tbuckley/cabot-search huggingface dataset:
Zero tolerance
Authors: Des Spence
Journal: BMJ (2008)

<h3>Abstract</h3> Recent innovations in droplet-based single-cell RNA-sequencing (scRNA-seq) have provided the technology necessary to investigate biological questions at cellular resolution. With the ability to assay thousands of cells in a single capture, pooling cells from multiple individuals has become a common strategy. Droplets can subsequently be assigned to a specific individual by leveraging their inherent genetic differences, and numerous computational methods have been developed to address this problem. However, another challenge implicit with droplet-based scRNA-seq is the occurrence of doublets - droplets containing two or more cells. The inaccurate assignment of cells to individuals or failure to remove doublets contribute unwanted noise to the data and result in erroneous scientific conclusions. Therefore, it is essential to assign cells to individuals and remove doublets accurately. We present a new framework to improve individual singlet classification and doublet removal through a multi-method intersectional approach. We developed a framework to evaluate the enhancement in donor assignment and doublet removal through the consensus intersection of multiple demultiplexing and doublet detecting methods. The accuracy was assessed using scRNA-seq data of ∼1.4 million peripheral blood mononucleated cells from 1,034 unrelated individuals and ∼90,000 fibroblast cells from 81 unrelated individuals. We show that our approach significantly improves droplet assignment by separating singlets from doublets and classifying the correct individual compared to any single method. We show that the best combination of techniques varies under different biological and experimental conditions, and we present a framework to optimise cell assignment for a given experiment. We offer <i>Demuxafy</i> (https://demultiplexing-doublet-detecting-docs.readthedocs.io/en/latest/index.html) - a framework built-in Singularity to provide clear, consistent documentation of each method and additional tools to simplify and improve demultiplexing and doublet removal. Our results indicate that leveraging multiple demultiplexing and doublet detecting methods improves accuracy and, consequently, downstream analyses in multiplexed scRNA-seq experiments.
A1.51 The AGC kinases protein kinase B (PKB) and serum and glucocorticoid kinase (SGK) differentially regulate the metabolic activity and inflammatory activation of rheumatoid arthritis fibroblast-like synoviocytes
Authors: L M Hartkamp, I E van Es, B Malvar Fernandez, P P Tak, K A Reedquist
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Phosphatidylinositol 3-kinase (PI3K) – dependent activation of PKB, and subsequent PKB phosphorylation and inactivation of FoxO transcription factors, is a critical regulator of cellular proliferation and survival. Constitutive activation of the PI3K/PKB pathway, and inactivation of FoxO proteins is observed in rheumatoid arthritis (RA) patient synovial tissue, and rescue of FoxO1 activity induces RA fibroblast-like synoviocyte (FLS) apoptosis. However, SGK, an AGC kinase related to PKB, can also target the same residues of FoxO proteins. Here, we sought to determine the relative contributions of PKB and SGK to RA FLS survival and inflammatory activation. <h3>Materials and Methods</h3> PKB and SGK isoform expression was detected by qRT-PCR and immunoblotting experiments on isolated cell populations. Effects of specific PKB (Akt inhibitor VIII) and SGK (GSK 650394) inhibitors on metabolic activity and IL6 production was assessed by MTT assay and ELISA, respectively. The influence of pharmacological inhibition of PKB or SGK on RA FLS expression of IL1 responsive genes was determined using low density qPCR arrays. Furthermore, effects of pharmacological targeting of PKB or SGK on RA FLS IL-1β- or PDGF-induced FoxO1 phosphorylation was assessed by immunoblotting. <h3>Results</h3> All PKB isoforms (<i>AKT1, AKT2, </i>and <i>AKT3</i>) were expressed at equivalent levels in RA FLS, while only <i>SGK1</i> and <i>SGK3</i>, but not <i>SGK2</i>, were detected. PKBi, but not SGKi, significantly decreased FLS mitochondrial activity. In contrast, only SGKi significantly reduced IL-1β-induced IL-6 production. Examining 84 genes induced by IL-1β in RA FLS, we found that PKBi suppressed transcription of <i>CCL7</i>, <i>CXCL6 CXCL9</i>, <i>CXCL10</i>, <i>CXCL11</i>, <i>IL1RN</i>, and <i>MMP13</i>, but enhanced <i>IL23A</i> and <i>TNFα</i> expression. SGKi enhanced <i>EREG</i> expression, but suppressed <i>CXCL10, CCL4,</i><i>CCL5</i>, <i>CSF3</i>, <i>IL6</i>, <i>MMP3</i>, <i>MMP7</i> and <i>VCAM1</i> expression. Neither compound interfered with IL-1β-induced FoxO1 phosphorylation at AGC kinase consensus sites. <h3>Conclusions</h3> Our results provide the first evidence for a role of SGK in the inflammatory activation of RA FLS, point to an unidentified third AGC kinase regulating FoxO1, and suggest that targeting distinct PI3K-dependent AGC kinases can preferentially modulate specific components of RA FLS activation.
Intraoperative Hand-Held Imaging γ-Camera for Sentinel Node Detection in Patients With Breast Cancer
Authors: Sotirios Chondrogiannis, Alice Ferretti, Enzo Facci, Maria Cristina Marzola, Lucia Rampin, Sara Tadayyon, Anna Margherita Maffione, Margherita Maffione, Domenico Reale, Roberto Mencarelli, Adriano Marcolongo, Domenico Rubello
Journal: Clinical Nuclear Medicine (2013)

