tbuckley/cabot-search huggingface dataset:
Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4 + and CD8 + T cells—clinical applications in primary immunodeficiency diagnostics
Authors: Michael Bitar, Andreas Boldt, Stefanie Binder, Michael Borte, Karim Kentouche, Stephan Borte, Ulrich Sack
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 105: Increased Myocardial Sensitivity to Ischemic Injury in an Animal Model of Posttraumatic Stress Disorder
Authors: Boyd R Rorabaugh, Albert Bui, Sarah L Seeley, Anna Krivenko, Eric D Eisenmann, Megan E Fry, Joseph D Lawson, Lauren E Stoner, Phillip R Zoladz
Journal: Circulation Research (2015)

Background: Posttraumatic stress disorder (PTSD) is a psychological disorder characterized by the formation of traumatic memories following exposure to a life threatening event. In addition to psychological manifestations, PTSD promotes atherosclerosis and increases the incidence of myocardial infarction. However, it is unknown whether the effects of PTSD are limited to increasing the incidence of myocardial infarction or if PTSD also increases infarct severity. Therefore, we used an animal model of PTSD to determine whether posttraumatic stress influences infarct size and postischemic recovery of cardiac contractile function. Methods: Rats were subjected to a well-established animal model of PTSD that is based on predator exposure and psychosocial stress (Zoladz et al., Stress 11:259-281). Rats subjected to this model exhibit many PTSD-like characteristics including the formation of traumatic memories, increased anxiety, increased startle reflex, hypertension, and alterations in the hypothalamic-pituitary adrenal axis. Male rats (7 weeks of age) were either subjected to psychosocial stress (n = 9) or continuously housed in their home cages (n = 8) for 31 days. Hearts were subsequently isolated and subjected to 20 minutes of ischemia and 2 hours reperfusion on a Langendorff isolated heart system. Results: Stressed rats exhibited significantly elevated corticosterone concentrations and anxiety-like behavior in the elevated plus maze. Infarct sizes were significantly larger in hearts from stressed rats (44.7 ± 1.7 % of area at risk) compared to nonstressed rats (31.0 ± 5.4 % of area at risk). Consistent with increased myocardial injury, postischemic recovery of rate pressure product (stressed = 16,922 ± 1,554 mmHg*bpm; nonstressed = 26,407 ± 2,977 mmHg*bpm) and +dP/dT (stressed = 1,901 ± 189 mmHg/sec; nonstressed =3,259 ± 498 mmHg/sec) were significantly attenuated in hearts from stressed rats. Furthermore, postischemic end diastolic pressure was significantly elevated in hearts from stressed (57 ± 6 mmHg) compared to nonstressed (32 ± 7 mmHg) rats. Conclusion: This animal model suggests that PTSD may make the myocardium more sensitive to ischemic injury through a mechanism that is independent from its ability to promote atherosclerosis.
Promoting Compliance to Practice Guidelines May Improve Primary Care for Thyroid Diseases
Authors: Qianrui Li, Haoming Tian, Sheyu Li
Journal: JAMA Internal Medicine (2017)

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The combination of preoperative computed tomography lymphography and intraoperative fluorescence imaging navigation for sentinel lymph node biopsy of early breast cancer patients.
Authors: Hajime Abe, Atsuko Teramoto, Keiichi Yamasaki, Kohri Yoneda, Masao Ogawa, Masayasu Kawasaki, Masao Kameyama
Journal: Journal of Clinical Oncology (2017)

