tbuckley/cabot-search huggingface dataset:
Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance
Authors: Amin Emad, Junmei Cairns, Krishna R. Kalari, Liewei Wang, Saurabh Sinha
Journal: Genome biology (2017)

Identification of genes whose basal mRNA expression predicts the sensitivity of tumor cells to cytotoxic treatments can play an important role in individualized cancer medicine. It enables detailed characterization of the mechanism of action of drugs. Furthermore, screening the expression of these genes in the tumor tissue may suggest the best course of chemotherapy or a combination of drugs to overcome drug resistance. We developed a computational method called ProGENI to identify genes most associated with the variation of drug response across different individuals, based on gene expression data. In contrast to existing methods, ProGENI also utilizes prior knowledge of protein–protein and genetic interactions, using random walk techniques. Analysis of two relatively new and large datasets including gene expression data on hundreds of cell lines and their cytotoxic responses to a large compendium of drugs reveals a significant improvement in prediction of drug sensitivity using genes identified by ProGENI compared to other methods. Our siRNA knockdown experiments on ProGENI-identified genes confirmed the role of many new genes in sensitivity to three chemotherapy drugs: cisplatin, docetaxel, and doxorubicin. Based on such experiments and extensive literature survey, we demonstrate that about 73% of our top predicted genes modulate drug response in selected cancer cell lines. In addition, global analysis of genes associated with groups of drugs uncovered pathways of cytotoxic response shared by each group. Our results suggest that knowledge-guided prioritization of genes using ProGENI gives new insight into mechanisms of drug resistance and identifies genes that may be targeted to overcome this phenomenon.
AB0482 MORE THAN ONE POSITIVITY FOR ANTIPHOSPHOLIPID SYNDROME DETERMINES LONG TERM ANTIBODY PERSISTENCE
Authors: Filipa Pedro, Filipa Carreiro, Maria Moraes-Fontes
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> It is generally assumed that once Antiphospholipid syndrome (APS) is diagnosed, patients should be treated with anticoagulation (ACO), possibly for a lifetime<sup>1</sup>. <h3>Objectives:</h3> Our main objective was the characterization of a group of patients with primary APS, evaluation of clinical profile, presence of APS antibodies (Ab) over time, recurrent thrombotic events and treatment. <h3>Methods:</h3> Demographic and clinical features of patients with APS were identified through the Unit's database. APL significant titers were retrospectively collected, 3, 6 and 9 months, every 6 months until year 6, every year until the last follow-up. LAC and aPL Ab (anticardiolipin IgG and Beta-2 Glycoprotein 1 IgG) were considered positive or negative by DRVVT/ELISA. Comparisons were made using the Wilcoxon Rank Sum and Chi square tests, p values &lt; 0.05 were considered statistically significant (SPSS 22). <h3>Results:</h3> 67 patients were analysed; the majority were female (n=49); mean average age of APS diagnosis was at 40[±13] y-old. Evaluation period: 2 - 20 years. 52 patients had at least one thrombotic event: 7 arterial thrombosis, 30 venous thrombosis and 8 both arterial and venous thrombotic events; 7 patients had obstetrical APS and one of these had both thrombotic and obstetrical APS; 9 had severe non-thrombotic APS manifestations. Fifty-four patients are currently under warfarin, 8 of which had a thrombotic event despite ACO. Patients could be grouped into two distinct patterns: those that became persistently antibody negative (aPL-; n=19) and those in whom the antibodies remained positive, persistently or intermittently (aPL+; n=48). The major difference between groups was the occurrence of cumulative double or triple positivity in 69% of aPL+ versus 37% in aPL- (p=0.026). There were no significant differences in age, age at diagnosis, duration of the disease and frequency/type of thrombosis, between each group (Table I). From the group that became persistently aPL-, 3 patients suspended ACO, without any event after 2 years of follow-Up. <h3>Conclusion:</h3> Our study suggests that more than one aPL/LAC positivity is associated with antibody persistence over time. In our small series, as previously reported, ACO was safely discontinued in selected patients that become aPL-, in the absence of other risk factors for thrombotic events<sup>2</sup>. Regular antibodies measurements may help identify a subset of patients in whom ACO may be safely discontinued under careful observation. References: <h3>Disclosure of Interests:</h3> None declared
PS1573 B0 VS. NON-B0 GENOTYPE: DIFFERENCES IN TDT PATIENTS
Authors: A. Meloni, L. Pistoia, A. Massa, L. Rigoli, C. Paci, C. Argento, M. Caniglia, G. Palazzi, L. Tedesco, M. Missere, V. Positano, A. Pepe
Journal: HemaSphere (2019)

