tbuckley/cabot-search huggingface dataset:
Overcoming adaptive therapy resistance in AML by targeting immune response pathways
Authors: Katelyn Melgar, Morgan M. Walker, LaQuita M. Jones, Lyndsey C. Bolanos, Kathleen Hueneman, Mark Wunderlich, Jian-Kang Jiang, Kelli M. Wilson, Xiaohu Zhang, Patrick Sutter, Amy Wang, Xin Xu, Kwangmin Choi, Gregory Tawa, Donald Lorimer, Jan Abendroth, Eric O’Brien, Scott B. Hoyt, Ellin Berman, Christopher A. Famulare, James C. Mulloy, Ross L. Levine, John P. Perentesis, Craig J. Thomas, Daniel T. Starczynowski
Journal: Science Translational Medicine (2019)

Immune stress pathways drive resistance to FLT3 inhibition in FLT3-mutant AML, but a dual inhibitor of FLT3 and IRAK1/4 overcomes this resistance.
Diversified Application of Barcoded PLATO (PLATO-BC) Platform for Identification of Protein Interactions
Authors: Weili Kong, Tsuyoshi Hayashi, Guillaume Fiches, Qikai Xu, Mamie Z. Li, Jianwen Que, Shuai Liu, Wei Zhang, Jun Qi, Netty Santoso, Stephen J. Elledge, Jian Zhu
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract Proteins usually associate with other molecules physically to execute their functions. Identifying these interactions is important for the functional analysis of proteins. Previously, we reported the parallel analysis of translated ORFs (PLATO) to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the “bait” molecules, followed by the deep sequencing analysis of mRNA. However, the sample processing, from extraction of precipitated mRNA to generation of DNA libraries, includes numerous steps, which is tedious and may cause the loss of materials. Barcoded PLATO (PLATO-BC), an improved platform was further developed to test its application for protein interaction discovery. In this report, we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis (IBM). Tripartite motif containing 21 (TRIM21) was identified as a potentially new IBM autoantigen. We also expanded the application of PLATO-BC to identify protein interactions for JQ1, single ubiquitin peptide, and NS5 protein of Zika virus. From PLATO-BC analyses, we identified new protein interactions for these “bait” molecules. We demonstrate that Ewing sarcoma breakpoint region 1 (EWSR1) binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4. RIO kinase 3 (RIOK3), a newly identified ubiquitin-binding protein, is preferentially associated with K63-ubiquitin chain. We also find that Zika NS5 protein interacts with two previously unreported host proteins, par-3 family cell polarity regulator (PARD3) and chromosome 19 open reading frame 53 (C19orf53), whose attenuated expression benefits the replication of Zika virus. These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of “bait” molecules.
Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease
Authors: Juliette Le Douce, Marianne Maugard, Julien Veran, Marco Matos, Pierrick Jégo, Pierre-Antoine Vigneron, Emilie Faivre, Xavier Toussay, Michel Vandenberghe, Yaël Balbastre, Juliette Piquet, Elvire Guiot, Nguyet Thuy Tran, Myriam Taverna, Stéphane Marinesco, Ayumi Koyanagi, Shigeki Furuya, Mylène Gaudin-Guérif, Sébastien Goutal, Aurélie Ghettas, Alain Pruvost, Alexis-Pierre Bemelmans, Marie-Claude Gaillard, Karine Cambon, Lev Stimmer, Véronique Sazdovitch, Charles Duyckaerts, Graham Knott, Anne-Sophie Hérard, Thierry Delzescaux, Philippe Hantraye, Emmanuel Brouillet, Bruno Cauli, Stéphane H.R. Oliet, Aude Panatier, Gilles Bonvento
Journal: Cell Metabolism (2020)
EGF-based cancer vaccine: Optimizing predictive and surrogate biomarkers.
