tbuckley/cabot-search huggingface dataset:
A narrative review of the definition of ‘flare’ in hidradenitis suppurativa
Authors: J.S. Kirby, B. Moore, P. Leiphart, K. Shumaker, A. Mammis‐Gierbolini, F. Benhadou, V. del Marmol
Journal: British Journal of Dermatology (2019)

Hidradenitis suppurativa (HS) is a chronic, inflammatory condition that can have periodic worsening or flares. Measurement of flare is important because it can inform treatment efficacy; however, it is unclear how HS flare should be defined. This study reviewed the literature for definitions of HS flare. The PubMed MEDLINE online database was searched on 10 January 2018 and the search was repeated on 8 December 2018 for new publications. Titles and abstracts were screened for inclusion. Subsequently, full articles were screened for inclusion. Papers were included if the publication was a systematic review, clinical trial, cohort study, case report or series, or cross‐sectional study. Studies were excluded if they were journalistic reviews, did not discuss clinical findings of HS or did not use the words 'flare', 'exacerbation', 'relapse' or 'recurrence'. Two hundred and seventy‐four papers were identified and 154 fulfilled the study criteria. Of these, 27 (17.5%) included the term 'flare' and 16 (10.4%) included the term 'exacerbation'. Two of the 27 papers (7%) defined the term flare and both included patient report of changes in symptoms or signs. One of 16 papers (6%) defined exacerbation, which was taken as one new HS lesion. The terms 'recurrence' and 'relapse' were more apt to be defined: 13% (13 of 100) and 14% (six of 44), respectively. The lack of a specific and measurable definition of HS flare is a barrier to assessment of this important outcome. Once a specific and measurable definition is established, validated and reliable measures of HS flare can be incorporated into future studies. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin condition. The ability to assess flares is important to people who have HS; however, it is unclear how this is defined. HS flare is one of the core outcomes in the core outcome set for HS clinical trials; however, it is unclear how this should be assessed. What does this study add? This literature review reveals the paucity of measurable definitions associated with the use of the term 'flare' in the HS literature. It also highlights the variation and lack of a validated and reliable measure of HS flare.
Stem cells in homeostasis and cancer of the gut
Authors: Maartje van der Heijden, Louis Vermeulen
Journal: Molecular Cancer (2019)

The intestinal epithelial lining is one of the most rapidly renewing cell populations in the body. As a result, the gut has been an attractive model to resolve key mechanisms in epithelial homeostasis. In particular the role of intestinal stem cells (ISCs) in the renewal process has been intensely studied. Interestingly, as opposed to the traditional stem cell theory, the ISC is not a static population but displays significant plasticity and in situations of tissue regeneration more differentiated cells can revert back to a stem cell state upon exposure to extracellular signals. Importantly, normal intestinal homeostasis provides important insight into mechanisms that drive colorectal cancer (CRC) development and growth. Specifically, the dynamics of cancer stem cells bear important resemblance to ISC functionality. In this review we present an overview of the current knowledge on ISCs in homeostasis and their role in malignant transformation. Also, we discuss the existence of stem cells in intestinal adenomas and CRC and how these cells contribute to (pre-)malignant growth. Furthermore, we will focus on new paradigms in the field of dynamical cellular hierarchies in CRC and the intimate relationship between tumor cells and their niche.
HGG-24. COMPREHENSIVE GENOMIC ANALYSIS OF PEDIATRIC GLIOMAS UNCOVERS NOVEL MUTATIONS IN HISTONE-ENCODING GENES
Authors: Erin Bonner, Madhuri Kambhampati, Krutika Gaonkar, Sabine Mueller, Adam Resnick, Pichai Raman, Javad Nazarian
Journal: Neuro-Oncology (2019)

