong, Qifeng Qiu, Rui Wu, Alan Wilhelm, Kathleen Whiteman, Jan Pinkas, Hans Erickson, Tinya Abrams, Siew Schleyer
Journal: Cancer Research (2015)

Abstract We have developed an antibody-drug conjugate (ADC) targeting the c-Kit receptor tyrosine kinase, which is selectively expressed on the cell surface of various tumors including gastrointestinal tumors (GIST), small cell lung cancer (SCLC) and acute myelogenous leukemia (AML). The ADC consists of a humanized c-Kit-binding monoclonal antibody (c-Kit-Ab) covalently attached to a maytansinoid tubulin inhibitor, DM1, via a non-cleavable linker, SMCC. Like other ADCs, the c-Kit ADC is a pro-drug that is activated upon metabolism inside cells. Its target-mediated internalization and lysosomal degradation generates active maytansinoid metabolites that bind and inhibit microtubule dynamics. To understand the activation of the ADC, we studied the kinetics and efficiency of its metabolism in cancer cells and xenograft tumor models. Using radiolabeled ADC and c-Kit-Ab, we followed the formation of metabolites in SCLC and AML cells and in SCLC tumors, as well as in engineered cell lines that express various mutant forms of c-Kit. We found that the ADC and c-Kit-Ab are efficiently metabolized in c-Kit-positive cancer cells irrespective of the mutational status or the activation state of c-Kit. The degradation half-life of c-Kit-Ab is 3-fold lower than that observed for T-DM1 and SGN35, indicating a faster rate of activation. Moreover, cell surface repopulation with c-Kit is highly efficient after ADC-mediated internalization, allowing multiple rounds of ADC recruitment and activation. Interestingly, cell surface repopulation of c-Kit is more rapid for cells with a c-Kit mutation than those with wild-type c-Kit, leading to generation of greater levels of active metabolites in cells with mutant c-Kit. This may lead to better targeting of the c-Kit-mutated cancer cells over normal cells with wild-type c-Kit, which may improve the safety of the c-Kit ADC. Consistent with the in vitro findings, the ADC was found to undergo efficient metabolism in tumors in vivo. While tumor localization of the ADC over a non-targeting conjugate is similar to that observed with T-DM1 and SAR3419, its tumor-specific formation of active metabolites is 3-fold greater. Thus, the c-Kit-targeting ADC is particularly efficient at achieving high levels of active metabolites inside c-Kit-positive tumor cells, consistent with its robust efficacy in mouse xenograft models. Citation Format: Erica Hong, Qifeng Qiu, Rui Wu, Alan Wilhelm, Kathleen Whiteman, Jan Pinkas, Hans Erickson, Tinya Abrams, Siew Schleyer. A c-Kit targeting antibody-drug conjugate is efficiently metabolized and activated inside cancer cell lines and xenograft tumors. [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 5325. doi:10.1158/1538-7445.AM2015-5325
Lymphoma and Pregnancy—Reply
Authors: Chelsea C. Pinnix, Michelle A. Fanale
Journal: JAMA Oncology (2016)

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Second-line chemotherapy after disease progression following first-line FOLFOXIRI in advanced pancreatic cancer patients
Authors: E. Vasile, C. Vivaldi, L. Fornaro, C. Caparello, G. Musettini, G. Pasquini, S. Catanese, M. Lencioni, S. Ricci, A. Falcone
Journal: Annals of Oncology (2015)