Authors: Tania Crombet Ramos, Elia Neninger, Jorge Gonzalez, Pedro Camilo Rodriguez, Beatriz Garcia, Xitlally Popa, Zaima Mazorra, Carmen Viada, Patricia Lorenzo Luaces, Gisela Gonzalez, Agustin Lage
Journal: Journal of Clinical Oncology (2013)

3013 Background: EGFR is overexpressed in many epithelial tumors. EGF is one of the most important growth factors that stimulates EGFR, in a paracrine way. CIMAvax-EGF is a therapeutic cancer vaccine intended to induce antibodies against EGF. It is composed by recombinant EGF conjugated to P64 from N.Meningitides as a carrier and Montanide, as adjuvant. Methods: Two controlled trials were done in advanced NSCLC and castration-resistant prostate cancer patients (CRPC). A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity, and safety of CIMAVAx-EGF in advanced NSCLC patients. Patients with histology- or cytology-proven NSCLC at stage IIIB/ IV were enrolled. All subjects received 4 platinum-based cycles before entering the study. On the other hand, a multicentric, randomized Phase II trial was designed to assess the immunogenicity and safety of the vaccine in CRPC patients. The EGF cancer vaccine was administered in combination with mitoxantrone and prednisone. Results: 405 patients bearing NSCLC and 200 men with CRPC were enrolled in the 2 trials. In both studies the vaccine was immunogenic. Antibody titers against EGF increased with vaccination and EGF concentration in sera showed a fast reduction after immunization. The anti-EGF antibody response was directly correlated with overall survival. CIMAVax-EGF was safe and most prevalent adverse events were grade 1-2 injection site pain, fever, headache, nausea, vomiting, and chills. The vaccine significantly increased the survival of the NSCLC patients while it did not augment significantly the overall survival of the CRPC patients. In both studies, EGF concentration was measured at baseline and it was found to be much higher than in normal subjects. High EGF concentration predicted greater benefit after vaccination. On the contrary, NSCLC and prostate control patients with high levels of EGF had a poorer outcome. Conclusions: Antibody response against EGF is a surrogate marker of survival. High EGF concentration might be a predictive marker of vaccine efficacy and a poor prognostic biomarker for non-vaccinated NSCLC and CRPC patients. The predictive and prognostic value of the EGF concentration will be validated prospectively. Clinical trial information: IIC EC 081.
Five-year mortality and morbidity impact of prolonged versus brief ICU stay: a propensity score matched cohort study
Authors: Greet Hermans, Nathalie Van Aerde, Philippe Meersseman, Helena Van Mechelen, Yves Debaveye, Alexander Wilmer, Jan Gunst, Michael Paul Casaer, Jasperina Dubois, Pieter Wouters, Rik Gosselink, Greet Van den Berghe
Journal: Thorax (2019)

Purpose Long-term outcomes of critical illness may be affected by duration of critical illness and intensive care. We aimed to investigate differences in mortality and morbidity after short (&lt;8 days) and prolonged (≥8 days) intensive care unit (ICU) stay. Methods Former EPaNIC-trial patients were included in this preplanned prospective cohort, 5-year follow-up study. Mortality was assessed in all. For morbidity analyses, all long-stay and—for feasibility—a random sample (30%) of short-stay survivors were contacted. Primary outcomes were total and post-28-day 5-year mortality. Secondary outcomes comprised handgrip strength (HGF, %pred), 6-minute-walking distance (6MWD, %pred) and SF-36 Physical Function score (PF SF-36). One-to-one propensity-score matching of short-stay and long-stay patients was performed for nutritional strategy, demographics, comorbidities, illness severity and admission diagnosis. Multivariable regression analyses were performed to explore ICU factors possibly explaining any post-ICU observed outcome differences. Results After matching, total and post-28-day 5-year mortality were higher for long-stayers (48.2% (95%CI: 43.9% to 52.6%) and 40.8% (95%CI: 36.4% to 45.1%)) versus short-stayers (36.2% (95%CI: 32.4% to 40.0%) and 29.7% (95%CI: 26.0% to 33.5%), p&lt;0.001). ICU risk factors comprised hypoglycaemia, use of corticosteroids, neuromuscular blocking agents, benzodiazepines, mechanical ventilation, new dialysis and the occurrence of new infection, whereas clonidine could be protective. Among 276 long-stay and 398 short-stay 5-year survivors, HGF, 6MWD and PF SF-36 were significantly lower in long-stayers (matched subset HGF: 83% (95%CI: 60% to 100%) versus 87% (95%CI: 73% to 103%), p=0.020; 6MWD: 85% (95%CI: 69% to 101%) versus 94% (95%CI: 76% to 105%), p=0.005; PF SF-36: 65 (95%CI: 35 to 90) versus 75 (95%CI: 55 to 90), p=0.002). Conclusion Longer duration of intensive care is associated with excess 5-year mortality and morbidity, partially explained by potentially modifiable ICU factors. Trail registration number NCT00512122 .