567 Background: This study investigated a usefulness of the combination of fluorescence imaging and computed tomography lymphography (CTLG) for sentinel lymph node biopsy (SLN) biopsy of early breast cancer patients. Methods: Between January 2013 and August 2016, 350 breast cancer patients without clinical evidence of lymph node metastasis were treated. Preoperaitve CTLG was performed using 64-row multidetector CT injected contrast agent. The contrasted lymph route and SLN were identified in reconstructed three-dimensional imaging. The SLN spot was indicated by CT laser light navigator system. We established typical pattern of the lymphography: stain defect of SLN, stagnation of lymphatic route for preoperative diagnosis of metastatic SLN. Intraoperative fluorescence images were obtained using the fluorescence imaging system (pde-neo). After dye mixed indocyanine green and indigocarmin was injected, lymphatic route was observed with fluorescence images. SLN biopsy was performed referring to the point by axillary compression technique by plastic device. Results: The median age of the 350 patients was 59 (range 28 – 90) years old. CTLG could visualize lymphatic route and accurately identify SLN in 336 (96.0 %) and 343 (98.0 %) cases, respectively, whereas fluorescence imaging identified successfully lymphatic route and SLN in all patients. Lymphatic routes of CTLG were completely consistent with those of fluorescence imaging. The number of SLN identified by CTLG was significantly lower than that by fluorescence imaging (1.1 vs. 1.6, p&lt;0.01). Fifty of 350 patients had metastatic SLN pathologically, and 11 of them had micrometastases of SLNs. The accuracy for metastatic diagnosis of SLN using CTLG without micrometastasis was 84.1 %, sensitivity was 82.1 % and specificity was 84.3 %. The positive predictive value was 40.5 % and negative predictive value was 97.3 %. Conclusions: This combined navigation method of fluorescence imaging and CTLG revealed more easy and effective to detect SLN than fluorescence imaging alone. In addition, the information from CTLG would be helpful for the preoperative diagnosis of SLN metastasis.
Pre‐fibrotic/early primary myelofibrosis vs. WHO‐defined essential thrombocythemia: The impact of minor clinical diagnostic criteria on the outcome of the disease
Authors: Georg Jeryczynski, Jürgen Thiele, Bettina Gisslinger, Albert Wölfler, Martin Schalling, Andreas Gleiß, Sonja Burgstaller, Veronika Buxhofer‐Ausch, Thamer Sliwa, Ernst Schlögl, Klaus Geissler, Maria‐Theresa Krauth, Alexander Nader, Michael Vesely, Ingrid Simonitsch‐Klupp, Leonhard Müllauer, Christine Beham‐Schmid, Heinz Gisslinger
Journal: American Journal of Hematology (2017)

The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
Trop2 gene expression (Trop2e) in primary breast cancer (BC): Correlations with clinical and tumor characteristics.
Authors: Neelima Vidula, Christina Yau, Hope S. Rugo
Journal: Journal of Clinical Oncology (2017)

1075 Background: Trophoblast antigen 2 (Trop2) is a glycoprotein expressed by many cancers. A phase I study of the trop2 antibody drug conjugate (ADC) IMMU-132 has shown promising activity in triple negative (TN) BC. We studied associations of primary BC trop2e with clinical characteristics, outcomes, and selected genes in publically available databases. Methods: Trop2e was evaluated with microarray data from the neoadjuvant I-SPY 1 (n=149), METABRIC (n=1992) &amp; TCGA (n=817) databases. Associations with clinical features were assessed with the Kruskal-Wallis test (all). Correlations with chemotherapy response were evaluated with the Wilcoxon rank sum test (I-SPY 1) &amp; with recurrence free survival (RFS) by the Cox proportional hazard model (I-SPY 1 &amp; METABRIC). Pearson correlations were used to study associations between trop2e &amp; selected genes (all). Results: In all 3 datasets, trop2 was detectable and had a wide range of expression in all BC subtypes. In I-SPY 1, trop2e did not vary by hormone receptor (HR) &amp; HER2 or intrinsic subtype; in METABRIC &amp; TCGA trop2e was lower in HER2+ than HR+/HER2- &amp; TNBC (METABRIC p=0.03, TCGA p=0.007) &amp; in HER2+ enriched and luminal B BC (p &lt; 0.001, METABRIC &amp; TCGA). Trop2e was higher in grade I vs. II/III BC in METABRIC (p &lt; 0.001). No association with chemotherapy response was seen (I-SPY 1) or with RFS (I-SPY 1 &amp; METABRIC). The table below shows significant (p&lt;0.05) gene correlations with trop2e in ≥2 datasets. Conclusions: Trop2e is seen in all BC subtypes, particularly luminal A and TNBC. Trop2e correlates with the expression of genes involved in cell epithelial transformation, adhesion, and proliferation and inversely with immune genes, which may contribute to tumor growth. These findings support the use of trop 2 directed ADC in all BC subtypes. [Table: see text]
Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups
Authors: A Burns, R Alsolami, J Becq, B Stamatopoulos, A Timbs, D Bruce, P Robbe, D Vavoulis, R Clifford, M Cabes, H Dreau, J Taylor, S J L Knight, R Mansson, D Bentley, R Beekman, J I Martín-Subero, E Campo, R S Houlston, K E Ridout, A Schuh
Journal: Leukemia (2017)

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.
NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation
Authors: Loïc Rolas, Abdelali Boussif, Emmanuel Weiss, Philippe Lettéron, Oualid Haddad, Jamel El-Benna, Pierre-Emmanuel Rautou, Richard Moreau, Axel Périanin
Journal: Gut (2017)

