tbuckley/cabot-search huggingface dataset:
Efficacy and safety of biosimilar epoetin alpha in treated patients with multiple myeloma.
Authors: Giusy Antolino, Alessandro Moscetti, Francesca Saltarelli, Bruno Monarca, Federica Resci, Daniela De Benedittis, Virginia Naso, Maria Paola Bianchi, Giacinto La Verde
Journal: Journal of Clinical Oncology (2012)

e18563 Background: The biologic drugs are pharmaceutical products derived from living organisms through biotechnology. For some of the biotech drugs patent coverage is now decayed. This has allowed other companies to produce, at lower costs, similar products called biosimilar pharmaceuticals. Among the first biosimilar products marketed there were two growth factors, epoetin alpha and filgrastim. Methods: We retrospectively analyzed 15 chemo-treated patients with Multiple Myeloma (MM) referred to UOS Diagnosi e Cura delle Discrasie Plasmacellulari e delle Amiloidosi of Sant’Andrea Hospital in Rome, who were treated with biosimilar epoetin alpha between November 2010 and November 2011. In particular, 6 males and 9 females (median age 70 years) had started therapy with subcutaneous biosimilar epoetin alpha 40,000 IU weekly for haemoglobin level below 10 g/dl. In these patients, we evaluated the Hb levels before treatment, after 4 weeks and, in those who continued therapy, after 8 weeks from the drug administration start. Results: In all cases there was a significant and steady increase of Hb values: we observed an increase of 1 g/dl after 4 weeks in 80% of patients. In 5 of 11 patients the data are not available at 8 weeks because it was observed a so quick increase in Hb values as to cause discontinuation of treatment; in 100% of the remaining patients we observed an increase ≥2 g/dl after 8 weeks. None of patients needed supportive therapy with red blood cells transfusion. Although the duration of treatment in our patients was limited, we did not observe any adverse event in the short and medium term by the administration. Conclusions: The results reported do not fall in a comparative study and our initial data are still limited, however in our analysis biosimilar epoetin alpha was effective in increasing Hb values in MM patients against lower costs. It should be emphasized that this growth factor has been used in overtreated patients with impaired bone marrow reserve. In our analysis biosimilar epoetin alpha has shown efficacy and safety data to suggest the possibility of their use in alternative to biotech generators.
Results of observational study of docetaxel, platinum compounds, 5-fluorouracil and leucovorin as first-line therapy in advanced gastric cancer (AGC).
Authors: Elena Trusilova, Nataliya Besova, Vera A. Gorbunova
Journal: Journal of Clinical Oncology (2013)