In order to define the mutational landscape across histone genes in pediatric CNS cancers, we surveyed 1,000 patients from the Children’s Brain Tumor Tissue Consortium (CBTTC) cohort, representing 1,100 samples from 35 studies. In addition, we amassed genomic data from 152 pediatric high grade glioma subjects (114 WGS, 38 WES) representing both upfront biopsies and autopsy specimens. Using existing and newly generated genomic data, we comprehensively mapped the histone mutation landscape in pediatric gliomas. We identified previously unknown and novel histone mutations, mostly associated with midline gliomas (pontine and thalamic). Mutations were classified as protein damaging (causing a change in amino acid or frameshift), rare (present in less than 0.01% of the population), and somatic by comparison to matched germline DNA, or to a large panel of normal brain samples from the CBTTC cohort (n=40). Mutations were found in both linker and core histone genes, validated by Sanger sequencing, and defined in the context of their clinical impact. The majority of these mutations are expected to decrease protein stability, and to perturb post-translational modifications (in particular methylation and/or phosphorylation) at the protein level. Novel mutations were identified in tumor samples harboring K27M in H3.3 and H3.1, as well as in tumors classified as histone wild type (due to absence of K27M mutation). Subjects harboring novel histone mutations were found to have higher overall mutational load, and unsupervised clustering of methylation data has identified distinct epigenetic patterns within H3.3/3.1 K27M subjects with and without novel histone mutations. We also assessed co-occurrence of novel histone mutations with known partner mutations, and identified genes encoding DNA-binding proteins significantly associated with novel linker histone mutations. In vitro studies are underway to define the biological role of novel histone mutations in tumorigenicity.
HGG-20. NOVEL IDENTIFICATION OF SIMULTANEOUS H3F3A K27M AND G34W MUTATIONS IN A PEDIATRIC DIFFUSE MIDLINE GLIOMA OF THE SPINAL CORD
Authors: Tabitha Cooney, Joseph Torkildson, Peter Sun, Arie Perry, David Solomon
Journal: Neuro-Oncology (2019)

We report a case of a diffuse midline glioma centered in the thoracic spinal cord in a 13-year old boy with co-occurring H3F3A hotspot missense mutations p.K27M and p.G34W. At 7-years of age, he presented with scoliosis and leg length discrepancy. MR imaging revealed an expansile, non-enhancing intramedullary T6 to T12 mass. A surgical biopsy demonstrated a low-grade glioma, favored to be pilocytic astrocytoma, WHO grade I. However, a resection was not possible due to the degree of spinal cord infiltration. He received 8 months of irinotecan and temozolomide, with post-therapy imaging showing an expansile, non-enhancing T7-T11 mass, stable in size. He was followed conservatively until 13-years of age, when he developed lower extremity paresthesias and weakness. Imaging revealed an expansile mass of the thoracic cord extending from T8-T11, with new rounded area of T2 hyperintensity in the right dorsal lateral aspect of the conus, associated with new contrast enhancement. He underwent partial resection, with pathology showing a diffuse midline glioma with H3 K27M-mutation identified by immunohistochemistry. Targeted next-generation sequencing was performed that identified both p.K27M and p.G34W hotspot missense mutations in the H3F3A gene that were present in cis (on the same allele). Additional pathogenic mutations were identified involving PPM1D, PTPN11, FGFR1, and ATRX. No pathogenic germline mutations were identified. To the best of our knowledge, this is the first example of a diffuse midline glioma harboring G34 mutation, typically found in hemispheric and not midline gliomas. Interestingly, this was not the G34R or G34V mutation that has been found in hemispheric gliomas, but instead was G34W that has been found only in giant cell tumor of bone. It remains to be determined why this tumor simultaneously acquired both K27M and G34W mutations – and more broadly, the mechanism by which these histone H3.3 mutations drive gliomagenesis.
Regorafenib in advanced high-grade glioma: a retrospective bicentric analysis
Authors: Theophilos Tzaridis, Irina Gepfner-Tuma, Sophie Hirsch, Marco Skardelly, Benjamin Bender, Frank Paulsen, Christina Schaub, Johannes Weller, Niklas Schäfer, Ulrich Herrlinger, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2019)
Response of BRAFV600E-Mutant Lung Adenocarcinoma With Brain Metastasis and Leptomeningeal Dissemination to Dabrafenib Plus Trametinib Treatment
Authors: Gaku Yamamoto, Jun Sakakibara-Konishi, Tomoo Ikari, Hidenori Kitai, Hidenori Mizugaki, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa
Journal: Journal of Thoracic Oncology (2019)
Oscar Salvatierra: helped draft the US National Organ Transplant Act of 1984 and fought for its passage
Authors: Ned Stafford
Journal: BMJ (2019)

Lucile Packard Foundation for Children’s Health

Oscar Salvatierra Jr was widely acknowledged as an outstanding paediatric kidney transplantation surgeon. He approached each patient with one goal in mind: to make sure that the surgery was “perfect.” A deeply compassionate man, Salvatierra had an ability to connect with his young patients and to calm the fears of their parents.