No relevant activity of olaratumab in patient-derived soft tissue sarcoma xenografts selected for expression of platelet-derived growth factor receptor a.
Authors: Jasmien Cornillie, Britt Van Renterghem, Nathalie Van Winkel, Jasmien Wellens, Yemarshet Gebreyohannes, Maria Debiec-Rychter, Raf Sciot, Daphne Hompes, Agnieszka Wozniak, Patrick Schoffski
Journal: Journal of Clinical Oncology (2019)

e22556 Background: Soft tissue sarcoma (STS) comprises a heterogeneous family of rare tumors of mesenchymal origin. Single-agent doxorubicin (DOX) remains the standard-of-care for advanced and inoperable STS, but response rates are &lt; 15% and survival is generally poor. In 2016, Tap et al. reported impressive results of a phase Ib/II trial combining DOX and the platelet-derived growth factor receptor a (PDGFRA)-directed antibody olaratumab (OLA), suggesting an unprecedented survival advantage of the combination over DOX alone, without providing a mechanistic rationale for the observed activity (Lancet 2016;388:488-97). We decided to evaluate the efficacy of OLA in a panel of patient-derived STS xenografts (PDX). Methods: NMRI nu/nu mice were transplanted bilaterally with tumor tissue of models expressing PDGFRA, including PDX of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (STS39), myxofibrosarcoma (STS59) and undifferentiated pleomorphic sarcoma (STS84). Mice were randomly divided into 4 treatment groups: (1) control, (2) DOX (3 mg/kg once weekly), (3) anti-PDGFRA [OLA (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of DOX and anti-PDGFRA (same dose/schedule as single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy. Results: Anti-PDGFRA treatment as single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining DOX and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in models STS39 and STS59 and a pro-apoptotic effect was seen in all models except STS22. Antitumor effects on histology were not significantly different comparing DOX and the combination treatment. Anti-PDGFRA treatment, both as a single agent as well as with DOX, did not inhibit downstream MAPK and PI3K/AKT signaling pathways. Conclusions: In vivo findings in PDX models selected for PDGFRA expression support negative findings of the phase III trial NCT02451943 with OLA reported at this meeting.
OS10.4 Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for leptomeningeal metastasis from breast cancer - a randomized study. Final results
Authors: E Le Rhun, J Wallet, A Mailliez, M Le Deley, I Rodrigues, T Boulanger, V Lorgis, J Barriere, Y Robin, M Weller, J Bonneterre
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a common manifestation in metastatic breast cancer. Standards of care remain controversial, notably intrathecal pharmacotherapy. MATERIAL AND METHODS DEPO-SEIN was a randomized open-label phase III study to explore the addition of intrathecal liposomal cytarabine to systemic therapy for the treatment of newly diagnosed LM from breast cancer. Patients diagnosed with LM based on the detection of tumor cells in the cerebrospinal fluid or typical clinical and neuroimaging signs of LM were randomly assigned to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (five injections of 50 mg every two weeks, followed by one monthly injection of 50 mg until progression, unacceptable toxicity or for one year) (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint. RESULTS Thirty-seven and 36 patients were assigned to the control and the experimental groups. The median number of liposomal cytarabine injections in the experimental group was five (range 1–20). Focal radiotherapy was performed in six patients (16%) and three patients (8%) in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2·2 months (95% confidence interval (CI) 1·3-3·1) in the control versus 3·8 months (95% CI 2·3–6·8) in the experimental group (hazard ratio 0·61, 95% CI 0·38-0·98) (p=0·04). Seventy-one patients have died. Median OS was 4·0 months (95% CI 2·2–6·3) in the control versus 7·3 months (95% CI 3·9-9·6) in the experimental group (hazard ratio 0·85, 95% CI 0·53-1·36) (p=0·51). Serious adverse events were reported in 22 and 30 patients in the control and experimental groups. Quality of life until progression did not differ between groups. CONCLUSION Intrathecal liposomal cytarabine improves LM-related PFS. A larger confirmatory trial with optimized patient selection criteria may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.