e15156 Background: AGC is relatively chemosensitive, but a standard chemotherapy (CT) regimen has yet to emerge, and responses are of short duration. Docetaxel-containing scheme are new option for pts with AGC. The V325 trial demonstrated the efficacy benefit of adding docetaxel to CF (cisplatin + 5-FU) (DCF). DCF is associated with significant toxicity, making it less tolerable to pts. We modified the original DCF regimen to reduce its toxicity without decreasing efficacy. Methods: AGC pts received docetaxel 75mg/m 2 and cisplatin 75mg/m 2 (n=42) or oxaliplatin 100mg/m 2 (n=39) in day2 with leucovorin 50mg and 5-FU 500mg/m 2 (3-hour infusion) in day1-3 every 3w (TPFL or TOFL) instead of original DCF (docetaxel 75mg/m 2 , cisplatin 75mg/m 2 in day1 and fluorouracil 750 mg/m 2 in day 1-5 continuous infusion). Results: 81 CT-naïve pts with AGC were included in our observational study from Feb 2008 to Dec 2012 (42 female, 39 male). ECOG 0/1/2 were 9.9/85.2/4.9% pts. ORR was 41% (32/79), SD – 37% (29/79), PD – 23% (18/79). Median PFS and median OS were evaluated in 80pts and were 5.6m and 12.4m, respectively. ORR, PFS, and OS comparable TOFL and TPFL results were: 49 and 34%, 5.4 and 6.5m, 11 and 12.8m respectively. Toxicity of both regimens was moderate. Grade 3+4 toxicities for TPFL/TOFL included leucopenia – 23/5%, neutropenia –50/61%pts, febrile neutropenia -7pts (9%) - 1pt from TPFL and 6pts from TOFL, thrombocytopenia – 2/0% pts. Nonhematologic toxicities were max grade 3: asthenia –2 /20%, stomatitis – 2/0%, diarrhea – 7/5%, vomiting – 0/2,5% pts. There were 2 pts experienced 3grade neurotoxicity in TOFL. We didn’t use G-CSF prophylaxis. There were no deaths and treatment discontinuation due to toxicity. At present 13 pts are still alive, 4 of them were operated on due to distant mts resolution after 4-17 CT courses. Their survival is 41m without PD, 43m, 52m and 22m with PD over 10m,12m and 7m after surgery. Conclusions: Our data suggest that docetaxel and platinum-contain regimens has the similar efficacy and better tolerability than the standard DCF. Both regimens can be safely given in an ambulant setting. Febrile neutropenia and neurotoxicity were more common in TOFL.
Metagenomic next-generation sequencing aids the diagnosis of viral infections in febrile returning travellers
Authors: Hanna Jerome, Callum Taylor, Vattipally B. Sreenu, Tanya Klymenko, Ana Da Silva Filipe, Celia Jackson, Chris Davis, Shirin Ashraf, Eleri Wilson-Davies, Natasha Jesudason, Karen Devine, Lisbeth Harder, Celia Aitken, Rory Gunson, Emma C. Thomson
Journal: Journal of Infection (2019)

ObjectivesTravel-associated infections are challenging to diagnose because of the broad spectrum of potential aetiologies. As a proof-of-principle study, we used MNGS to identify viral pathogens in clinical samples from returning travellers in a single center to explore its suitability as a diagnostic tool.MethodsPlasma samples from 40 returning travellers presenting with a fever of ≥38°C were sequenced using MNGS on the Illumina MiSeq platform and compared with standard-of-care diagnostic assays.ResultsIn total, 11/40 patients were diagnosed with a viral infection. Standard of care diagnostics revealed 5 viral infections using plasma samples; dengue virus 1 (n = 2), hepatitis E (n = 1), Ebola virus (n = 1) and hepatitis A (n = 1), all of which were detected by MNGS. Three additional patients with Chikungunya virus (n = 2) and mumps virus were diagnosed by MNGS only. Respiratory infections detected by nasal/throat swabs only were not detected by MNGS of plasma. One patient had infection with malaria and mumps virus during the same admission.ConclusionsMNGS analysis of plasma samples improves the sensitivity of diagnosis of viral infections and has potential as an all-in-one diagnostic test. It can be used to identify infections that have not been considered by the treating physician, co-infections and new or emerging pathogens.SummaryNext generation sequencing (NGS) has potential as an all-in-one diagnostic test. In this study we used NGS to diagnose returning travellers with acute febrile illness in the UK, highlighting cases where the diagnosis was missed using standard methods.
RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats
Authors: Shizuka B. Yamada, Tania F. Gendron, Teresa Niccoli, Naomi R. Genuth, Rosslyn Grosely, Yingxiao Shi, Idoia Glaria, Nicholas J. Kramer, Lisa Nakayama, Shirleen Fang, Tai J. I. Dinger, Annora Thoeng, Gabriel Rocha, Maria Barna, Joseph D. Puglisi, Linda Partridge, Justin K. Ichida, Adrian M. Isaacs, Leonard Petrucelli, Aaron D. Gitler
Journal: Nature Neuroscience (2019)
Adaptive Changes in Hemoglobin Function in High-Altitude Tibetan Canids Were Derived via Gene Conversion and Introgression
Authors: Anthony V Signore, Ying-Zhong Yang, Quan-Yu Yang, Ga Qin, Hideaki Moriyama, Ri-Li Ge, Jay F Storz
Journal: Molecular Biology and Evolution (2019)

