tbuckley/cabot-search huggingface dataset:
PF243 AN MLL‐AF9 ZEBRAFISH LEUKEMIA MODEL
Authors: M. Saberi, O. Delfi, P.J. Browett, P.M. Kakadiya, S. Bohlander
Journal: HemaSphere (2019)

Background: Acute Leukaemia (AL) is a genetically heterogeneous disease caused by somatic mutations and chromosomal translocations. Translocations can lead to the formation of fusion genes such as the MLL‐AF9 fusion, which results from the t (9;11)(p22;q23). MLL‐AF9 is one of the most common fusions involving the MLL (KMT2A) gene. MLLAF9 leukemias have an intermediate to poor prognosis. The MLL‐AF9 fusion is frequently used to establish murine leukemia models. However, to date, no MLL‐AF9 leukemia model in zebrafish has been reported. Aims: Our aim was to establish a transgenic zebrafish leukemia model using the MLL/AF9 fusion gene. Methods: We cloned two transgenic constructs (pTol2‐Runx1+23_MLL‐AF9_IRES‐EGFP and pTol2‐Runx1+23_MLL‐AF9_IRES‐mCherry). The Runx1+23 murine promoter was used to target MLL‐AF9 expression to zebrafish hematopoietic stem cells, while EGFP or mCherry were used as fluorescent markers. The final transgenic constructs were co‐injected with Tol2 transposase mRNA into fertilized embryos at the one cell stage. The embryos were sorted 24 hours post fertilization based on the expression of the heart marker. Results: About 40% of the transgenic embryos died in the first week after injection but the remaining 60% reached adulthood. After 6 to 12 months, 30% (30 out of 100) fish showed signs of disease. They became less active, sat at the bottom of the tank and, in some cases, they had splayed eyes. When this happened, the fish were euthanized and dissected. The autopsies showed enlarged kidneys, splenomegaly and in some cases a pale spleen. Histological sections revealed increased cellularity of the kidney and liver with massive infiltration of hematopoietic cells in these organs. In flow cytometry, kidney marrow cells from the transgenic fish showed a different forward scatter (FSC) and side scatter (SSC) profile compared to that of the normal zebrafish kidney marrow cells. The FSC/SSC profile in the transgenic F0 zebrafish showed an expansion of the hematopoietic progenitor cell population. These findings strongly suggest that the fish had developed a leukemia‐like disease. We performed whole mount in situ hybridization (WISH) with early hematopoietic markers in 24 hpf embryos and detected reduced expression of gata1 , myb and tal1 as well as increased expression of lyz in transgenic embryos. Currently, transplantation experiments are being performed to determine whether the disease is transplantable which is a sign of leukemia. Summary/Conclusion: Although our flow cytometry, histology and WISH data strongly suggest that we have established an MLL/AF9‐driven leukemia model in zebrafish, additional experiments are needed to further characterize our model and confirm the malignant nature of the observed disease. Our MLL/AF9 zebrafish leukemia model will be a helpful tool to study leukemia biology and test new therapeutic strategies.
THER-05. CONTINUOUS AND BOLUS INTRAVENTRICULAR TOPOTECAN PROLONG SURVIVAL IN A MOUSE MODEL OF LEPTOMENINGEAL MEDULLOBLASTOMA
Authors: Gregory Shackleford, Min Mahdi, Rex Moats, Debra Hawes, Hung Tran, Jonathan Finlay, Tuan Hoang, Ellis Meng, Anat Erdreich-Epstein
Journal: Neuro-Oncology (2019)