The inoculum effect of Escherichia coli expressing mcr-1 or not on colistin activity in a murine model of peritonitis
Authors: B. Fantin, J. Poujade, N. Grégoire, F. Chau, A. Roujansky, N. Kieffer, M. Berleur, W. Couet, P. Nordmann
Journal: Clinical Microbiology and Infection (2019)
Increasing of Ternary Complex Formation By Predominant Accumulation of Factor (F)X Accompanied By Increase of Fixa Contributes to Enhancement of Clotting Function By Apcc in Combination with Emicizumab
Authors: Koji Yada, Keiji Nogami, Tomoko Matsumoto, Takehisa Kitazawa, Midori Shima
Journal: Blood (2017)
Outcomes of sarcomatoid malignant pleural mesothelioma, a distinct clinical entity.
Authors: Elisabetta Gattoni, Federica Grosso, Annalisa Roveta, Roberta Libener, Daniela Degiovanni, Maurizio Mancuso, Ezio Piccolini, Gabriele Ferretti, Mario Botta, Pier Giacomo Betta
Journal: Journal of Clinical Oncology (2012)

7084 Background: Sarcomatoid malignant pleural mesotheliomas (SMPM), accounting for 10% of MPM, are resistant to chemotherapy (CT) with median survival in the range of 6 months. Here we report on clinical outcome of a large series of SMPM patients treated at our Oncological Department, located in a particularly asbestos-polluted area in Piedmont (Italy). Methods: Patients consecutively diagnosed, treated and included in our MesoDB between 1993 and 2010 were considered for this study. Clinical and pathological data, treatments, response to CT and outcomes were analyzed for the present study. Diagnosis was always confirmed by the same expert pathologist. Results: Data of 672 patients were considered for the analysis. Among these, 53 (8%) were diagnosed with SMPM (17F/36M). Median age was 67,6 years. Asbestos exposure was occupational certain in 12, possible in 15, domestic in 3 and environmental in 23. The predominant symptom at diagnosis was thoracic pain in 34 patients (64%), followed by dyspnea in 16 (30%), fatigue and weight loss in 2 and palpable mass in 1. The predominant radiological finding at diagnosis was diffuse pleural thickening in 23 patients (43%), pleural effusion in 14 (26%), pleural effusion and pleural thickening in 10 (19%), localized mass in 4 (8%), unknown in 2 (4%). Forty-eight patients received first line CT with the following regimens: carboplatin/cisplatin and pemetrexed in29, pemetrexed in 8, cisplatin and raltitrexed in 3, cisplatin and gemcitabine in 3, gemcitabine in 2, doxorubicin based combination in 3 patients. The median number of cycles was 4. Overall response rate to first line CT was as follows: 11 SD (21%), 31 PD (58%) and 6 (11%) patients were not evaluable for response. Median progression free survival was 3.3 (95%CI 2.6-4.1) months. Eleven patients received a second line CT and no responses or disease stabilization was observed. Median OS was 7.6 months. Conclusions: This large series of SMPM suggests that standard CT has only negligible impact on the prognosis, underlying a highly unmet clinical need. SMPM patients should be treated within phase I-II studies with investigational agents. Research should focus to a deeper knowledge of tumor biology and to the identification of druggable targets.
