tbuckley/cabot-search huggingface dataset:
738. Engineered MicroRNA Silences C9ORF72 Variants in BAC Transgenic Mouse
Authors: Gabriela Toro Cabrera, Owen M. Peters, Tania F. Gendron, Alisha Gruntman, Robert H. Brown, Christian Mueller
Journal: Molecular Therapy (2016)

Amyotrophic Lateral Sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that affects upper and lower motor neurons causing progressive muscle weakening. Respiratory failure is ultimately the cause of death approximately 2-5 years after symptom onset. The recent discovery of an expanded hexanucleotide repeat located in chromosome 9 open reading frame 72(C9ORF72) now accounts for the majority of familial ALS cases as well as frontotemporal dementia (FTD) cases. Analysis of patient brain samples have shown that in the presence of the expansion, C9ORF72 mRNA is reduced and RNA sequences complimentary to the expansion aggregate into nuclear foci. Interestingly this RNA can translate by non-ATG repeat associated (RAN) translation into long dipeptide chains. These findings have led to the three following hypothesis on the pathogenies of C9ORF72: 1) An RNA gain-of-function, in which the expanded RNA foci sequester RNA binding and/or splicing proteins. 2) RAN translation from the repeat expansion generates inclusions of toxic poly-dipeptide proteins. 3) Haploinsufficiency, where decreased levels of mRNA lead to insufficient gene product. Our group has generated mice containing a bacterial artificial chromosome (BAC) composed of exons 1-6 of the human C9ORF72 gene and a 500 repeat hexanucleotide expansion. This mouse model recapitulates the major histopathological features seen in human ALS/FTD patients such as: lower levels of C9ORF72 mRNA, RNA nuclear foci, and the RAN translation products. We have used this mouse as a platform in which to test RNAi therapeutic strategies. To this end we have designed artificial microRNAs that target the human C9ORF72 gene with the purpose of decreasing the mRNA levels to determine if we can reduce the toxic RNA foci and/or RNA dipeptide proteins. We packaged one of the microRNAs into a recombinant adeno-associated virus (rAAV) serotype 9 to use with primary neuron cultures and in vivo experiments. Silencing was initially validated in primary cortical neurons from the C9ORF72 mouse model. Our results suggest that AAV9-mediated microRNA not only reduced the mRNA levels of C9ORF72 but also decreased the presence of the most abundant poly dipeptide (GP). Currently, experiments are underway to silence C9orf72 in vivo via intra cranial ventricular (ICV) injection of this microRNA in C9ORF72 transgenic pups and the results will be presented at the meeting.
Influence of palliative care consult on radiation therapy utilization for metastatic cancer patients within the last six months.
Authors: Jessica Moore Schuster, Karman Tam, Nevena Skoro, Brian Cassel, Mitchell Steven Anscher, Drew Moghanaki
Journal: Journal of Clinical Oncology (2014)

149 Background: Palliative care encounters (PCE) have been demonstrated to reduce resource utilization and costs within an inpatient setting. Little is known about influence PCE on delivery of radiation therapy (RT). We hypothesize that terminally ill cancer patients completing PCE would have increased utilization of palliative RT (PRT) with decreased fractions and overall costs. Methods: Retrospective review of 3,128 cancer patients that had at least one hospital contact within 6 months prior to death. Data from single academic institution decedent database, hospital billing claims, and radiation oncology electronic medical record (RO EMR) was combined into one database that could be queried. Results: From January 2009 to June 2011, 417 patients with soft tissue/bone/not other specified (NOS) excluding brain metastatic disease and at least one palliative contact within 6 months prior to death were identified. Palliative contact: PRT or palliative care consult or admission (PCE). 232 patients completed 321 RT courses (87% palliative, 8% curative, and 5% unknown). 18% of PRT was delivered in 1 fraction, 30% in 2-5, 4% in 6-9, 36% in 10, and 12% &gt; 10 fractions. PRT and PCE were both completed in 48% (33% before, 13% during and 54% after delivery of RT). PCE prior to PRT vs. PCE none/during/after PRT were more likely to result in 5 or fewer PRT treatments (62% vs. 40%, p=0.0309) and there was a trend for increased delivery of single fraction PRT (18 vs. 15%). Based on timing of PCE, no increase in PRT courses per patient and no overall cost reduction was observed beyond direct cost reduction by reducing PRT fractions. Other non-significant factors included sex, race, and payer type. Majority of PCE were within 30 days prior to death 52% vs. only 44% of PRT. Conclusions: Relationship between PCE and PRT is complex and are likely compounded by factors not accounted for in this study. Despite these limitations, PCE prior to delivery of PRT correlates to reduced treatment numbers. This report highlights that overall referrals for palliative services could be integrated into comprehensive cancer much earlier and in a more multi-disciplinary way.