Background: Transfusion-dependent-thalassemia (TDT) is the most severe clinical presentation of β-thalassemia. It is characterized by extremely diverse clinical manifestations, further complicated by the inclusion in TDT group of the patients with TI patients who started regular transfusion in adult age. Determination of factors causing such a diverse clinical presentation has clinical significance. Aims: Our study aimed to investigate if the presence of a β°/β° homozygous genotype was associated to increased iron overload and rate of complications. Methods: We considered 747 TDT patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Magnetic Resonance Imaging (MRI) was used to quantify iron overload (T2∗ technique), biventricular morphological and functional parameters (cine sequences), and the presence of myocardial fibrosis (late gadolinium enhancement-LGE technique). All complications were classified according to international guidelines. Results: Two groups of patients were identified: non homozygous β°/β° genotype (N = 493) and homozygous β°/ β° genotype (N = 254). No significant differences for sex was found between the groups while the homozygous β°/β° group was significantly older (30.8 ± 8.9 yrs vs 29.1 ± 9.4 yrs; P = 0.009) and showed a significant higher frequency of transfusions in the past 12 months (41.7 ± 11.8 vs 37.4 ± 11.2; P < 0.0001). Mean haemoglobin levels, serum ferritin levels, liver transaminases and MRI liver iron concentration (LIC) values were comparable between the groups. Patients with homozygous β°/β° genotype had a significant higher frequency of liver fibrosis, also adjusting for age (12.4% vs 3.2%; P = 0.015). The homozygous β°/β° group showed significantly lower global heart T2∗ values (26.6 ± 13.0 ms vs 30.1 ± 11.6 ms; P = 0.001) and a higher number of patients with a global heart T2∗ value<20 ms (33.1% vs 21.3%; P < 0.0001). Left ventricular (LV) stroke volume index was significantly lower in the homozygous β°/β° group, also adjusting for age and number of transfusions (52.1 ± 10.1 ml/m2 vs 54.4 ± 11.7 ml/m2; P = 0.001). No difference between groups was detected in terms of frequency of diabetes, osteoporosis, hypogonadism, and hypoparathyroidism while frequency of hypothyroidism was significantly higher in the homozygous β°/β° group, also adjusting for age (23.4% vs 13.5%, P = 0.004) Frequency of heart failure was comparable between groups while the frequency of arrhythmias was significantly higher in the homozygous β°/β° group (7.8% vs 1.9%; P = 0.001). Summary/Conclusion: Patients with β°/β° homozygous genotype had more cardiac iron and showed an higher frequency of liver fibrosis, hypothyroidism, and arrhythmias. These data support the knowledge of different phenotypic groups in the management of TDT patients.
B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) with t(5;14)(q31;q32)/ IL3-IGH Rearrangement and Eosinophilia: A Peculiar IGH BCP-ALL
Authors: Benjamin Fournier, Estelle Balducci, Nicolas Duployez, Emmanuelle Clappier, Wendy Cuccuini, Elodie Bottolier-Colomb, Denis Caillot, Helene Cave, Aurélie Caye-Eude, Eric Delabesse, Coralie Derrieux, Nathalie Dhedin, Florent Dumezy, Pascaline Etancelin, Odile Fenneteau, Jamilé Frayfer, Antoine Gourmel, Marie Loosveld, Gerard Michel, Nathalie Nadal, Claire-Helene Oudin, Dominique Penther, Isabelle Tigaud, Nathalie Grardel, Marine Lafage, Andre Baruchel
Journal: Blood (2017)
PB2188 ANALYSIS OF MINIMAL RESIDUAL DISEASE IN PATIENTS WITH MULTIPLE MYELOMA RECEIVING DARATUMUMAB
Authors: T. Glazanova, Z. Chubukina, L. Bubnova, E. Karyagina, A. Garifullin, S. Voloshin, S. Bessmeltsev
Journal: HemaSphere (2019)