One of those parents was Carlos Esquivel, a colleague of his at Stanford University. Esquivel, chief of abdominal transplantation at Stanford, had learnt that one of his sons needed surgery for a kidney problem. “I chose Oscar to do his surgery,” Esquivel said. “For a surgeon, to pick someone to do an operation on your own child means you think that surgeon is the best person in the world. And I did.”

In addition to his masterful surgical skills, Salvatierra also was a leading clinical researcher and the author of more than 300 papers. In the late 1970s and early 1980s he pioneered the use of donor specific blood transfusions in living donor kidney transplantation, a forerunner of bone marrow and kidney transplantation to induce tolerance.1

Salvatierra also made several important contributions to paediatric kidney transplantation, including developing methods that enabled small children successfully to receive adult kidneys.23 He helped pioneer an immune suppression protocol for paediatric kidney transplant recipients that avoided steroid drugs, which have harmful side effects in children.456

“So many of the techniques we now use in paediatric kidney transplantation are because of him,” said Waldo Concepcion, who succeeded Salvatierra as chief of paediatric kidney transplantation at Stanford’s Lucile Packard Children’s Hospital.

Late in his life, Salvatierra …
ATRT-06. ISPINESIB IS AN EFFICACIOUS THERAPEUTIC AGENT FOR ATYPICAL TERATOID RHABDOID TUMORS
Authors: Jia-Min Ho, Sekar Karthik, Jack M.F. Su, Qi Lin, YuChen Du, Jianhe Shen, Wing-Yuk Chow, Ching C Lau, Adesina Adekunle, Angela Major, Anat Erdreich-Epstein, M Tarek Elghetany, Kam-Man Hui, Xiaonan Li, Wan-Yee Teo
Journal: Neuro-Oncology (2019)

BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and deadly embryonal brain tumor in children. KIF11 is needed for formation of the bipolar spindle in metaphase. KIF11 suppression leads to prolonged mitotic arrest and subsequent cell death in mitosis. KIF11 inhibitors are currently in Phase 2 trials for recurrent myeloma. There are >20 high affinity, specific small-molecule KIF11 inhibitors, including ispinesib. Previously, ispinesib was reported to be effective in-vitro on 2 ATRT cell lines from a large screen on different tumor types, however there were no functional studies, nor in-vivo evaluation due to a lack of ATRT animal models. Our group has developed patient-derived orthotopic xenograft (PDOX) mouse models of ATRT in preclinical testing. AIMS: Our objectives were to (1) Evaluate in-vitro and in-vivo efficacy of ispinesib, (2) Investigate the functional mechanisms of ispinesib in ATRT. RESULTS: We discovered KIF11 was upregulated in patient ATRT tumors, compared to normal brain controls. In our cohort of 7 patient-derived tumor cell lines, we found 3 cell lines highly expressing KIF11. Ispinesib effectively inhibited tumor cell proliferation (Day 7 IC50 4nM-533nM) for 7 cell lines. Ispinesib concentration of 215nM demonstrated sustained time-dependent killing-effect on 5/7 cell lines. Ispinesib at only 10nM is highly effective against the most tumorigenic cell line, causing 80% cell death (Day 13) and induced G2/M arrest. In-vivo, this highly aggressive tumor model is lethal in all mice within 1 month of tumor implantation. By Day 29 of tumor implantation, 4/4 untreated mice (control) died. By Day 36, after 1 treatment-cycle (3 doses), 3/5 ispinesib-treated mice died. Two surviving ispinesib-treated mice underwent and completed 2nd treatment cycle (3 doses), these 2 mice died on Day 50 and Day 54. CONCLUSIONS: We are currently elucidating mechanisms of proliferation inhibition and cell death, and further evaluating in-vivo efficacy in our xenografts.
Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study
Authors: Noa Biran, David Siegel, Jesus G. Berdeja, Noopur Raje, Robert Frank Cornell, Melissa Alsina, Tibor Kovacsovics, Belle Fang, Amy S. Kimball, Ola Landgren
Journal: American Journal of Hematology (2019)