Abstract 215: Tracking transplanted cells with paramagnetic fluorinated nanoemulsions
Authors: Alexander A. Kislukhin, Hongyan Xu, Stephen R. Adams, Kazim Narsinh, Roger Y. Tsien, Eric T. Ahrens
Journal: Cancer Research (2015)

Abstract Visualization of distinct cell populations in vivo is one of the most formidable challenges in biomedical sciences. Clinical translation of cutting-edge therapies that involve administration of live immunotherapeutic or stem cells can benefit from understanding the fate of injected cells in vivo. Magnetic resonance imaging (MRI) is emerging as a prime method for non-invasive, longitudinal cell tracking. Fluorine-19 MRI (19F MRI) involves the use of non-radioactive 19F label in the form of biologically inert, cytocompatible perfluorocarbons (PFC). Immediately prior to injection, cells of interest are labeled ex vivo with water-based PFC nanoemulsions. 19F MRI yields background-free images of labeled cells in an anatomical context provided by conventional 1H MRI. Both datasets are acquired on the same scanner in one imaging session. This technology has recently been used to detect immunotherapeutic dendritic cells delivered to colorectal adenocarcinoma patients. We sought to enhance sensitivity and versatility of 19F MRI by using paramagnetic relaxation agents. Covalent modification of clinically relevant PFCs with metal-binding ligands enabled stable and uniform incorporation of gadolinium and iron in the fluorous phase of nanoemulsions. Paramagnetic relaxation enhancement resulted in up to 50-fold reduction in 19F longitudinal relaxation time (T1) compared to state-of-the-art commercial tracers. The ultralow 19F T1 of our paramagnetic tracers enabled in vivo cell tracking with rapid, three-dimensional, zero time-to-echo (ZTE) 19F MRI pulse sequences in mice bearing subcutaneous allografts of 19F-labeled GL261 cells. Moreover, the high local concentration of paramagnetic metals imparted negative contrast in T2*-weighted 1H images. Combination of the new agents with conventional 19F tracers comprises a previously unavailable toolbox of 19F contrast agents, selectively detectable by appropriate acquisition methods. This enables “multicolor” 19F MRI tracking of multiple cell populations, e.g., for monitoring the interaction of host immune cells with injected therapeutic cells or cancer xenografts. Overall, the design of biocompatible, fast-relaxing 19F tracers addresses the issue of modest sensitivity of 19F MRI and reduces the barriers to widespread adoption of this powerful imaging technique. Citation Format: Alexander A. Kislukhin, Hongyan Xu, Stephen R. Adams, Kazim Narsinh, Roger Y. Tsien, Eric T. Ahrens. Tracking transplanted cells with paramagnetic fluorinated nanoemulsions. [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 215. doi:10.1158/1538-7445.AM2015-215
Association of metabolic syndrome with high mortality in patients with cancer.