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 µM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 µg/day), daily bolus IVT topotecan injections with a similar daily dose (6 µg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 µg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.
SP0099 MRI DIFFICULT CASES OF THE AXIAL SKELETON
Authors: Lennart Jans
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> MRI has revolutionized the assessment of axial spondyloarthritis (SpA) in clinical practice. MRI of the sacroiliac joint is a cornerstone for diagnosis and classification, MRI of the spine may help with difficult cases as spinal changes may antedate sacroiliac changes and indicate disease burden. In daily practice, however, the interpretation of axial MRI is challenging. Experience has tempered the initial enthusiasm as the limitations of the ASAS criteria in daily practice become evident. Firstly, the ASAS criteria are intended to classify patients with 'back pain" of more than 3 months' duration and with onset before 45 years of age as having axial SpA. In other patient groups, however, sacroiliitis on MRI as defined by ASAS has a lower sensitivity and specificity. Secondly, the definition of a 'positive" MRI for sacroiliitis is validated to limited extend only. MRI of the sacroiliac joint requires inflammatory changes to meet the criteria, without a clear quantitative requirement. Bone marrow oedema lacks sensitivity and specificity as MRI findings suggestive of sacroiliitis may be produced by non-inflammatory disorders, a point that remains poorly investigated. Thirdly, structural changes in the sacroiliac joints are not taken into account in the ASAS criteria. The diagnostic performance of MRI of the sacroiliac joint could be improved by including structural lesions, but to date this is not the case. Fourthly, spinal imaging is not included in the ASAS criteria. MRI of the spine is considered 'positive" when at least 3 inflammatory or several structural lesions are present, with a sensitivity and specificity similar to those of the sacroiliac joints. The difficulty here is the lack of data. It has not been reliably shown that inflammation proceeds syndesmophyte formation and MRI seems uncapable of accurately evaluating treatment response. Only about 4% of patients with 'negative" sacroiliac MRI are reclassified based on positive spinal MRI findings. Clinicians should be aware of unreasonable expectations on MRI. If MRI findings are considered in isolation the findings are not reliable. The diagnosis of SpA can only be made by an expert if patient"s history, clinical examination, laboratory findings, and imaging studies converge. When solving difficult cases, collaboration is key: clear communication between rheumatologist and radiologist is mandatory. Radiologists should withstand the pressure to call if a patient has SpA or not based on MRI alone. <h3>Reference:</h3> [1] Wendling D, Claudepierre P, Pham T, et al. MRI in axial spondyloarthritis: From light to shadow? Joint Bone Spine 2015;82:302-304. <h3>Disclosure of Interests:</h3> None declared
Partha Kar: Let’s not make excuses for prejudice
Authors: Partha Kar
Journal: BMJ (2019)

It’s not actually the overt comments that really hurt. At least things are out in the open—in your face, even. They may be unpleasant, but you can choose to stand up to them or walk away. What’s worse is the seeping undercurrent, festering beneath the surface. It’s never in your face, but it’s always there.

I’m talking, of course, about racism. It’s well and truly alive in our society, the NHS, and the medical profession, lurking around a corner with a smirk, a nudge, or a nod.

I’ve worked in the NHS for over two decades, and attitudes to race have changed in that time, though perhaps only marginally. What used to be overt is now more …
Drug-induced systemic lupus erythematosus: should immune checkpoint inhibitors be added to the evolving list?
Authors: Emanuel Raschi, Ippazio Cosimo Antonazzo, Elisabetta Poluzzi, Fabrizio De Ponti
Journal: Annals of the Rheumatic Diseases (2019)

Arnaud and colleagues used WHO’s VigiBase, an international spontaneous reporting system, to compile an updated list (19 March 2018) of drugs suspected to be implicated in drug-induced systemic lupus erythematosus (SLE), an evolving clinical entity.1 They analysed 12 166 reports of drug-induced SLE and identified 118 suspected drugs with pharmacovigilance signal, which were reported in 8163 cases, mainly occurring in women (81%, 49 years as median age), defined as serious (55%), with a median onset of 172 days. Of note, 76 drugs (64.4%) were already known to cause SLE in the literature, including anti-TNF agents (infliximab received the highest number of reports), procainamide and hydralazine (receiving the highest disproportional reporting).

Our attention was drawn to the lack of pharmacovigilance signal for immune checkpoint inhibitors (ICIs), emerging oncological drugs recently associated with a unique and distinct spectrum of …
Evaluation of Barriers to Telehealth Programs and Dermatological Care for American Indian Individuals in Rural Communities
Authors: Anna M. Morenz, Siobhan Wescott, Arash Mostaghimi, Thomas D. Sequist, Matthew Tobey
Journal: JAMA Dermatology (2019)