Twice-weekly carfilzomib (27 mg/m
EPEN-02. MULTIPLATFORM MOLECULAR PROFILING REVEALS INTRATUMOR HETEROGENEITY IN EPENDYMOMA
Authors: S John Liu, Stephen Magill, Harish Vasudevan, Stephanie Hilz, Vikas Daggubati, Javier Villanueva-Meyer, Abrar Choudhury, Sean Ferris, Brent Orr, Nancy Ann Oberheim Bush, Andrew Bollen, Michael McDermott, Joseph Costello, David Raleigh
Journal: Neuro-Oncology (2019)

OBJECTIVES: Ependymomas are associated with distinct anatomic, genomic and clinical characteristics, but the diversity of molecular features within individual ependymomas is unknown. Here, we perform multiplatform molecular profiling of 6 spatially- and radiographically-distinct regions of an ependymoma with C11orf95-RELA fusion to elucidate intratumor heterogeneity. METHODS: Immunohistochemistry, whole exome sequencing, 850k DNA-methylation profiling, RNA-seq, and quantitative MRI were performed to define the genomic and radiographic characteristics of stereotactically-collected regions of an ependymoma. Molecular phylogenetic analysis was performed using methylation- and DNA-based variants, and functional assays were conducted in cell culture. RESULTS: All ependymoma regions were diffusely positive for L1CAM and contained the pathogenic C11orf95-RELA fusion, but not YAP1 fusion, along with chromosome 11 chromothripsis. Principal component analysis of transcriptomic data identified three molecularly distinct regions corresponding to stem cell/proliferation (OLIG2), neuronal differentiation (LBX1, HDAC9), and immune/stress response (CXCL2, HSPA1A), each of which reflected transcriptional programs of distinct cell types in neural development. Furthermore, transcriptional heterogeneity correlated with differences in blood perfusion quantified by MRI. Phylogenetic analysis of methylation-derived CNVs and whole exome-derived SNVs revealed early chromosomal structural alterations followed by point mutations that distinguish various regions. A novel mutation in SETD2 was discovered in all regions, and overexpression of this novel mutant (SETD2K2R) led to increased cell proliferation and viability, suggesting that epigenetic misregulation could be a driver of ependymoma heterogeneity. CONCLUSION: Anaplastic ependymoma is associated with a previously unappreciated molecular heterogeneity that may influence tumorigenesis and design of molecular therapeutics.
Additional Approaches to Treatment of Depression
Authors: Nikolaos Kazantzis, Stefan G. Hofmann
Journal: JAMA (2019)

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DIPG-36. CLINICAL, RADIOLOGICAL, AND HISTO-MOLECULAR CHARACTERISTICS OF DIFFUSE INTRINSIC PONTINE GLIOMA IN PATIENTS WHO SURVIVE LESS THAN 3 MONTHS FROM DIAGNOSIS: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Nathan Dahl, Adam Lane, Pratiti Bandopadhayay, Jane Minturn, Andrew Dodgshun, Sara Parkin, Chie-Schin Shih, Tim Hassall, Jordan Hansford, Yvan Samson, LinBo Cai, Sarah Leary, Jie Ma, Ute Bartels, Cynthia Hawkins, Michelle Monje-Diesseroth, Paul Fisher, Karen Tsui, David Ziegler, Mariko DeWire-Schottmiller, Brooklyn Chaney, Katie Black, Renee Doughman, James Leach, Blaise Jones, Christine Fuller, Maryam Fouladi, Lindsey Hoffman
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is aggressive brainstem tumor with median survival of < 1 year. We queried data from the International DIPG Registry to define clinical, radiological, histological, and molecular characteristics of DIPG patients who survived < 3 months from diagnosis. Among 909 patients enrolled on the registry, 59 (6.5%) had overall survival (OS) of < 3 months. Median age at diagnosis was 5.8 years (range 0–13 years), and 12 (20%) were age < 3 years at diagnosis. Most presented with short duration of symptoms (< 6 weeks, 50/58; 86%) and at least one cranial nerve palsy, cerebellar sign, and/or pyramidal tract sign (52/54; 96%). Twenty-two (41%) presented with hydrocephalus, including 10 who required CSF diversion. All had extra-pontine extension on diagnostic imaging. Less than half of patients (25/56, 45%) received therapy; of these, 11 received radiation (RT) only, 12 received RT and chemotherapy, and 2 received chemotherapy only. Most received steroids (48/52; 92%), including 27 who received palliative steroids at the end of life. Biopsy and autopsy were performed in 11/57 (19%) and 13/58 (22%) cases, respectively. Of 22 for whom histology was known, 19 represented high-grade glioma subtypes, 2 low-grade gliomas, and 1 embryonal tumor. Six were molecularly characterized, and 3 harbored H3K27M mutations. Ongoing work will aim to further characterize the molecular features of these tumors with exceptional poor outcomes despite therapy.
Encapsulation of primary human hepatocytes and mesenchymal stromal cells in alginate to improve hepatic functions in hepatocyte transplantation
Authors: Valeria Iansante, Ragai R. Mitry, Emer Fitzpatrick, Sharon Lehec, Raquel Fernandez-Dacosta, Charlotte A. Lee, Simon Walker, Anil Chandrashekran, Anil Dhawan, Celine Filippi
Journal: Hepatology (2016)
ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients
Authors: Ignacio Martin-Loeches, Massimo Antonelli, Manuel Cuenca-Estrella, George Dimopoulos, Sharon Einav, Jan J. De Waele, Jose Garnacho-Montero, Souha S. Kanj, Flavia R. Machado, Philippe Montravers, Yasser Sakr, Maurizio Sanguinetti, Jean-Francois Timsit, Matteo Bassetti
Journal: Intensive Care Medicine (2019)
Dentists could help detect diabetes and cardiovascular disease during oral health checks
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Dentists could help to detect major health conditions linked to oral health, such as diabetes and cardiovascular disease, says the Faculty of Dental Surgery at the Royal College of Surgeons.