A key question in evolutionary biology concerns the relative importance of different sources of adaptive genetic variation, such as de novo mutations, standing variation, and introgressive hybridization. A corollary question concerns how allelic variants derived from these different sources may influence the molecular basis of phenotypic adaptation. Here, we use a protein-engineering approach to examine the phenotypic effect of putatively adaptive hemoglobin (Hb) mutations in the high-altitude Tibetan wolf that were selectively introgressed into the Tibetan mastiff, a high-altitude dog breed that is renowned for its hypoxia tolerance. Experiments revealed that the introgressed coding variants confer an increased Hb-O2 affinity in conjunction with an enhanced Bohr effect. We also document that affinity-enhancing mutations in the β-globin gene of Tibetan wolf were originally derived via interparalog gene conversion from a tandemly linked β-globin pseudogene. Thus, affinity-enhancing mutations were introduced into the β-globin gene of Tibetan wolf via one form of intragenomic lateral transfer (ectopic gene conversion) and were subsequently introduced into the Tibetan mastiff genome via a second form of lateral transfer (introgression). Site-directed mutagenesis experiments revealed that the increased Hb-O2 affinity requires a specific two-site combination of amino acid replacements, suggesting that the molecular underpinnings of Hb adaptation in Tibetan mastiff (involving mutations that arose in a nonexpressed gene and which originally fixed in Tibetan wolf) may be qualitatively distinct from functionally similar changes in protein function that could have evolved via sequential fixation of de novo mutations during the breed's relatively short duration of residency at high altitude.
Immunization with MUC1/X protein enhances cDNA immunization in generating anti-MUC1 alpha/beta junction antibodies that target cancer cells
Authors: D. B. Rubinstein, R. Ziv, M. Karmely, O. Leitner, D. Wreschner
Journal: Journal of Clinical Oncology (2006)

10072 Background: MUC1, a glycoprotein highly expressed in epithelial malignancies including breast, prostate, and ovarian, and on the malignant cells of multiple myeloma has generated considerable interest as a tumor marker and target for tumor killing. The most intensively studied MUC1 protein is a type I transmembrane protein (MUC1/TM) which is proteolytically cleaved soon after synthesis into α and β subunits which bind in a strong non-covalent interaction. Almost all antibodies generated to date against MUC1 recognize epitopes within the highly immunogenic tandem-repeat-array. A major shortcoming in use of such antibodies is the fact that the tandem-repeat-array-containing part of MUC1 is shed from the cell surface into the circulation. Soluble, shed MUC1 sequesters circulating anti-tandem-repeat-array antibodies, limiting their ability to reach targeted MUC1-expressing cells. Antibodies to MUC1 epitopes tethered to the cell surface would likely be more effective therapeutic agents. Despite efforts in recent years, such antibodies have remained elusive; generation of anti-cell antibodies requires characterization of cell-bound epitopes. The junction of the MUC1 α-subunit binding the membrane-tethered β-subunit provides such an epitope. Methods: By use of a novel protocol, entailing immunization with MUC1/TM cDNA and boosting with MUC1/X protein, a MUC1 isoform lacking the tandem-repeat-array, we generated monoclonal antibodies designated DMC209 which recognize the MUC1 α/β junction. Results: DMC209 is exquisitely unique for the target site; all amino acid mutations which abrogate MUC1 cleavage also abrogate DMC209 binding. Additionally, DMC209 binds the MUC1 α/β junction on cell-tethered tandem-repeat-array-containing MUC1 (MUC1/TM) on breast and ovarian cancer, and on myeloma cells. Conclusion: DMC209 is likely to have clinical application by targeting MUC1-expressing cells directly, and as an immunotoxin conjugate. Moreover, the novel high-titer immunization procedure used in generating DMC209 can be used to generate anti-MUC1 α/β junction antibodies acting as ligand and, analogously to herceptin, may have direct cytotoxic activity. No significant financial relationships to disclose.
Attenuated Rubella Virus
Authors: Harry M. Meyer, Paul D. Parkman, Theodore C. Panos
Journal: New England Journal of Medicine (1966)