This study aimed to assess the feasibility and potential usefulness of a new intraoperative portable high-resolution imaging γ-camera for the localization of sentinel lymph node in patients with breast cancer.Sixteen T1 to T2 breast cancer female patients were evaluated (mean age, 62 years) with preoperative lymphoscintigraphy, acquired 30 minutes after intradermal injection of 60 to 70 MBq (1.6-1.9 mCi) of (99m)Tc-nanocolloids in saline volumes of 0.1 to 0.2 mL. Surgery took place the day after (18-20 hours after tracer injection). For intraoperative sentinel lymph node localization, a traditional γ-probe was used by the surgeon. Moreover, a portable imaging γ-camera was used by the nuclear physician who was present in the operating room.The portable imaging γ-camera showed very high spatial resolution (2.4 mm) in the 4.4 × 4.4 cm(2) FOV, with a good sensitivity of 180 cps/MBq at a Plexiglas depth of 1 cm. In 11 patients, lymphoscintigraphy, γ-probe, and imaging γ-camera depicted the same number of radioactive lymph nodes (17 nodes; 5 of which were metastatic and detected in 6 different patients). In 6 patients, the portable imaging γ-camera detected 1 node more than lymphoscintigraphy (in total, 5 nodes more), one of which was metastatic (the only one metastatic in that patient).Our preliminary results showed that a portable high-resolution hand-held imaging γ-camera is a feasible, not time-consuming, noninvasive procedure in intraoperative sentinel node localization, offering extra confidence to the surgeon. In our hands, it was a very useful auxiliary imaging tool especially in the identification of nodes located deep in the axilla, which are difficult to detect at the preoperative lymphoscintigraphy. Additional multicenter studies involving a greater number of patients are necessary to confirm these promising data.
Reply to Dr. García-Cano
Authors: S. D. Johnston, T. C. Tham
Journal: Endoscopy (2004)

We appreciate the interest in our recent paper [1] by Dr. García-Cano. It would be worth commenting on whether there was echocardiographic evidence of preexisting impairment of left ventricular function and if there was a rise in troponin to suggest an acute ischaemic event. There is no mention of whether the patient was given intravenous fluids following endoscopic retrograde cholangiopancreatography (ERCP) or whether the rate of infusion might have been a contributing factor in precipitating pulmonary oedema. This case may suggest that a formal cardiovascular evaluation of patients with a previous cardiac history may be required before ERCP. It is reassuring to know that cardiopulmonary complications, such as this, are rare following ERCP in other institutions.
Bone Scintigraphy in a Case of Oncogenous Osteomalacia
Authors: HITOYA OHTA, SHIGEO NAKAISHI, SHOGO OKI, MASAHIRO SIMIZU, HIDEO WATANABE, SHIGEYOSHI FUJIKAWA, MASAHARU NAKADE, HIROYOSHI WATANABE, KEIJIRO KOHNO, MASAYUKI SHINTAKU
Journal: Clinical Nuclear Medicine (1998)