Authors: J. Rodriguez-Cid, D. Motola-Kuba, G. Alvarado-luna, K. Sanchez-Lara, D. Green
Journal: Journal of Clinical Oncology (2011)

e21068 Background: Metabolic syndrome is a worldwide public health problem. In Mexico, diseases related to metabolic syndrome are the cause of 81,900 deaths annually being the leading cause of mortality. Cancer is the third cause of death in Mexican adults. Epidemiologic studies have associated physical activity and obesity as risk factors for breast, colon, endometrium, esophagus, and kidney cancer development. There are few studies that associate presence of metabolic syndrome in patients with cancer diagnosis and survival. This study aim is to determine this association in Mexican population. Methods: This retrospective study included patients with cancer diagnosis treated in an oncology center from Mexico City from 1999 to 2010. A review of files was made to determine clinicopathologic variables at diagnosis that included: height, weight, body mass index, blood pressure, waist circumference and laboratory values (triglyceride, and fasting glucose). Metabolic syndrome was defined by the modified Adult Treatment Panel III criteria at diagnosis. Analysis of variables was assessed to determine association between presence of metabolic syndrome at diagnosis and cancer survival. Mortality was the primary end point for analysis. Results: We included 120 (75.9%) women and 38 (24.1%) men. Median age at diagnosis was 52.8 years. Seventy patients (44.3%) were diagnosed with metabolic syndrome, 78 (49.4%) with obesity, 75 (47.5%) with hypertrigliceridemia, and 77 (48.7%) with hyperglicemia. Multivariate analysis showed significant higher risk of death in patients with: Metabolic syndrome (HR 1.7; 95% CI 0.49-0.93, p=0.03); BMI >25 (HR 3.7; 95% CI 0.58- 0.89, p=0.026); and Low HDL levels (HR 2.5; 95% CI 0.78-0.98, p=0.01). Conclusions: The metabolic syndrome is associated with a higher risk of death in patients with cancer.
Abstract 1710: Xanthohumol suppresses estrogen-signaling in endocrine resistant breast cancer through the specific inhibition of BIG3-PHB2 interactions
Authors: Toyomasa Katagiri
Journal: Cancer Research (2015)

Abstract Estrogen-receptor-α (ERα) plays a pivotal role in the development and progression of breast cancer. The current endocrine therapies for breast cancer are mainly based on targeting ERα signaling using selective ERα modulators, ERα downregulators, and aromatase inhibitor (AI)1-3. However, tamoxifen treatment often fails, and patients succumb to recurrent, endocrine-resistant tumors. Moreover, some patients who have undergone AI treatment still relapse. The precise molecular events that determine alterations in the effectiveness of these endocrine therapies remain unknown. We previously reported that the oncoprotein brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) and tumor suppressor prohibitin 2 (PHB2) complex play a pivotal role in E2 signaling modulation in ERα-positive breast cancer. Namely, BIG3 binds PHB2, thereby inhibiting the E2-dependent suppressive ability of PHB2 and resulting in constitutive ERα activation. Considering these findings, strategies utilising the tumour suppressive activity of PHB2 upon its release from BIG3 by inhibitors of protein-protein interaction may represent novel therapies for breast cancer. Accordingly, we focus on whether XN potentially binds to the tumor suppressor protein PHB2, forming a novel natural anti-tumor compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2 /ERα signaling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signaling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancers, especially endocrine resistant breast cancers. Citation Format: Toyomasa Katagiri. Xanthohumol suppresses estrogen-signaling in endocrine resistant breast cancer through the specific inhibition of BIG3-PHB2 interactions. [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 1710. doi:10.1158/1538-7445.AM2015-1710
753. Lentiviral-Mediated Gene Correction of Mobilized Peripheral Blood Progenitors and Repopulating Cells from FA-A Patients
Authors: Paula Río, Susana Navarro, Guillermo Guenechea, Anne Galy, Rebeca Sánchez, María L. Lamana, Rosa Yañez, José A. Casado, José C. Segovia, Jordi Surrallés, Ricardo López, Nagore García de Andoaín, Pedro Ruiz, Albert Catalá, Cristina Díaz de Heredia, Julián Sevilla, Juan A. Bueren
Journal: Molecular Therapy (2016)

Fanconi anemia (FA) is an inherited disease mainly characterized by congenital abnormalities, progressive bone marrow failure and cancer predisposition. Based on previous FA gene therapy studies we aimed at improving the therapeutic efficacy of gene therapy in FA-A patients using optimized protocols of hematopoietic stem cell (HSC) harvesting and transduction. The mobilization regimen consisted on the administration of G-CSF (neupogen; 12 µg/Kg/12 hours) and plerixafor (mozobil; 240 µg/kg body weight/day). Two out of six patients with 15 and 16 years old did not reach the threshold level of CD34+ cells in PB, and therefore, apheresis was not conducted. In the four youngest patients, the total number of collected CD34+ cells/kg ranged between 1.6×106 to 7.6×106 (8.6×105 to 5.1×106 CD34+ cells/Kg after purification), and were cryopreserved for clinical use. The short transduction of small aliquots of mPB CD34+ samples from these patients with a GMP-produced lentiviral vector that harbors the FANCA therapeutic gene showed transduction efficacies between 20-40%, measured by the survival of transduced colony forming cells (CFCs) to mitomycin C (MMC). To assess the repopulating ability of transduced FA-A CD34+ cells, aliquot samples were transplanted into NSG mice conditioned with 1.5 Gy. Remarkably, most of the transplanted samples engrafted into the NSG mice (1-10% of the BM cells were hCD45+/mCD45−). Moreover, a selection advantage of corrected CD34+ FA-A cells was observed in engrafted mice, as deduced from the high MMC-resistance of hCFCs obtained from recipients' BM. Our results show for the first time that clinically applicable transduction protocols can correct the phenotype of human FA-A hematopoietic repopulating cells. Currently a gene therapy trial of FA-A patients based on the ex vivo transduction of mPB CD34+ cells with lentiviral vectors is open in our Institutions.
Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) - a Putative Diagnostic Marker for Chronic Lymphocytic Leukemia (CLL).
Authors: Sabrina Uhrmacher, Magdalena Hertweck, Julian Paesler, Felix Erdfelder, Alexandra Filipovich, Simon Jonas Poll-Wolbeck, Regina Razavi, Rajesh Kumar Gandhirajan, Iris Gehrke, Michael Hallek, Karl Anton Kreuzer
Journal: Blood (2009)
Impaired health-related quality of life in meningioma patients—a systematic review
Authors: Amir H. Zamanipoor Najafabadi, Marthe C. M. Peeters, Linda Dirven, Daniel J. Lobatto, Justus L. Groen, Marieke L.D. Broekman, Saskia M. Peerdeman, Wilo C. Peul, Martin J. B. Taphoorn, Wouter R. van Furth
Journal: Neuro-Oncology (2016)

While surgical and radiotherapeutic improvements increased life expectancy of meningioma patients, little is known about these patients' health-related quality of life (HRQoL). Therefore, the objectives of this systematic review were to assess HRQoL in meningioma patients, the methodological quality of the used questionnaires (COSMIN criteria), and the reporting level of patient-reported outcomes (PROs) in the included studies (International Society of Quality of Life Research criteria).Nineteen articles met our inclusion criteria. HRQoL was measured with 13 different questionnaires, 3 validated in meningioma patients. According to our predefined cutoff, HRQoL data were reported sufficiently in 5 out of 19 studies. Both findings hamper interpretation of the PRO results.In general, meningioma patients reported clinically worse HRQoL than healthy controls. Although meningioma patients had better HRQoL than glioma patients, this difference was not clinically relevant. Radiotherapy seemed to improve some domains of HRQoL in the short term, while HRQoL decreased to pre-radiotherapy levels in the long term. Tumor resection increased HRQoL, but long-term follow-up showed persistent reduced HRQoL compared with healthy controls. These results suggest an impaired HRQoL in meningioma patients, even years after anti-tumor treatment. Results of this systematic review warrant high quality prospective studies, better instruments to assess HRQoL, and improved level of reporting for this group of patients.
Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial
Authors: K. Davison, B.E. Chen, V. Kukreti, S. Couban, A. Benger, N.L. Berinstein, L. Kaizer, P. Desjardins, J. Mangel, L. Zhu, M.S. Djurfeldt, A.E. Hay, L.E. Shepherd, M. Crump
Journal: Annals of Oncology (2016)
A Randomized, Double-Blind, Placebo-Controlled, Clinical Outcome Study of ARC1779 In Patients with Thrombotic Thrombocytopenic Purpura (TTP)
Authors: Spero R Cataland, Flora Peyvandi, Pier M. Mannucci, Bernhard Lämmle, Johanna A Kremer Hovinga, Samuel J Machin, Marie Scully, Gail Rock, James Gilbert, Paul Knoebl, Shangbin Yang, Haifeng Wu, Bernd Jilma
Journal: Blood (2010)
2016 AHA/ACC Clinical Performance and Quality Measures for Prevention of Sudden Cardiac Death
Authors: Sana M. Al-Khatib, Clyde W. Yancy, Penelope Solis, Lance Becker, Emelia J. Benjamin, Roger G. Carrillo, Justin A. Ezekowitz, Gregg C. Fonarow, Bharat K. Kantharia, Monica Kleinman, Graham Nichol, Paul D. Varosy
Journal: Journal of the American College of Cardiology (2016)
Phase I study of PF-04554878, a second-generation focal adhesion kinase (FAK) inhibitor, in patients with advanced solid tumors.