THE intensive research effort of the past few years has greatly increased the knowledge of rubella virus and of the infections that it causes. Despite these advances the search for a live-virus vaccine has been disappointing, and there has been no published evidence that the virus could be attenuated. Several investigators have tested tissue-culture-propagated rubella viruses in man.1 2 3 In these studies typical rubella with rash developed in inoculated subjects, and the disease spread to uninoculated persons.In our laboratory protracted serial passage of rubella viruses in primary African green-monkey-kidney (GMK) cell cultures provided 2 virus strains that exhibited modified biologic . . .
Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Sarcomas and GISTs.
Authors: Carine A. Bellera, Monia Ouali, Nicolas Penel, Sylvie Bonvalot, Paolo Giovanni Casali, Martine Delannes, Ole Steen Nielsen, Simone Mathoulin-Pelissier
Journal: Journal of Clinical Oncology (2013)

10570 Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used as replacement for OS in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in Cancer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. We present results for sarcomas and GISTs. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertise were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints and events of interest. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process is finalized. It involved 2 rounds of scoring (28 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death related to primitive cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 16 events were rated for inclusion or not in the definitions of 14 time-to-event endpoints. Consensus was reached for 73% of the events after the 2 rounds of scoring. Consensus was finalized at the in-person meeting for the remaining events. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.
Hydrogel-based delivery of antimiR-221 enhances cartilage regeneration by endogenous cells
Authors: Andrea Lolli, Kavitha Sivasubramaniyan, Maria L. Vainieri, Jacopo Oieni, Nicole Kops, Avner Yayon, Gerjo J.V.M. van Osch
Journal: Journal of Controlled Release (2019)

Articular cartilage is frequently injured by trauma or osteoarthritis, with limited and inadequate treatment options. We investigated a new strategy based on hydrogel-mediated delivery of a locked nucleic acid microRNA inhibitor targeting miR-221 (antimiR-221) to guide in situ cartilage repair by endogenous cells. First, we showed that transfection of antimiR-221 into human bone marrow-derived mesenchymal stromal cells (hMSCs) blocked miR-221 expression and enhanced chondrogenesis in vitro. Next, we loaded a fibrin/hyaluronan (FB/HA) hydrogel with antimiR-221 in combination or not with lipofectamine carrier. FB/HA strongly retained functional antimiR-221 over 14 days of in vitro culture, and provided a supportive environment for cell transfection, as validated by flow cytometry and qRT-PCR analysis. Seeding of hMSCs on the surface of antimiR-221 loaded FB/HA led to invasion of the hydrogel and miR-221 knockdown in situ within 7 days. Overall, the use of lipofectamine enhanced the potency of the system, with increased antimiR-221 retention and miR-221 silencing in infiltrating cells. Finally, FB/HA hydrogels were used to fill defects in osteochondral biopsies that were implanted subcutaneously in mice. FB/HA loaded with antimiR-221/lipofectamine significantly enhanced cartilage repair by endogenous cells, demonstrating the feasibility of our approach and the need to achieve highly effective in situ transfection. Our study provides new evidence on the treatment of focal cartilage injuries using controlled biomaterial-mediated delivery of antimicroRNA for in situ guided regeneration.
Integrative Epigenetic and Single-Cell RNA-Seq Profiling of Human Hematopoietic Stem Cells Reveals Epigenetic Reprogramming of Enhancer and Regulatory Elements during Normal Aging
Authors: Emmalee Adelman, André Olsson, Tingting Qin, R. Coleman Lindsley, Rafael Bejar, Nathan Salomonis, Lee Grimes, Maria E. Figueroa
Journal: Blood (2017)
Implications of generating genetic test results for colon cancer in the international, population-based colon cancer family registry.
Authors: Louise A. Keogh, Douglass Fisher, Sherri Sheinfeld Gorin, Sheri D Schully, Jan Lowery, Dennis J. Ahnen, Judith A Maskiell, Noralane M. Lindor, John L. Hopper, Terrilea Burnett, Spring Holter, Julie Arnold, Steven Gallinger, Mercy Laurino, Mary-Jane Esplen, Pamela S Sinicrope
Journal: Journal of Clinical Oncology (2012)