A 67-year-old man was admitted because of lumbar and knee pain. Bone scintigraphy revealed multifocal lesions of increased activity. Laboratory data showed hypophosphatemia, decreased 1,25-dihydroxyvitamin-D3 levels, and elevated alkaline phosphatase levels. Roent-genograms and CT scans disclosed a rib tumor, and surgical removal of the rib tumor revealed a phosphaturic mesenchymal tumor. The patient improved clinically, and laboratory values returned to normal. Repeated bone scintigraphy 11 months after surgery revealed markedly improved findings.
Abstract 265: EGFR positively regulates GBP1 expression to promote glioma cell invasion
Authors: Ming Li, Frank Furnari, Webster Cavenee
Journal: Cancer Research (2010)

Abstract Glioma is the most common and deadly human brain tumor. Epidermal growth factor receptor (EGFR) amplification or constitutively active mutation (EGFRVIII) is one of the most frequent genetic lesions in gliomas. To identify target genes regulated by EGFR signaling, we performed expression array analysis and found that human guanylate binding protein-1 (GBP1), a large GTPase that is induced by inflammatory cytokines, is one of the predominant genes induced by EGFR/EGF or EGFR VIII kinase activity. Our results demonstrate that EGF/EGFR signaling could dramatically induce GBP1 expression at both the mRNA and protein level through the p38 MAPK signaling cascade that is distinct from Stat1 signaling used by interferon γ. Moreover, we identified IRF1 and YY1 as downstream transcriptional regulator for GBP1 enhancement by EGFR/p38 signaling. Interestingly, we show that GBP1 is required for EGFR-mediated matrix metallopeptidase-1 (MMP1) expression, and plays a role in glioma cell invasion in vitro. Overexpression of GBP1 enhances glioma cell invasion through MMP1 induction, which was independent of GBP1 GTPase activity. In contrast, siRNA-mediated knockdown of GBP1 inhibited MMP1 expression and in turn blocked cell invasion as well. Consistently, we found that GBP1 is overexpressed and positively correlated with EGFR/EGFRVIII and MMP1 expression in human glioma clinical samples and glioma cell lines, particularly in neural subtypes of GBM as demonstrated by TCGA database analysis. Therefore, Our results suggest that the dysregulation of EGFR-mediated GBP1 expression may contribute to glioma invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 265.
Abstract 3896: New heat shock protein 90 inhibitors based on the 1,2,3-triazole structure
Authors: Giuseppe Giannini, Maurizio Taddei, Serena Ferrini, Domenico Alloatti, Tiziana Brunetti, Silvia Vincenti, Loredana Vesci, Massimo Castorina, Ferdinando Milazzo, Maria Luisa Cervoni, Marcella Barbarino, Mario Berardino Guglielmi, Claudio Pisano, Walter Cabri
Journal: Cancer Research (2012)

Abstract Hsp90 (heat shock protein 90) is a component of a molecular chaperone complex, involved in the folding, maturation and stabilisation of key signalling proteins which control cell proliferation, survival and transformation. It works by modulating a set of cancer-associated proteins, that are often over-expressed and/or mutated in tumor cells, collectively referred as ‘‘clients’’. Inhibition of Hsp90 causes destabilization and eventual degradation of client proteins involved in cell cycle, tumor growth, angiogenesis and apoptosis. Therefore, their modulation results in suppression of tumor growth by multiple parallel mechanisms. Consequently, inhibition of Hsp90 is believed to be a potential target for cancer therapy, also supported by a number of molecules currently under investigation in different phase of clinical trials. We recently synthesized 1,4,5-trisubstituted-1,2,3-triazole derivatives and surprisingly found that these new molecules demonstrated to be extremely active both on the biological target and on human tumor cell lines, even at nanomolar concentration. 3D QSAR analysis was also performed in order to rationalize HSP90 binding data. The overall profile of this new class of 1,2,3-triazoles, including stereoselective synthesis and a comprehensive pharmacological in vitro characterization, will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3896. doi:1538-7445.AM2012-3896
Healing and Heroism
Authors: H. Brownell Wheeler
Journal: New England Journal of Medicine (1990)