Objective Cirrhosis downregulates phagocyte oxidant production via their antibacterial superoxide-generating system, NADPH oxidase (NOX2) and increases patients’ susceptibility to infection and mortality rate. To explore novel biochemical parameters that explain susceptibility to infections, we investigated the expression of NOX2 and partners in neutrophils of patients with severe alcoholic cirrhosis and have provided a novel approach to restore superoxide production capacity in patients’ neutrophils and blood. Design Neutrophils were isolated from patients with decompensated alcoholic cirrhosis. NOX2 activity was assessed after stimulation of purified neutrophils or whole blood with the bacterial-derived peptide fMet-Leu-Phe. The expression of NOX2 and partners was studied by western blot analysis, flow cytometry and reverse transcription-PCR. Results The impaired superoxide production by patients’ neutrophils was associated with a severe deficient expression of the NADPH oxidase catalytic core flavocytochrome-b558 (gp91 phox /NOX2 and p22 phox ), its cytosolic partner p47 phox but not p67 phox . NOX2 expression decreased rapidly by protein degradation involving elastase released during degranulation of healthy neutrophils stimulated with fMet-Leu-Phe, or highly present in patients’ plasma. Interestingly, the deficient superoxide production was reversed by treatment of patients’ neutrophils and whole blood with toll-like receptor 7/8 (TLR7/8) agonists. This treatment stimulated a rapid NOX2 transcription and translation through a process involving mammalian target of rapamycin (mTOR) whose expression was also deficient in patients’ neutrophils. NOX2 expression was also increased by the TLR4 agonist lipopolysaccharide but with only a modest improvement of reactive oxygen species production. Conclusion Impairment of neutrophil oxidants production in alcoholic cirrhosis is associated with NOX2 degradation and deficient mTOR-dependent translational machinery. The NOX2 depletion can be reversed via TRL7/8 activation and might be used to restore antimicrobial responses of immunocompromised patients.
Whole Exome Sequencing from Nine Independent Sites of Extraosseous Disease in a Single Patient with Relapsed Multiple Myeloma Show That Extramedullary Disease Arise through a Combination of Branched and Parallel Evolution
Authors: Heather Landau, Jun Fan, Sergio A. Giralt, Jonathan U. Peled, Hani Hassoun, Alexander M. Lesokhin, Nikoletta Lendvai, Neha S Korde, Sham Mailankody, David J. Chung, Guenther Koehne, Eric L. Smith, Elli Papaemmanuil, Ola Landgren, Christine Iacobuzio-Donahue
Journal: Blood (2016)
The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia (ALL).
Authors: Shannon L. Maude, George E Hucks, Alix Eden Seif, Mala Kiran Talekar, David T. Teachey, Diane Baniewicz, Colleen Callahan, Vanessa Gonzalez, Farzana Nazimuddin, Minnal Gupta, Noelle V. Frey, David L. Porter, Bruce L Levine, Jan J. Melenhorst, Simon F. Lacey, Carl H. June, Stephan A. Grupp
Journal: Journal of Clinical Oncology (2017)

103 Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with relapsed B-ALL treated with murine (CTL019) or humanized (CTL119) anti-CD19 CAR T cells received 1-3 doses of the PD-1 inhibitor pembrolizumab (PEM) for partial/no response or prior history of poor CAR T cell persistence starting 14d-2mo post CAR T cell infusion. Results: PEM increased and/or prolonged detection of circulating CAR T cells in all 4 children, with objective responses in 2/4. It was well tolerated, with fever in 2 pts and no autoimmune toxicity. Pts 1-3 received CTL119 for CD19+ relapse after prior murine CD19 CAR T cells. Pt 1 had 1.2% CD19+ residual disease despite expansion with detectable CTL119 by D28 and received PEM at 2mo for progressive disease with decreasing circulating CTL119. CTL119 became detectable at 0.2% of CD3+ cells by flow cytometry, but disease progressed. Pt 2 had no response after initial CTL119 expansion with a rapid disappearance by D28. After CTL119 reinfusion with PEM added 14d later, circulating CAR T cells remained detectable at 4.4% by D28, but disease progressed with decreased CD19 expression. In Pt 3, prior treatment with both CTL019 and CTL119 produced CR with poor CAR T cell persistence followed by CD19+ relapse. CTL119 reinfusion combined with PEM at D14 resulted in CR with prolonged CTL119 persistence (detectable at D50 compared to loss by D36 after 1 st CTL119 infusion). Pt 4 received PEM for widespread extramedullary (EM) involvement at D28 post CTL019 infusion despite marrow remission. Initial CTL019 expansion peaked at 63% at D10 and fell to 20% at D28. Resurgence of CTL019 expansion, with a 2 nd peak of 70% 11d after PEM, was associated with dramatic reduction in PET-avid disease by 3mo post CTL019. Conclusions: PEM was safely combined with CAR T cells and increased or prolonged CAR T cell detection, with objective responses seen. Immune checkpoint pathways may impact response to CAR T cell treatments and warrant further investigation. Clinical trial information: NCT02374333, NCT02906371.
Treatments/clinical outcomes in ER+ HER2-negative breast cancer (BC) where treatment decisions were recurrence score (RS)-guided: Analysis by histologic subtype.
Authors: Salomon M. Stemmer, Mariana Steiner, Shulamith Rizel, Noa Ben Baruch, David B Geffen, Lior Soussan-Gutman, Avital Bareket-Samish, Bella Nisenbaum, Kevin Isaacs, Georgeta Fried, Ora Rosengarten, Beatrice Uziely, Christer Svedman, Debbie McCullough, Shmuel Klang, Ella Evron, Natalya Karminsky, Hadassah Goldberg, Steven Shak, Nicky Liebermann
Journal: Journal of Clinical Oncology (2017)