3567 Background: The ability to genotype large numbers of people rapidly and inexpensively for research purposes highlights the need to develop guidelines for providing medically-relevant research results - including unanticipated findings - to study participants. The Colon Cancer Family Registry (C-CFR) is the oldest and largest international colon cancer population-based registry; its experience managing genetic research findings can offer guidance to clinicians and researchers. The C-CFR has enrolled 10,019 cases with colon cancer and 24,708 family members in six registries in the US, Canada, Australia, and New Zealand. Deleterious (“high risk”) germline mutations have been identified in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and the MutYH gene. The aims of this presentation are to: (1) report the uptake of genetic test results by C-CFR participants; (2) systematically compare disclosure protocols and barriers to uptake by registry; (3) make recommendations to guide clinicians and researchers. Methods: Uptake of genetic test results was calculated from data collected by the C-CFR; key investigators (KIs) from each registry completed a survey about disclosure decision-making; KIs also took part in discussions to generate recommendations. Results: Registry-wide molecular testing has identified deleterious MMR germline mutations for at least one member of 424 families (4%) and 48 biallelic MutYH gene carriers. Uptake of test results ranged from 56-86% (n= 1542) across registries. Barriers to disclosure include: (1) lack of pre-existing notification protocols; (2) logistics of re-consent; (3) limited involvement of genetic counselors at some registries; (4) in the US, the requirement that genetic testing be performed in a CLIA approved laboratory; (5) IRBs declining approval; and (6) budget constraints. Conclusions: Based on our international registry’s findings we recommend that researchers generating genetic information establish plans for disclosure at the outset; obtain subject consent a priori; consider subject knowledge and disclosure preferences; provide guidance and budget for clinical follow-up; and involve genetic counselors.
The role of advanced genetic testing in the management of prostate cancer post radical prostatectomy.
Authors: Edward M. Schaeffer, Ismael A. Vergara, Anamaria Crisan, Nicholas Erho, Mercedeh Ghadessi, Felix Yi-Chung Feng, Elai Davicioni, Ashley E. Ross
Journal: Journal of Clinical Oncology (2013)

5089 Background: The genomic classifier (Decipher, GC) is a prospectively validated assay that predicts clinical metastasis post radical prostatectomy (RP) more accurately than standard clinicopathologic factors. While over 70% of high risk patients tested in a previous validation had low GC scores and good prognosis, patients with high GC scores had a cumulative incidence of metastasis over 25% over the study duration. Among men diagnosed with localized prostate cancer, these most at risk patients may derive the greatest benefit from novel therapies. We thus examined differential expression (DE) of druggable genes that may be targeted in this group. Methods: High-density microarray expression profiles of primary FFPE tumor specimens from 764 men treated with RP at the Mayo Clinic (1987-2006) were evaluated. A subset of 323 patients was flagged as high risk of clinical metastasis (mets) by virtue of having GC score ≥ 0.4. Enrichment and identification of DE genes as druggable targets were pursued using DAVID and DrugBank. Results: Median follow-up of patients was 15.1 years. Among the 323 patients with high GC scores, 62% had mets during follow-up.We identified 2,262 genes DE between mets and non-mets, 230 of which are associated with 331 approved pharmaceuticals and 547 experimental agents. These agents included multiple established anti-neoplastic therapies not currently used to treat prostate cancer such as bortezomib, capecitabine, dasatinib, etoposide, gemcitabine, imatinib, irinotecan, pemetrexed and vinblastine. The two most enriched pathways, spliceosome and ubiquitin-mediated proteolysis, have been proposed previously as therapeutic targets in cancer. Conclusions: Advanced genomic testing that includes validated molecular risk scores as well as transcriptome profiling from a single assay may better enable application of directed, multimodal therapy for individual patients with high risk prostate cancer.