tbuckley/cabot-search huggingface dataset:
World Health Organization‐defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management
Authors: Jason Gotlib
Journal: American Journal of Hematology (2017)

Abstract Disease overview The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end‐organ damage. Diagnosis Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm 3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ ‐hybridization, flow immunocytometry, and T‐cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi‐molecular classification scheme of disease subtypes which includes the major category “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA , PDGFRB , or FGFR1 or with PCM1‐JAK2 ,” and the “MPN subtype, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte‐variant hypereosinophilia is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. Risk‐adapted therapy The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g., &lt; 1500/mm 3 ) without symptoms or signs of organ involvement, a watch and wait approach with close‐follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant hypereosinophilia and HES. Hydroxyurea and interferon‐alpha have demonstrated efficacy as initial treatment and steroid‐refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin‐5 (IL‐5) (mepolizumab), the IL‐5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils remains an active area of investigation.
P144 Effect of low-dose ionizing radiation on the inflammatory phenotype of adipocytes and differentiation of osteoclasts (in vitro)
Authors: K Shreder, F Rapp, D Kraft, S Hassan, C Fournier
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Adipose tissue is a complex endocrine organ that produces a variety of immune and inflammatory mediators. Adipocytes, the dominant cell type of adipose tissue, are known to support inflammatory processes in muskuloskeletal diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA) by release of different cytokines and adipokines. During this process, osteoclastogenesis is also enhanced and results in an imbalance of bone metabolism. Low-dose radiation therapy (LD-RT) is known to attenuate inflammation and to increase the mobility of patients suffering from RA or OA.<sup>1</sup> <h3>Objectives</h3> In our previous work, we observed a decrease of visfatin levels in serum of patients treated with low-dose ionizing radiation during exposure to the alpha-emitter radon.<sup>2</sup> In the same study, a decrease of markers for bone resorption after radon exposure was detected. Based on this, we next compared the response of human adipocytes derived from subcutaneous and infrapatellar adipose tissue to ionizing radiation with respect to release of adipokines and other inflammatory factors (IL-6, IL-8). In parallel, we analyzed the effect of ionizing radiation on differentiation capacity of osteoclast (OC) precursors into mature, bone resorbing OC. <h3>Methods</h3> Human subcutaneous predipocytes and human infrapatellar preadipocytes were irradiated with different doses of ionizing radiation, and release of inflammatory factors was measured in the cell culture supernatants using ELISA. OC precursors were isolated from human donor blood, differentiated according to standard protocols and analyzed by fluorescent stainings for cell nuclei, tartrate-resistant acidic phosphatase (TRAP) and actin filaments. <h3>Results</h3> The results revealed that the release of adipokines and inflammatory cytokines (IL-6, IL-8) was not significantly affected by ionizing radiation. Further, it was found that differentiation of OC precursor cells into mature OC is reduced after irradiation. <h3>Conclusions</h3> The observations made in this study suggest that adipocytes are probably not the main source of modified adipokine levels in the arthritic joint. However, an observed tendency of adipocytes to increase fat accumulation after irradiation suggests radiation-induced changes in functionality of human adipocytes which could have an indirect impact on the radiation response of the tissue. OC respond to radiation by reduced differentiation and structural changes, but the impact on functionality needs to be further tested. <h3>References</h3> Frey B, <i>et al. Cancer Lett</i> 2015;368:230–237. Cucu A, Shreder K, <i>et al. Front Immunol</i> 2017;8:1–9. <h3>Acknowledgements</h3> German Federal Ministry of Education and Research (02NUK017A). <h3>Disclosure of Interest</h3> None declared.
Abstract 5107: Phenotypic characterization of circulating tumor cells (CTCs) in triple negative breast cancer patients.
Authors: Galatea Kallergi, Haris Markomanolaki, Dimitrios Mavroudis, Vassilis Georgoulias, Sofia Agelaki
Journal: Cancer Research (2013)