e12053 Background: The RS assay is widely used to guide treatment decisions in ER+ HER2-negative early BC regardless of tumor histology. However, the RS validation studies did not include an analysis by histologic subtype. We investigated treatments/clinical outcomes in RS-tested Clalit Health Services (CHS) patients (pts) by histologic subtype, focusing on invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). Methods: This exploratory analysis of the CHS cohort included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 through 12/2010 (N0) or 12/2011 (N1mi/N1). Data from medical records were analyzed to assess risks of distant recurrence and BC death by histologic subtype. Results: The cohort included 2510 pts: 2060 (82%) IDC, 298 (12%) ILC, and 152 (6%) unknown/others. Median follow up for IDC/ILC pts was 6.0/6.1 yrs. Median age in IDC/ILC pts was 60/62 yrs; median tumor size was 1.5/1.8 cm; 71%/71% were N0, and 29%/29% were N1mi/N1. RS distribution (&lt;18, 18-30, ≥31) was 50%, 39%, and 11%, respectively for IDC pts and 48%, 48%, and 4%, respectively, for ILC pts. Chemotherapy (CT) use for each RS group was similar between IDC and ILC pts; 5-yr Kaplan-Meier estimates for the risk of distant recurrence and BC death differed significantly across RS groups in both IDC and ILC; clinical outcomes for IDC and ILC pts were similar within risk groups see Table. Conclusions: For both IDC and ILC pts, treatment was aligned with the RS results. Within each RS group, there was no difference in clinical outcomes between these histologic subtypes, however the number of pts with ILC and RS≥31 was limited. [Table: see text]
Phase II study of eribulin with trasutuzumab for pretreated locally advanced or metastatic HER2-positive breast cancer.
Authors: Nobuyuki Tsunoda, Masaya Hattori, Toru Murata, Kazuhisa Akahane, Keitaro Kamei, Yasutomo Goto, Takeshi Amemiya, Kazumi Nishimae, Tomoyuki Kubota, Yuko Ito, Yasuhiro Kurumiya, Motoi Yoshihara, Kenichi Nakanishi, Toyone Kikumori, Masahiko Ando, Masato Nagino
Journal: Journal of Clinical Oncology (2017)

e12505 Background: Eribulin mesylate demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received 2 or more chemotherapy regimens. There are limited studies reported about the efficacy of eribulin with trastuzumab as first-line therapy for locally advanced or metastatic HER2-positive breast cancer. The aim of this study was to assess the efficacy and safety of eribulin with trastuzumab as late-line therapy for locally advanced or metastatic HER2-positive breast cancer. Methods: In this multicenter, phase II, single-arm study, patients with locally advanced or metastatic HER2 positive breast cancer who previously received at least one chemotherapeutic regimen, received eribulin at 1.4 mg/m 2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary end point was ORR, and secondary end points included PFS and safety. Results: Thirty-six patients (median age: 60.5 years) were enrolled. The median number of prior treatment regimens was 4 (range, 1‐8). Twenty-two patients (61.1%) had received prior pertuzumab treatment, 10 patients (27.8%) had prior T-DM1. Patients received a median of 6 cycles of eribulin with trastuzumab (2-13 cycles). The ORR was 17% (CR 0, PR 6) with median PFS of 4.6 months (3.3-7.0 months). The clinical benefit rate was 33%. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 22 (61%) patients, peripheral neuropathy in 3 (8%; all Grade 3) patients, fatigue in 1 (3%) patients. Five (13.9%) patients had asymptomatic LVEF decline. However, no grade 3 LVEF decline or symptomatic congestive heart failure was observed. The reasons for treatment discontinuation were disease progression in 27 (75%) patients and adverse events in 8 (22%) patients. Conclusions: Eribulin with trastuzumab is an acceptable option in late-line treatment for locally advanced or metastatic HER2-positive breast cancer. Clinical trial information: 000012350.
Development of classification criteria for discoid lupus erythematosus: Results of a Delphi exercise
Authors: Scott A. Elman, Cara Joyce, Filippa Nyberg, Fukumi Furukawa, Mark Goodfield, Minoru Hasegawa, Branka Marinovic, Jacek C. Szepietowski, Jan Dutz, Victoria P. Werth, Joseph F. Merola
Journal: Journal of the American Academy of Dermatology (2017)