Integration of cascade delivery and tumor hypoxia modulating capacities in core-releasable satellite nanovehicles to enhance tumor chemotherapy
Authors: Jingjing Wang, Xingyue Wang, Shi-Yu Lu, Jie Hu, Wei Zhang, Luen Xu, Dachong Gu, Wenting Yang, Wei Tang, Fujuan Liu, Yang Cao, Hui Liu
Journal: Biomaterials (2019)
Know Thy PDX Model
Authors: Terrence F. Meehan
Journal: Cancer Research (2019)

Abstract Patient-derived tumor xenograft (PDX) models are frequently used to study cancer mechanisms and potential therapeutics, however, differences in tumor evolution between models and patients have called into question their clinical relevance. In this issue, Mer and colleagues describe the Xenograft Visualization and Analysis (Xeva) software tool that empowers pharmacogenomic analysis through integration of PDX model tumor–drug response with genetic data. By performing the largest PDX model meta-analysis of its kind, the authors demonstrate PDX models are robust platforms for cancer treatment studies. With a clear need for more integrative studies, Xeva is well placed to make more important contributions to pharmacogenomic discovery. See related article by Mer et al., p. 4539
Prioritising the most needed paediatric antiretroviral formulations: the PADO4 list
Authors: Martina Penazzato, Claire L Townsend, Natella Rakhmanina, Yao Cheng, Moherndran Archary, Tim R Cressey, Maria H Kim, Victor Musiime, Anna Turkova, Theodore D Ruel, Helena Rabie, Nandita Sugandhi, Pablo Rojo, Meg Doherty, Elaine J Abrams, Elaine Abrams, Jintanat Ananworanich, Isabelle Andrieux-Meyer, Moherndran Archary, Yodit Belew, Brookie Best, Rosa Bologna, Jessica Burry, Deborah Carpenter, Yao Cheng, Polly Clayden, Angela Colbers, Magda Conway, Timothy R. Cressey, Mutsa Dangarembizi, Shaffiq Essajee, Maribel Gonzalez Tome, Andrew Hill, Saye Khoo, Maria Kim, Linda Lewis, Janice Lee, Shahin Lockman, Imelda Mahaka, Mark H. Mirochnick, Lynne Mofenson, Mireille Muhimpundu, Angela Mushavi, Victor Musiime, Elizabeth Obimbo, Fernando Pascual, Carmen Perez Casas, Anton Pozniak, Helena Rabie, Natella Rakhmanina, Pablo Rojo, Theodore Ruel, Jonathan Schapiro, George Siberry, Teresa Beatriz Simione, Nandita Sugandhi, Cheick Tidiane Tall, Anna Turkova, Francois Venter, Marissa Vicari, Jenny Walsh, Jacque Wambui, Melynda Watkins
Journal: The Lancet HIV (2019)
OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial
Authors: H Wirsching, E Terksikh, S Manuela, K Carsten, R Patrick, B Becher, M Weller
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail. PATIENTS AND METHODS Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. RESULTS At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors. CONCLUSION We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.
Successful Surgical Treatment of Atrial Fibrillation
Authors: James L. Cox
Journal: JAMA (1991)

Atrial fibrillation is the most common of all sustained cardiac arrhythmias, yet it has no effective medical or surgical therapy. During the past decade, multipoint computerized electrophysiological mapping systems were used to map both experimental and human atrial fibrillation. On the basis of these studies, a new surgical procedure was developed for atrial fibrillation. Between September 25, 1987, and July 1,1991, this procedure was applied in 22 patients with paroxysmal atrial flutter (n = 2), paroxysmal atrial fibrillation (n = 11), or chronic atrial fibrillation (n = 9) of 2 to 21 years' duration. All patients were refractory to all antiarrhythmic medications, and each patient failed to receive the desired therapeutic benefits of an average of five drugs administered preoperatively. There were no operative deaths and all perioperative morbidity resolved. All 22 patients have been successfully treated for atrial fibrillation with surgery alone. Three patients developed one late isolated episode of atrial flutter at 5, 6, and 15 months postoperatively, and each of these patient's symptoms is now controlled by a single antiarrhythmic drug. Preservation of atrial transport function has been documented in all patients postoperatively, and all have experienced marked clinical improvement. (<i>JAMA</i>. 1991;266:1976-1980)