Abstract Triple negative (ER-negative, PR-negative, HER2-negative) considered as poor prognosis breast cancer patients without many therapeutic options. Circulating Tumor Cells (CTCs) have been proposed as a “real time liquid biopsy” in breast cancer patients. CTCs are associated with disease relapse and could serve as a target for molecular cancer therapies. The aim of the present study was the phenotypic characterization of CTCs in triple negative patients to explore new therapeutic strategies for these patients. We evaluated peripheral blood mononuclear cells (PBMC) cytospins from 29 triple negative patients, before the initiation of adjuvant (19 early) and front-line (10 metastatic) treatment. The expression of Cytokeratins (CK) (marker for CTCs), Estrogen Receptor (ER), Progesterone Receptor (PR), EGFR and HER2 in CTCs was assessed using double immunofluorescent experiments. Our results revealed that median expression per patient for ER, PR, EGFR and HER2 was 16.7%, 0%, 42.9% and 91.4%. The respective numbers for early versus (vs) metastatic patients were 29.7% vs 0% for ER, 27.1% vs 0% for PR, 70.8% vs 52.3% for EGFR and 50% vs 48.7% for HER2. In addition ER, PR, EGFR and HER2 were expressed in 33.1%, 28%, 67.7% and 45.1%, respectively, of the total examined CTCs. Triple staining experiments with the Ariol system could not revealed any no co-expression of CK/EGFR/ER in CTCs; however, there was only one patient with CTCs co-expressing CK/HER2/ER. Consequently in order to identify whether chemotherapy could induce phenotypic changes of CTCs, 18 patients were analyzed after the completion of adjuvant treatment. ER, PR, EGFR and HER2 median expression per patients was identified in 0.2%, 15.2%, 66.7%, and 50% suggesting that adjuvant chemotherapy does not significantly influence the phenotype of CTCs in triple negative patients.The majority of CTCs in triple negative patients revealed expression of HER2 and EGFR implying that these receptors could be a potential target for the limitation of metastasis in these patients. Citation Format: Galatea Kallergi, Haris Markomanolaki, Dimitrios Mavroudis, Vassilis Georgoulias, Sofia Agelaki. Phenotypic characterization of circulating tumor cells (CTCs) in triple negative breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5107. doi:10.1158/1538-7445.AM2013-5107
Outcomes of Allogeneic Stem Cell Transplantation for AML and MDS Based on Pre-Transplant MRD Status By Next-Generation Sequencing
Authors: Benjamin M Manning, Robyn T Sussman, Safoora Deihimi, Noelle V. Frey, Elizabeth O. Hexner, Alison W. Loren, Selina Luger, James K. Mangan, Mary Ellen Martin, Shannon R. McCurdy, Jennifer J.D. Morrissette, Alexander E. Perl, Edward A. Stadtmauer, David L. Porter, Saar I. Gill
Journal: Blood (2018)
Poly(ethylene glycol)-block-poly(d,l-lactic acid) micelles containing oligo(lactic acid)8-paclitaxel prodrug: In Vivo conversion and antitumor efficacy
Authors: Yu Tong Tam, Dae Hwan Shin, Karen E. Chen, Glen S. Kwon
Journal: Journal of Controlled Release (2019)

Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles affect drug solubilization, and a paclitaxel (PTX) loaded-PEG-b-PLA micelle (PTX-PM) is approved for cancer treatment due to injection safety and dose escalation (Genexol-PM®) compared to Taxol®. However, PTX-PM is unstable in blood, has rapid clearance, and causes dose-limiting toxicity. We have synthesized a prodrug for PTX (7-OH), using oligo(lactic acid) as a novel pro-moiety (o(LA)8-PTX) specifically for PEG-b-PLA micelles, gaining higher loading and slower release of o(LA)8-PTX over PTX. Notably, o(LA)8-PTX prodrug converts into PTX by a backbiting reaction in vitro, without requiring esterases. We hypothesize that o(LA)8-PTX-loaded PEG-b-PLA micelles (o(LA)8-PTX-PM) has a lower Cmax and higher plasma AUC than PTX-PM for improved therapeutic effectiveness. In Sprague-Dawley rats at 10 mg/kg, compared to o(LA)8-PTX-PM (10% w/w loading) and PTX-PM (10%), o(LA)8-PTX-PM (50% w/w loading) produces a 2- and 3-fold higher plasma AUC0–24 of PTX, lactic acid-PTX, and o(LA)2-PTX (o(LA)0-2-PTX), respectively. For o(LA)8-PTX-PM at 10 and 50% w/w loading, PTX and lactic acid-PTX are major bioactive metabolites, respectively. Fast prodrug conversion of o(LA)8-PTX in vivo versus in vitro (by backbiting) suggests that o(LA)8 is a good substrate for esterases. At 60 mg/kg (qwx3), o(LA)8-PTX-PM (50%) has higher antitumor activity than o(LA)8-PTX-PM (10%) and PTX-PM (10%) in a syngeneic 4T1-luc breast tumor model based on measurements of tumor volume, 4T1-luc breast tumor bioluminescence, and survival. Importantly, intravenous administration of o(LA)8-PTX-PM is well tolerated by BALB/c mice. In summary, oligo(lactic acid)8-PTX is more compatible than PTX with PEG-b-PLA micelles, more stable, and may expand the role of PEG-b-PLA micelles from "solubilizer" into "nanocarrier" for PTX as a next-generation taxane for cancer.
Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis
Authors: Weicang Wang, Jun Yang, Matthew L. Edin, Yuxin Wang, Ying Luo, Debin Wan, Haixia Yang, Chun-Qing Song, Wen Xue, Katherine Z. Sanidad, Mingyue Song, Heather A. Bisbee, Jennifer A. Bradbury, Guanjun Nan, Jianan Zhang, Pei-an Betty Shih, Kin Sing Stephen Lee, Lisa M. Minter, Daeyoung Kim, Hang Xiao, Jun-Yan Liu, Bruce D. Hammock, Darryl C. Zeldin, Guodong Zhang
Journal: Cancer Research (2019)