Authors: S. F. Jones, G. Shapiro, J. C. Bendell, E. X. Chen, P. Bedard, J. M. Cleary, S. Pandya, K. J. Pierce, B. Houk, N. Hosea, K. S. Zandi, W. G. Roberts, S. M. Shreeve, L. L. Siu
Journal: Journal of Clinical Oncology (2011)

3002 Background: FAK is a non-receptor tyrosine kinase that transduces signaling from integrins and growth factor receptors to modulate cell invasion, migration, metastasis and survival. PF-04554878 is a potent ATP-competitive inhibitor of FAK that also inhibits the related protein proline-rich tyrosine kinase (Pyk2). Methods: This is an ongoing phase 1 dose escalation study of PF-04554878 given as continuous oral dosing in 21-day cycles in patients (pts) with solid tumors. Endpoints include safety, pharmacokinetics (PK), and response by RECIST. Results: 36 patients (data cut-off 09 Dec 2010) received doses ranging from 12.5 mg to 750 mg BID on a fasting schedule. Demographics: M:F 16:20, and mean age: 56 yrs (range 31-84). Primary tumor types: colorectal (CRC) 15, pancreatic 4, ovarian 3, bile duct 3, breast 2, other 9. 72% of pts had ≥3 prior systemic treatments. Adverse events (AEs) possibly related to PF-04554878 in >10% pts: nausea (33%), vomiting (31%), unconjugated hyperbilirubinemia (28%), fatigue (25%), headache (19%), diarrhea (19%), and decreased appetite (17%). All AEs (including unconjugated hyperbilirubinemia) were typically CTCAE grades 1-2, easily managed and reversible even with continued dosing. There have been three dose limiting toxicities (DLTs): a grade 3 headache (at 200 mg BID), and two grade 3 unconjugated hyperbilirubinemias (at 300 mg BID and 425 mg BID). All DLTs were reversed on stopping drug. PK analysis supports the BID dosing regimen and shows that doses above 100 mg BID lead to exposures above the minimal efficacious concentration predicted preclinically. Increasing the dose beyond 425 mg BID did not increase drug exposure. Stable disease (SD) was observed at the end of 2 cycles in 12 (33%) pts once the dose reached ≥100 mg BID. Two of these pts (ovarian, CRC) had SD observed at the end of 6 cycles and a further two pts (bile duct, lung mucoepidermoid) had SD observed for ≥9 cycles. The recommended Phase 2 dose, on a fasting schedule, is 425 mg BID. Conclusions: Clinical safety, tolerability, PK, and the sustained disease control seen in some pts, all support further development.
Genetic Polymorphisms and the Toxicity of Antileukemic Agents in Children with Acute Lymphoblastic Leukemia.
Authors: Shinji Kishi, Cheng Cheng, Deqing Pei, Soma Das, Edwin H. Cook, Nobuko Hijiya, Carmelo Rizzari, Gary Rosner, Ching-Hon Pui, William E. Evans, Mary V. Relling
Journal: Blood (2004)
Touch Receptor-Derived Sensory Information Alleviates Acute Pain Signaling and Fine-Tunes Nociceptive Reflex Coordination
Authors: Alice Arcourt, Louise Gorham, Rahul Dhandapani, Vincenzo Prato, Francisco J. Taberner, Hagen Wende, Vijayan Gangadharan, Carmen Birchmeier, Paul A. Heppenstall, Stefan G. Lechner
Journal: Neuron (2016)
S1P1 Overexpression Inhibits SDF1/CXCR4 Dependent Migration and In Vivo Homing of Hematopoietic Stem Cells.
Authors: Martin F. Ryser, Fernando A. Ugarte, Romy Lehmann, Harry L. Malech, Joachim Roesler, Angela Roesen-Wolff, Sebastian Brenner
Journal: Blood (2005)