The centennial anniversary of this distinguished lecture series provides an opportunity to survey our profession from a long perspective, one that encompasses decades and perhaps even centuries. I would like to speak briefly about the physicians in the Shattuck family and then reflect at greater length on Sir William Osler, who was the fourth Shattuck Lecturer. I will consider what made Osler a hero to the public as well as to the medical profession, and why for a hundred years he has been regarded as the preeminent role model for a physician. A centennial anniversary is also a time to . . .
1225 FAT-1 TRANSGENIC MICE EXPRESSING AN OMEGA-3 FATTY ACID DESATURASE ARE PROTECTED FROM STEATOHEPATITIS
Authors: C. López-Vicario, E. Titos, A. González-Périz, B. Rius, E. Morán-Salvador, V. García-Alonso, M. Cofán, J.X. Kang, V. Arroyo, J. Claria
Journal: Journal of Hepatology (2012)
Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura
Authors: Flora Peyvandi, Marie Scully, Johanna A. Kremer Hovinga, Spero Cataland, Paul Knöbl, Haifeng Wu, Andrea Artoni, John-Paul Westwood, Magnus Mansouri Taleghani, Bernd Jilma, Filip Callewaert, Hans Ulrichts, Christian Duby, Dominique Tersago
Journal: New England Journal of Medicine (2016)

Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high.Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses.Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.Caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.).
Septic Subclavian Vein Thrombosis Complicating Hemodialysis
Authors: GAYLA J. HERBEL, MICHAEL F. HARTSHORNE, ANTONIOS H. TZAMALOUKAS
Journal: Clinical Nuclear Medicine (2002)