Abstract Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis in vivo. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer. Significance: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis.
Teaching Pelvic Examination Under Anesthesia Without Patient Consent
Authors: Eli Y. Adashi
Journal: JAMA (2019)

guidelines reaffirm the use of the pooled cohort equations for the US population, and state that they should be used as a "starting point, not as the final arbiter, for decisionmaking in primary prevention of ASCVD."To address the uncertainties and to help provide more information to patients who are on the fence about statins, there's new advice for people with LDL-C levels of 70 mg/dL or higher and a 10-year ASCVD risk of 7.5% through 19.9%.Among these intermediate-risk patients, "risk-enhancing" factors can tip the decision-making scales in favor of statins, according to
The Capicua/ETS Translocation Variant 5 Axis Regulates Liver‐Resident Memory CD8+ T‐Cell Development and the Pathogenesis of Liver Injury
Authors: Sungjun Park, Jiho Park, Eunjeong Kim, Yoontae Lee
Journal: Hepatology (2019)

Liver-resident memory T (liver TRM ) cells exert protective immune responses following liver infection by malaria parasites. However, how these TRM cells are developed and what the consequence is if they are not properly maintained remain poorly understood. Here, we show that the transcriptional repressor, Capicua (CIC), controls liver CD8+ TRM cell development to maintain normal liver function. Cic-deficient mice have a greater number of liver CD8+ TRM cells and liver injury phenotypes accompanied by increased levels of proinflammatory cytokine genes in liver tissues. Excessive formation of CD69+ CD8+ TRM -like cells was also observed in mice with acetaminophen-induced liver injury (AILI). Moreover, expansion of liver CD8+ TRM cell population and liver injury phenotypes in T-cell-specific Cic null mice were rescued by codeletion of ETS translocation variant [Etv]5 alleles, indicating that Etv5 is a CIC target gene responsible for regulation of CD8+ TRM cell development and liver function. We also discovered that ETV5 directly regulates expression of Hobit, a master transcription factor for TRM cell development, in CD8+ T cells. Conclusion: Our findings suggest the CIC-ETV5 axis as a key molecular module that controls CD8+ TRM cell development, indicating a pathogenic role for CD8+ TRM cells in liver injury.
SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain
Authors: Paul B. Sinclair, Sarra Ryan, Matthew Bashton, Shaun Hollern, Rebecca Hanna, Marian Case, Edward C. Schwalbe, Claire J. Schwab, Ruth E. Cranston, Brian D. Young, Julie A. E. Irving, Ajay J. Vora, Anthony V. Moorman, Christine J. Harrison
Journal: Leukemia (2019)

In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.
Induction Therapy with Bortezomib and Dexamethasone and Conditioning with High-Dose Melphalan and Bortezomib Followed By Autologous Stem Cell Transplantation for AL Amyloidosis: Long Term Follow-up Analysis
Authors: Vishal K Gupta, Dina Brauneis, Anthony C Shelton, Karen Quillen, John Mark Sloan, Vaishali Sanchorawala
Journal: Blood (2018)
Effects of Light Therapy on Mood and Insulin Sensitivity in Patients With Type 2 Diabetes and Depression: Results From a Randomized Placebo-Controlled Trial
Authors: Annelies Brouwer, Daniel H. van Raalte, Hoang-Ton Nguyen, Femke Rutters, Peter M. van de Ven, Petra J.M. Elders, Annette C. Moll, Eus J.W. Van Someren, Frank J. Snoek, Aartjan T.F. Beekman, Marijke A. Bremmer
Journal: Diabetes Care (2019)