Background: Over the past two decades, with the advent of new drugs, the tactics of treatment of patients with multiple myeloma (MM) has changed significantly; however, the general problem of the effectiveness of MM therapy remains unresolved to date. This disease is characterized by a progressive course and development of resistance to both proteasome inhibitors (bortezomib) and immunomodulatory drugs (lenalidomide), i.e. double refractoriness. Anti‐CD38 monoclonal antibodies are suggested for the treatment of heavily‐pretreated patients, including patients with double refractoriness. Aims: To study the dynamics of minimal residual disease (MRD) in patients with MM with double refractoriness receiving daratumumab. Methods Seven patients with MM refractory to prior bortezomib and lenalidomide treatment were included in the study from 2017 to 2019. The number of lines of previous therapy was 5 (median = 3). The average age of patients–61 years (48–76 years). Daratumumab was administered to all patients as an intravenous infusion at a dose of 16 mg/kg: weekly at Weeks 1‐8, biweekly at Weeks 9‐24 and from Week 25 till progression. MRD assessment in bone marrow aspirate using multicolor flow cytometry (with a sensitivity of 10 −5 ) was performed every 3 months from the start of treatment. To assess the effectiveness of treatment, generally accepted criteria were used. Results: Overall response was 86%. Fifty‐seven % of patients achieved a very good partial response, 29% had a partial response and 14% developed disease progression during therapy. After 3 months of therapy, 6 (86%) patients were MRD‐positive (median 0.072%, range 0.017–0.15%), of these, in 5 patients the monitoring showed a decrease in the number of myeloma cells, while in one patient MRD‐negativity was achieved. One patient (14%) with a very good partial response, after 3 months from the start of therapy, achieved an indicator of MRD‐negativity &lt;0.01% (median ‐ 0.005%), however, after 6 months the MRD status changed to positive. Summary/Conclusion: Daratumumab treatment regimen demonstrated a high level of general response. The MRD score reflects the clearance of residual tumor cells and is an important independent prognostic criterion for determining the depth of remission, for stratification by risk groups and disease prognosis.
Abstract 199: Neurological Recovery “Life after Death” following Total Brain Ischemia with Controlled Reperfusion
Authors: Eui Ho Whang, Zhongtuo Tan, Gerald D Buckberg, Sean Sakhai, Bradley S Allen
Journal: Circulation (2008)