In a new position paper,1 the professional body said that dentists and oral health professionals have “clear opportunities” to spot certain conditions and to provide patients with preventive lifestyle advice. This comes in response to the …
Abstract MP17: Galectin-3 and Subsequent Risk of Lower-extremity Peripheral Artery Disease: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Kunihiro Matsushita, Chao Yang, Shoshana H Ballew, John W McEvoy, Maya Salameh, David Aguilar, Ron C Hoogeveen, Vigay Nambi, Elizabeth Selvin, Aaron R Folsom, Gerardo Heiss, Josef Coresh, Christie M Ballantyne
Journal: Circulation (2018)

Background: Galectin-3 is involved in the regulation of inflammation and the formation of fibrosis and has been liked to atherosclerosis. However, there are no studies investigating prospective associations of galectin-3 with incidence of lower-extremity peripheral artery disease (PAD). Methods: Among 9,827 ARIC participants without a history of PAD, we investigated whether galectin-3 (measured at visit 4 [1996-98]) was associated with incident clinical PAD through 2013, defined as hospitalizations with PAD diagnosis or leg revascularization. We defined PAD cases with rest pain or tissue loss as critical limb ischemia (CLI). We constructed Cox models with galectin-3 modeled categorically (quartiles) and continuously (log transformed). Results: During a median follow-up of 15.8 years, 287 participants developed PAD (105 incident CLI cases). In demographically adjusted models, galectin-3 demonstrated a dose-response association with incident PAD: hazard ratios (HRs) 2.55 (95% CI 1.80-3.61) and 1.69 (1.18-2.41) for the highest and second highest quartiles, as compared to the lowest quartile (Table; Model 1). Additional adjustment for traditional cardiovascular risk factors attenuated the associations, although the highest quartile remained borderline significant (HR 1.44 [0.99-2.07], p=0.051, Table: Model 2) and galectin-3 as a continuous variable remained significant (1.15 [1.02-1.29]). Similar results were observed for the association of galectin-3 with CLI. Conclusions: Galectin-3 was modestly associated with future risk of clinical PAD events in a community-based cohort, supporting the involvement of inflammation and fibrosis in the development of clinical PAD.
Abstract 712: The Right Atrium of Patients with Various Heart Diseases Retain Progenitor Cells with Regenerative Capacity
Authors: Ayelet Itzhaki-Alfia, Jonathan Leor, Shiri Netser, Leonid Sternik, David Mishaly, Jacob Lavee, Ehud Raanani, Israel M Barbash
Journal: Circulation (2007)

BACKGROUND: The notion that the adult human heart contains a pool of cardiac progenitor cells (hCPC) can be translated into an attractive approach to repair damaged hearts. However, significant amo...