Understanding geographic and financial barriers to health care is an important step toward creating more accessible health care systems. Yet, the barriers to dermatological care access for American Indian populations in rural areas have not been studied extensively.To evaluate the driving distances and insurance coverage for dermatological care and the current availability of teledermatological programs within the Indian Health Service (IHS) or tribal hospitals system.This mixed-methods study was conducted from May 7, 2018, to September 1, 2018, and did not take place in any IHS or tribal health care facility in the continental United States. The study design involved a geographic analysis and a cross-sectional telephone survey with brick-and-mortar dermatology clinics (n = 27) and teledermatological programs (n = 49). Brick-and-mortar clinics were selected for their proximity to a rural IHS or tribal hospital.Mean driving distance from rural IHS or tribal hospital to nearest dermatology clinic, number of dermatology clinics within a 35-mile or 90-mile radius of IHS or tribal hospitals, insurance and referral types accepted by dermatology clinics, and number of teledermatological programs collaborating with IHS or tribal hospitals or health centers.In total, 27 brick-and-mortar dermatology clinics and 49 teledermatological programs were identified and contacted for the survey. The median (interquartile range [IQR]) driving distance between rural IHS or tribal hospitals and the nearest dermatology clinic was 68 (30-104) miles. Of the 27 dermatology clinics in closest proximity to rural IHS or tribal hospitals (median [IQR] driving distance, 82.4 [31-114] miles), 25 (93%) responded to the survey, 6 (22%) did not accept patients with Medicaid, and 6 (22%) did not accept IHS referrals for patients without insurance. Of the 49 teledermatological programs, 45 (92%) responded and 14 (29%) were no longer active. Ten (20%) teledermatology programs were currently partnering (n = 6), previously partnered (n = 2), or were setting up services (n = 2) with an IHS or tribal site. Only 9% (n = 27) of the 303 rural IHS or facility in the continental United States reported receiving teledermatological services.Substantial geographic and insurance coverage barriers to dermatological care exist for American Indian individuals in rural communities; teledermatological innovations could represent an important step toward minimizing the disparities in dermatological care access and outcomes.
“Like sugar in milk”: reconstructing the genetic history of the Parsi population
Authors: Gyaneshwer Chaubey, Qasim Ayub, Niraj Rai, Satya Prakash, Veena Mushrif-Tripathy, Massimo Mezzavilla, Ajai Kumar Pathak, Rakesh Tamang, Sadaf Firasat, Maere Reidla, Monika Karmin, Deepa Selvi Rani, Alla G. Reddy, Jüri Parik, Ene Metspalu, Siiri Rootsi, Kurush Dalal, Shagufta Khaliq, Syed Qasim Mehdi, Lalji Singh, Mait Metspalu, Toomas Kivisild, Chris Tyler-Smith, Richard Villems, Kumarasamy Thangaraj
Journal: Genome biology (2017)

The Parsis are one of the smallest religious communities in the world. To understand the population structure and demographic history of this group in detail, we analyzed Indian and Pakistani Parsi populations using high-resolution genetic variation data on autosomal and uniparental loci (Y-chromosomal and mitochondrial DNA). Additionally, we also assayed mitochondrial DNA polymorphisms among ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India. Among present-day populations, the Parsis are genetically closest to Iranian and the Caucasus populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred ~1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement. Finally, we show that Parsis are genetically closer to Neolithic Iranians than to modern Iranians, who have witnessed a more recent wave of admixture from the Near East. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7th century and in agreement with their assimilation into the Indian sub-continent's population and cultural milieu "like sugar in milk". Moreover, in a wider context our results support a major demographic transition in West Asia due to the Islamic conquest.
AB0383 LATENT TUBERCULOSIS INFECTION SHOULD BE MONITORED IN BOTH TUMOR NECROSIS FACTOR INHIBITORS AND NON-TUMOR NECROSIS FACTOR INHIBITORS IN BIOLOGICAL-NAïVE PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: Yun-Ju Huang, Yao-Fan Fang, Shue-Fen Luo, Kuang-Hui Yu, Chang-Fu Kuo, Ping-Ha Tsai, Yen-Fu Chen
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The risk of latent tuberculosis infection (LTBI) increased during the treatment of biologic agents for patients with rheumatoid arthritis. Taiwan rheumatology association recommend performing at least annual interferon-gamma release assays (IGARs) testing during biologic treatment course because of the moderate prevalence of tuberculosis in Taiwan.[1] Although increased tuberculosis reactivation rate in patients with TNF inhibitor is reported, the risk of LTBI in patients with RA treated by non-TNF inhibitors is limited. <h3>Objectives</h3> The aim is to use serial interferon-gamma release assays (IGRAs) as a diagnostic tool for LTBI in biologic-naïve patients with rheumatoid arthritis treated with TNF and non-TNF inhibitors in Taiwan. <h3>Methods</h3> We retrospectively collected 313 biologic-naïve patients with rheumatoid arthritis receiving biologic agents between 2013 to 2017 in Chang Gung Memorial hospital in Taiwan. All RA patients underwent semi-annual IGRA test during biologic agent treatment. Cox proportional hazard model was used for analysis to compared RA patients with TNF and non-TNF inhibitors. <h3>Results</h3> The age of patients and disease duration are 55.9 13.1 year-old and 5.2 2.0 years(Table 1). The LTBI rate in patients with rheumatoid arthritis after biologic treatment is 6.7%. Out of the 21 patients with LTBI, 12(6%) patients were treated with TNF inhibitors, 9(8%) patients were treated with non-TNF inhibitors (Figure 1). 42.9%(9/21) received chemoprophylactic therapy by isoniazid but no patient suffered from active TB till the end of study period. Patients with TNF inhibitors was associated with a hazard ratio (HR) of 4.43 (95% CI, 0.80-24.39) after adjusted age, sex, diabetes history, prednisolone use and disease duration. This Cox regression analysis of RA patients found that the risk of LTBI was not different in TNF or non-TNF inhibitors. <h3>Conclusion</h3> Our study revealed biologic-naïve patients with rheumatoid arthritis have the same risk of LTBI. All RA patients who need either TNF or non-TNF inhibitors should be monitored LTBI in moderate prevalence TB area. <h3>References</h3> [1] Chen, Y.-H., 2015 TRA revised recommendations for screening and management of tuberculosis infection in patients before and after anti-tumor necrosis factor-alpha biological treatment. Vol. 29. 2015. 1-8. <h3>Disclosure of Interests</h3> None declared
PS1114 PATIENTS WITH GAUCHER DISEASE SHOW AN IMMUNE‐DYSREGULATION PATTERN SECONDARY TO A DEFECT OF APOPTOSIS
Authors: M. Miano, A. Madeo, E. Cappelli, F. Fioredda, E. Palmisani, P. Terranova, T. Lanza, R. Vené, C. Vernarecci, A. Beccaria, R. Maggiore, D. Guardo, C. Dufour, C. Micalizzi, M. Di Rocco
Journal: HemaSphere (2019)