Brain damage due to limited ischemic tolerance often precludes meaningful recovery from sudden death, despite cardiac salvage. This study tests the tolerance of 30 minutes of normothermic (37°C) to...
THU0578 COMMON VARIABLE INMUNODEFICIENCY IN PATIENTS WITH SARCOIDOSIS
Authors: Isabel Madroñal García, Clara Aguilera Cros, Maria Dolores Arcila Duran, Lara Mendez, Marina Gomez Vargas, Alberto Ruiz Roman, Marina Gomez Vargas, Alberto Ruiz Roman, Noemi Patricia Garrido Puñal, Ricardo Juan Gil Velez, Jose Antonio Rodriguez Portal, Esteban Rubio Romero
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and a deficient production of specific antibodies. Almost 30% of patients with CVID develop an autoinmmune and granulomatous disease, similar to clinical and histological sarcoidosis (S), it affects the lung fundamentally. This can lead to a misdiagnosis of S in a patient with CVID, this leads to inadequate treatment and increases the morbidity and mortality of the disease. <h3>Objectives:</h3> Describe the clinical and radiological characteristics of a cohort of patients diagnosed with S with predominant pulmonary involvent. Make a study of immunoglobulin (IG) levels to see the frequency of CVID in these patients. <h3>Methods:</h3> Retrospective descriptive study of patients treated in our Hospital (2008-2018), with diagnosis of S. The data was obtained by reviewing medical records. The delay in the diagnosis of S was defined as the difference in months between the initial diagnostic suspicion and the final diagnosis of S. In patients with low levels IG, we have done and expanded ID study. <h3>Results:</h3> 55 patients (31 women) were included, with a mean age of 52 ±12 years. The initial diagnosis was: 85% S, 10% lymphoma and 4% tuberculosis. The median of months from the start of the clinic to the diagnosis of S was 5.5 months. Regarding the clinic, 21% patients present fever at the beginning of the disease, and 65% extrathoracic localization (cutaneous was the most frequent in 27%, and renal was the least frequent 5%). Simple x-ray and high resolution tomography of chest were done in all patients. Pulmonary stage 2 was the most frequent (51%), followed by stage 3 (16%), stage 0 (14%) and stage 4 (9%). In 90% of the patients, histological confirmation was obtained by transbronchial (47%), cutaneous (11%) or lymph node biopsy (29%). Igs were normal in 87% of patients, only 4 patients had low IG levels (Ig G in 3 patients and Ig M in 1). An extended ID study was performed in these 4 patients, being diagnosed with CVID 3 patients. Results of the 4 patients and the differential characteristics between CVID and S in table 1. <h3>Conclusion:</h3> Although their clinical presentation and histological appearance may be identical, the management of these two conditions is very different. The difficulties in the differential diagnosis between S and CVID, shows the importance of a history of screening for recurrent infections and the measurement of IG levels before the diagnosis of possible S. <h3>Disclosure of Interests:</h3> None declared
Heterogeneity in the geographic distribution of diffuse grade II and III gliomas in France.
Authors: Luc Bauchet, Amelie Darlix, Sonia Zouaoui, Jean Marc Virion, Valerie Rigau, Helene Mathieu Daude, Marie Blonski, German Reyes-Botero, Faiza Bessaoud, Brigitte Tretarre, Fabienne Bauchet, Laurent Capelle, Michel Fabbro, Christine Kerr, Dominique Figarella-Branger, Hugues Duffau, Luc Taillandier
Journal: Journal of Clinical Oncology (2013)

2067 Background: Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors (incidence ≤ 2/10 5 person-years). Specific epidemiological studies are very rare. The main objective of this work is to study the geographical distribution of all newly diagnosed and histologically confirmed DGII/IIIG in metropolitan France. Methods: The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase. Personal addresses at the moment of the surgical procedure for all DGII/IIIG cases were collected for the years 2006-2009. For each area, the incidence of DGII/IIIG was analyzed and standardized on age and sex distribution of the French population (pop). Results: The total number of patients with newly diagnosed and histologically confirmed DGII/IIIG was 4790 (1220, 1190, 1228, and 1152 for years 2006-2009). The Table shows the number of tumors by histology, sex and median age at diagnosis. The overall crude rate was 19.4/10 6 . To enable international comparisons, standardized rates were calculated as follows: 19.8/10 6 (reference pop, Europe), 18.8/10 6 (reference pop, US 2000), and 16.0/10 6 (reference pop, world). The geographic distribution by regions in France showed significant differences. For example, the standardized rates (for 10 6 person-years, 95% confidence intervals, reference pop: France) for Auvergne, Champagne-Ardenne, and Basse-Normandie, were 30.9 (26.4-35.5), 28.5 (24.0-33.0), and 13.9 (10.9-17.0), respectively. Conclusions: To our knowledge, this work is the first to study the geographical distribution of DGII/IIIG across one entire country, and it shows significant heterogeneity. These results will enable to look for different environmental and genetic factors in these different regions. [Table: see text]
Integrative Pharmacogenomics Analysis of Patient-Derived Xenografts
Authors: Arvind S. Mer, Wail Ba-Alawi, Petr Smirnov, Yi X. Wang, Ben Brew, Janosch Ortmann, Ming-Sound Tsao, David W. Cescon, Anna Goldenberg, Benjamin Haibe-Kains
Journal: Cancer Research (2019)

Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for in vivo pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology. SIGNIFICANCE: A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX.See related commentary by Meehan, p. 4324.
Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study
Authors: Thomas Klopstock, Fernando Tricta, Lynne Neumayr, Ivan Karin, Giovanna Zorzi, Caroline Fradette, Tomasz Kmieć, Boriana Büchner, Hannah E Steele, Rita Horvath, Patrick F Chinnery, Anna Basu, Clemens Küpper, Christiane Neuhofer, Bernadette Kálmán, Petr Dušek, Zuhal Yapici, Ian Wilson, Feng Zhao, Federica Zibordi, Nardo Nardocci, Christine Aguilar, Susan J Hayflick, Michael Spino, Andrew M Blamire, Penelope Hogarth, Elliott Vichinsky
Journal: The Lancet Neurology (2019)
Solutions to Reduce Unnecessary Imaging
Authors: David C. Levin, Vijay M. Rao
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
SP0074 DIAGNOSIS OF CEREBRAL VASCULITIS
Authors: Leonard Calabrese
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Among all forms of vasculitis, perhaps that affecting the CNS (CNS-V) poses the greatest challenge in diagnosis given the lack of any non invasive high specificity test, the complex and extensive list of mimicking conditions, its inaccessibility for biopsy and its genuine rarity. The diagnosis still requires the presence of an unexplained neurologic sign or symptom(s) following an exhaustive evaluation, evidence of vascular involvement (by direct or indirect angiography) or biopsy and most importantly the meticulous exclusion of all those conditions capable of producing mimicking clinical, radiographic or histologic findings that would confound accurate diagnosis. Despite these challenges CNS-V has been increasingly reported due to a combination of increased diagnostic awareness and advances in diagnostics. Two of these major advances will be discussed including the use of direct vascular wall imaging to differentiate vascular inflammation from spasm or atherosclerosis and the use of next generations sequencing to identify infectious etiologies and obviate the use of biopsy. Clinical examples will be presented. <h3>References:</h3> [1] Byram K, Hajj-Ali RA, Calabrese L CNS VasculitiByram K, Hajj-Ali RA, Calabrese L CNS Vasculitis: an Approach to Differential Diagnosis and Management. Review. Long-term outcomes of patients with primary angiitis of the central nervous system. Curr Rheumatol Rep. 2018 May 30;20(7):37. doi: 10.1007/s11926-018-0747-zs: an Approach to Differential Diagnosis and Management. Review. Long-term outcomes of patients with primary angiitis of the central nervous system. Curr Rheumatol Rep. 2018 May 30;20(7):37. doi: 10.1007/s11926-018-0747-z [2] Michael R. Wilson, M.D., M.A.S., Brian D. O"Donovan, M.S., Jeffrey M. Gelfand, M.D., M.A.S, Hannah A. Sample, B.S, Felicia C. Chow, M.D., John P. Betjemann, M.D.1,2, Maulik P. Shah, M.D., Megan B. Richie, M.D.1,2, Mark P. Gorman, M.D., Rula A. Hajj-Ali, M.D., Leonard H. Calabrese, D.O. et al. Metagenomic next-generation sequencing for chronic meningitis: a case series JAMA Neurology Published online April 16, 2018. doi:10.1001/jamaneurol.2018.0463 [3] Obusez EC, Hui F, Hajj-Ali RA, Cerejo R, Calabrese LH, Hammad T, Jones SE. High-resolution MRI vessel wall imaging: Spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis. AJNR American Journal of Neuroradiology 2014 Aug;35(8):1527-32. doi: 10.3174/ajnr.A3909. Epub 2014 Apr 10. <h3>Disclosure of Interests:</h3> Leonard Calabrese Consultant for: Bristol-Myers-Squibb, Genentech and Astra-Zeneca.
US data on vaccine injury pay-outs show strong immunisation safety record
Authors: Owen Dyer
Journal: BMJ (2019)

Only 6600 people have been compensated for vaccine injuries in 31 years of the US National Vaccine Injury Compensation Program, says a New York Times review that suggests that immunisation in the United States has been far safer in recent years than is widely believed.1

The review was triggered by a congressman’s question to Facebook’s chief executive, Mark Zuckerberg, in a letter that accused the social media company of suppressing free speech by vaccine sceptics.2

“If vaccines do not cause injuries, why has the vaccine injury trust fund paid out $4 061 322 557.08 [£3.23bn; €3.63bn] for vaccine injuries?” asked Bill Posey, a Florida Republican.

But the newspaper’s review of the compensation programme’s data found that even unproven claims of death or injury from vaccination were extraordinarily rare, amounting to only about two claims in each million vaccine doses in recent years.

This is despite a national compensation …