OBJECTIVE Depression is common in patients with type 2 diabetes and adversely affects quality of life and diabetes outcomes. We assessed whether light therapy, an antidepressant, improves mood and insulin sensitivity in patients with depression and type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, placebo-controlled trial included 83 patients with depression and type 2 diabetes. The intervention comprised 4 weeks of light therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and insulin sensitivity (M-value derived from the results of a hyperinsulinemic-euglycemic clamp). Secondary outcomes were related psychological and glucometabolic measures. RESULTS Intention-to-treat analysis showed that light therapy was not superior to placebo in reducing depressive symptoms (−3.9 IDS points [95% CI −9.0 to 1.2]; P = 0.248) and had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI −0.41 to 0.70]; P = 0.608). Analyses incorporating only those participants who accurately adhered to the light therapy protocol (n = 51) provided similar results, but did suggest positive effects of light therapy on depression response rates (≥50% reduction in IDS points) (26% more response; P = 0.031). Prespecified analysis showed effect moderation by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication (P = 0.023). Light therapy did not affect depressive symptoms in participants with higher insulin sensitivity or those who use only oral glucose-lowering medication or none at all, but it did produce a relevant effect in participants with lower insulin sensitivity (−12.9 IDS points [95% CI −21.6 to −4.2]; P = 0.017) and a trend toward effectiveness in those using insulin (−12.2 IDS points [95% CI −21.3 to −3.1]; P = 0.094). Light therapy was well tolerated. CONCLUSIONS Although this trial is essentially inconclusive, secondary analyses indicate that light therapy might be a promising treatment for depression among a subgroup of highly insulin-resistant individuals with type 2 diabetes.
P009/O22 Transcriptomics unveils unique biological profile of tertiary lymphoid structures germinal centers
Authors: S Colafrancesco, E Pipi, J Campos, S Nayar, V Iannizzotto, R Priori, G Valesini, B Fisher, F Barone
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> The development of the B cell repertoire is regulated by the process of affinity maturation that occurs within the inner part of the B cell follicles within secondary lymphoid organs (SLOs). In autoimmunity process might occur in ectopic lymphoid structures (ELS), aggregates of lymphocytes that form in target organs of disease (i.e. the salivary glands of patients with Sjogren's Syndrome (SS)). The phenotypical and functional features supporting ELS pathogenic properties have not been identified. Moreover, the functional proof that ELS independently from SLOs contribute to the autoimmune response has not been provided. <h3>Objectives</h3> To characterise the transcriptome profile of human ELS isolated from SS salivary glands in comparison with SLO and to dissect, in an animal model of ELS development, the ability of ELS to contribute to the autoreactive response. <h3>Methods</h3> Frozen salivary gland biopsies were obtained from SS patients and selected for presence of germinal center +ELS. Samples were stained and microdissected, RNA isolated and transcribed and used for RNAseq using ClonTech SMARTseq v4 kit. Salivary gland ELS and autoimmunity was established as previoully described<sup>1</sup> in FAP-DTR mice. Animals were locally treated (day 2 and 6) with DTX to induce selective ELS disaggregation; glands and serum were harvested for analysis at day 15. <h3>Results</h3> Transcript analysis provide evidence that the ectopic ELS are characterised by upregulation of TNF, INFg, BAFF, APRIL, CXCL12 and CXCL13, FAS and FASL as compared to SLOs. Sequencing unveiled an alterated cell-proliferation profile with downregulation of BCL6 and AID, the enzymes responsible for B cell affinity maturation. Selective depletion of FAP +cells induced loss of anatomical segregation of ELS and profoundly compromised their anatomy with significant impact on the local autoimmune response. <h3>Conclusions</h3> Our study provides the first evidence of a significant molecular difference between ELS and SLOs. We demonstrated that, although characterised by similar anatomical organization, ELS pathogenic cytokine signature is associated with low levels of bcl6 and AID and aberrant apoptosis, unveiling impaired regulation of the B cell cycle, responsible for the survival of autoreactive, poorly selected B cell clones. Accordingly, selective depletion of ELS <i>in vivo</i> profoundly impact local and systemic autoimmunity. <h3>Reference</h3> Barone F, <i>et al. PNAS</i> 2015. <h3>Disclosure of Interest</h3> None declared.
Using a Developmental Ecology Framework to Align Fear Neurobiology Across Species
Authors: Bridget Callaghan, Heidi Meyer, Maya Opendak, Michelle Van Tieghem, Chelsea Harmon, Anfei Li, Francis S. Lee, Regina M. Sullivan, Nim Tottenham
Journal: Annual Review of Clinical Psychology (2019)

Children's development is largely dependent on caregiving; when caregiving is disrupted, children are at increased risk for numerous poor outcomes, in particular psychopathology. Therefore, determining how caregivers regulate children's affective neurobiology is essential for understanding psychopathology etiology and prevention. Much of the research on affective functioning uses fear learning to map maturation trajectories, with both rodent and human studies contributing knowledge. Nonetheless, as no standard framework exists through which to interpret developmental effects across species, research often remains siloed, thus contributing to the current therapeutic impasse. Here, we propose a developmental ecology framework that attempts to understand fear in the ecological context of the child: their relationship with their parent. By referring to developmental goals that are shared across species (to attach to, then, ultimately, separate from the parent), this framework provides a common grounding from which fear systems and their dysfunction can be understood, thus advancing research on psychopathologies and their treatment.