Background: Gaucher Disease (GD) is a congenital disorder secondary to GBA1 gene mutations that cause a defective function of the catabolic enzyme β‐glucocerebrosidase (GBA) and a progressive accumulation of its substrate‐ glucocerebroside (GC) in various organs, in particular in mononuclear phagocite system. Bone infiltration, hepatosplenomegaly and cytopenia represent the most common features of the disease. Since clinical manifestation can be subdolous, in some cases, phenotype can overlap with Autoimmune Lymphoproliferative Sindrome (ALPS). Nonetheless, GD patients were also shown to have hyperinflammatory features‐ secondary to machrophages engorgement and actviation‐ and an aspecific impaiment involving B, T and NK cells. In addition, some patients also showed more specific ALPS‐like immune‐dyregulation features suggesting an underlying apoptosis defect. Aims: To evaluate specific ALPS‐like immunological and serological pattern (Double Negative T‐cells, TCR alfa/beta B220, B‐memory cells, T‐regs/HLA‐DR ratio, IL‐10, IL‐18,) in a cohort patients with GD and to test apoptosis pathway function in those showing ALPS‐like features. Methods: All patients were diagnosed with GD by enzyme assay on lymphocytes culture or fibroblasts and by characterization of pathogenetic variants of GBA1. Lymphocytes subsets and ALPS‐related serum biomarkers (IL‐10, IL‐18, sFAS, Vit.B12) were analyzed in 41 GD patients followed‐up at Istituto Giannina Gaslini. Furthermore, in those patients who showed an ALPS‐like phenotype, apoptosis function was analyzed after FAS–induced stimulation of EBV‐immortalized B‐cells and Western blot analysis of CASP10, CASP8, and PARP proteins. Results: 10/41 (24%) patients showed an ALPS‐like immunological pattern which was more frequent in naïve patients (p = 0.003) and in patients with an earlier onset of the diesease (p = 0.010). EBV‐immortalized B‐cells of 7 out of these 10 patients were further studied and all of them showed a defective FAS‐induced apoptosis and caspases activation. Fig 1 shows apoptosis evalutation of the selected population. Summary/Conclusion: To the best of our knowledge, this study shows for the first time that untreated subjects with early‐onset GD present an immune‐dysregulation pattern secondary to a defect of apoptosis as seen in ALPS patients. These results suggest that diagnostic work‐up of both diseases must take into consideration their clinical and biochemical overlap. Further studies are needed to evaluate the potential role of cell‐membrane lipids impairment on FAS receptor structure as a cause of such defect. image
Genomic diagnosis for children with intellectual disability and/or developmental delay
Authors: Kevin M. Bowling, Michelle L. Thompson, Michelle D. Amaral, Candice R. Finnila, Susan M. Hiatt, Krysta L. Engel, J. Nicholas Cochran, Kyle B. Brothers, Kelly M. East, David E. Gray, Whitley V. Kelley, Neil E. Lamb, Edward J. Lose, Carla A. Rich, Shirley Simmons, Jana S. Whittle, Benjamin T. Weaver, Amy S. Nesmith, Richard M. Myers, Gregory S. Barsh, E. Martina Bebin, Gregory M. Cooper
Journal: Genome Medicine (2017)

Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.