HERBEL, GAYLA J. M.D.; HARTSHORNE, MICHAEL F. M.D.; TZAMALOUKAS, ANTONIOS H. M.D. Author Information
AB1245 Aortitis: Diagnosis by positron emission tomography (PET):
Authors: C. Bejerano, R. Blanco, J. Calvo, J. Narváez, E. Peirό, I. Pérez-Martín, J. Alonso, J. Rueda-Gotor, A. Corrales, J.L. Peña, I. Martínez, J.M. Carril, M.A. González-Gay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Non-infectious aortitis is often an underdiagnosed and potentially serious clinical entity. Although giant cell arteritis (GCA) is considered to be the most common cause of aortitis, it may also be idiopathic or associated with other conditions. Clinical manfiestations are frequently nonspecifc leading to inapropriate delay to the diagnosis. <h3>Methods</h3> Multicenter study of three hospitals of patients diagnosed as having aortitis by F18-FDG PET. <h3>Results</h3> Twelve patients (8 women/4 men) with a mean age of 68.4±12.7 years were diagnosed with aortitis by F18-FDG PET (TABLE). The median [interquartile range] of delay to the diagnosis was 12 [2-20] months. Aortitis was idiopathic (5 cases), associated with biopsy-proven GCA (n=4), Sarcoidosis (n=1), Ulcerative Colitis (n=1), and Takayasu arteritis (n=1). The most frequent symptoms were: A) Polymyalgia rheumatica (PMR) in 8 cases (67%), that was atypical in 5 of them. B) Fever and/or general syndrome in 6 cases (50%). And C) Severe low back pain in 4 cases (33%). Laboratory data disclosed anemia in all cases and high ESR in most cases (78.1±38.3 mm/1st hour). PET showed involvement of A) the whole aorta, thoracic aorta and/or supra-aortic vessels in 91% and B) involvement of arteries of the lower extremities in 50%. <h3>Conclusions</h3> F18 FDG-PET is a useful tool to confirm the diagnosis of aortitis. Atypical PMR, non-specific general syndrome, and/or unexplained severe low back pain along with anemia and elevated ESR may be red flags to suspect this condition. <h3>Disclosure of Interest</h3> None Declared
THU0408 Deep inspiratory breath hold PET/CT is useful for monitoring of activity in rheumatic disease associated lung interstitial pneumonitis
Authors: T. Uehara, M. Takeno, K. Terauchi, D. Kishimoto, K. Takase, M. Hama, A. Ihata, A. Ueda, Y. Ishigatsubo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> This study examined contributions of deep inspiratory breath hold (DIBH) -FDG-PET/CT to clinical assessment of ILD in collagen diseases. <h3>Methods</h3> We assessed ILD in 45 patients with collagen diseases including 6 RA, 9 SSc, and 17 DM/PM by using DIBHPET/CT. Distribution of positive signals was evaluated in the upper slice 2cm above the tracheal bifurcation, the middle slice 1 cm below the bifurcation, and the lower slice 2 cm above the right diaphragm. Individual slices were further divided into 6 regions. Visual score was determined by numbers of positive signal lesions in total 18 regions. <h3>Results</h3> Abnormal accumulation of FDG was found in the active ILD lesions which were concordant with nodular, reticular, consolidative shadows and ground glass opacity illustrated by plain CT scan. The visual score in the lesions was well correlated with serum levels of KL-6 (Pearson ρ=0.571, P=0.011) and CRP (Spearman ρ=0.506, P=0.016). The value was significantly higher in 26 patients who were judged as being clinically active than the other 19 patients. Of 24 patients who had follow-up examinations, abnormal FDG accumulation was reduced in response to the therapies in 11 patients, whereas the findings were unchanged or deteriorated in the remaining 13 patients who had stable or progressive ILD. In spite of no interval change in plain CT scan, PET/CT detected significant changes of FDG intensity in the follow-up studies in 5 patients. FDG signal was reduced in 4 of them, whereas it was increased in one patient. <h3>Conclusions</h3> In summary, DIBH PET/CT is useful for monitoring of activity in collagen disease associated ILD. <h3>Disclosure of Interest</h3> None Declared
Bone Mineral Density in Women with Depression
Authors: David Michelson, Constantine Stratakis, Lauren Hill, James Reynolds, Elise Galliven, George Chrousos, Philip Gold
Journal: New England Journal of Medicine (1996)

Depression is associated with alterations in behavior and neuroendocrine systems that are risk factors for decreased bone mineral density. This study was undertaken to determine whether women with past or current major depression have demonstrable decreases in bone density.We measured bone mineral density at the hip, spine, and radius in 24 women with past or current major depression and 24 normal women matched for age, body-mass index, menopausal status, and race, using dual-energy x-ray absorptiometry. We also evaluated cortisol and growth hormone secretion, bone metabolism, and vitamin D-receptor alleles.As compared with the normal women, the mean (+/-SD) bone density in the women with past or current depression was 6.5 percent lower at the spine (1.00+/-0.15 vs. 1.07+/-0.09 g per square centimeter, P=0.02), 13.6 percent lower at the femoral neck (0.76+/-0.11 vs. 0.88+/-0.11 g per square centimeter, P<0.001), 13.6 percent lower at Ward's triangle (0.70+/-0.14 vs. 0.81+/-0.13 g per square centimeter, P<0.001), and 10.8 percent lower at the trochanter (0.66+/-0.11 vs. 0.74+/-0.08 g per square centimeter, P<0.001). In addition, women with past or current depression had higher urinary cortisol excretion (71+/-29 vs. 51+/-19 micrograms per day [196+/-80 vs. 141+/-52 nmol per day], P=0.006), lower serum osteocalcin concentration (P=0.04), and lower urinary excretion of deoxypyridinoline (P=0.02).Past or current depression in women is associated with decreased bone mineral density.