tbuckley/cabot-search huggingface dataset:
Abstract 5201: Using Taqman assays to verify eQTL links arising from GWAS studies
Authors: Stephen M. Jackson, Harita Veereshlingham, Kamini Varma
Journal: Cancer Research (2019)

Abstract Tremendous progress has been made using genome-wide association studies (GWAS) to link genetic variation with phenotypes and pathologies. In spite of these success, it has been estimated that as many as 90% of SNPs identified in GWAS studies map to non-coding regions, complicating the mechanistic interpretation of the results. It is thought that these non-coding SNPs fall into regulatory regions and influence the expression of a gene or genes. The study of expression quantitative trait loci (eQTLs) provides a method for understanding the link between genetic variants and altered gene expression, and could potentially provide new insights connecting GWAS results to molecular mechanisms. To illustrate how eQTLs can be found and verified, we generated transcriptomic information from various tumor samples using Applied Biosystems’ Clariom D microarrays. We also generated SNP genotyping data from the same samples using Applied Biosystems’ Axiom UK Biobank microarrays. To find putative eQTLs, we compared the SNPs genotypes and the gene expression levels in these samples to the GTEx database. Potential eQTLs in this set of samples were verified using Applied Biosystems’ Taqman SNP Genotyping and Taqman Gene Expression assays. We therefore illustrate a workflow where candidate eQTLs can be confirmed and screened in larger cohorts using the more economical qPCR reagents available from Applied Biosystems. Citation Format: Stephen M. Jackson, Harita Veereshlingham, Kamini Varma. Using Taqman assays to verify eQTL links arising from GWAS studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5201.
Prevalence of pulmonary hypertension in pulmonary sarcoidosis: the first large European prospective study
Authors: Marloes P. Huitema, Annelies L.M. Bakker, Johannes J. Mager, Benno J.W.M. Rensing, Fokko Smits, Repke J. Snijder, Jan C. Grutters, Marco C. Post
Journal: European Respiratory Journal (2019)

<b>The prevalence of pulmonary hypertension in sarcoidosis seems to differ between ethnicities and was never investigated in a Caucasian cohort. This study shows a prevalence of 3% in a Caucasian cohort, significantly lower compared to other ethnicities.</b>http://bit.ly/2kRMrap
Decrease in blood pressure during continuous positive airway pressure treatment for obstructive sleep apnoea: still searching for predictive factors
Authors: Oreste Marrone, Maria R. Bonsignore
Journal: European Respiratory Journal (2019)

High blood pressure (BP) and non-dipping 24-hour BP profile may help to predict BP decrease after obstructive sleep apnoea treatment by CPAP.However, specific, highly reproducible traits associated with BP responsiveness to CPAP must still be identified.http://bit.ly/
First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: Michael Anthony Carducci, Montaser F. Shaheen, Channing Judith Paller, Julie E. Bauman, Nilofer Saba Azad, Poornima Shubhakar, Rui Tang, Mark Stroh, Gregory R. Friberg, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2012)

3009 Background: Aurora kinases A, B, and, C play essential roles in regulating cell division. Overexpression of aurora A and B in human tumors is associated with high proliferation rates and poor prognosis. AMG 900 is an investigational, orally administered, highly selective inhibitor of aurora A, B, and C that demonstrated activity in drug-resistant cell lines and human tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 900. Methods: Key eligibility criteria: ≥ 18 years old, advanced solid tumors, measurable disease, ECOG ≤ 2, and adequate organ function. AMG 900 was administered orally daily for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation phase, the starting dose was 1 mg and was escalated by 100% in subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation continued in a standard 3+3 design at ≤ 25% if DLT occurred or ≤ 50% if G2 related toxicity occurred. The maximum tolerated dose (MTD) was determined without prophylactic G-CSF support. Results: As of OCT 2011, 19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 mg) had received ≥ 1 dose of AMG 900. Demographics were 58% women, median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 DLTs: G4 neutropenia &gt; 7 days at 24 mg (n=1) and 30 mg (n=1); G4 neutropenia &gt; 7 days + G4 thrombocytopenia at 30 mg (n=1); and febrile neutropenia (FN) at 30 mg (n=1). MTD without G-CSF support was 24 mg. 89% of pts had treatment-related adverse events (AEs). G≥3 treatment-related AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 (11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed no obvious departures from dose-proportionality with a half-life of ~16 h. Tumor-response data were available for 17 pts: stable disease, 13 pts (range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease in CA-125 (SD &gt; 6 months). Conclusions: AMG 900 administered at 24 mg daily for 4D Q2W is the recommended dose for phase 2 trials. Dose escalation is now ongoing to determine the MTD with prophylactic G-CSF.
Trends in mortality rates for Stevens–Johnson syndrome and toxic epidermal necrolysis: experience of a single centre in France between 1997 and 2017
Authors: T. Bettuzzi, L. Penso, N. Prost, F. Hemery, C. Hua, A. Colin, A. Mekontso‐Dessap, L. Fardet, O. Chosidow, P. Wolkenstein, E. Sbidian, S. Ingen‐Housz‐Oro
Journal: British Journal of Dermatology (2019)
Licorice isoliquiritigenin-encapsulated mesoporous silica nanoparticles for osteoclast inhibition and bone loss prevention
Authors: Xiaoyue Sun, Jie Zhang, Zijun Wang, Bingqian Liu, Shenting Zhu, Lingxin Zhu, Bin Peng
Journal: Theranostics (2019)

Mesoporous silica nanoparticles (MSNs) are extensively used in bone tissue regeneration and local drug delivery. However, the effects of MSNs alone on osteoclast formation and function, as well as the utilization of MSNs to deliver natural molecules against bone resorption, remain unexplored. Here, we report the development of licorice-derived bioactive flavonoid isoliquiritigenin (ISL)-encapsulated MSNs (MSNs-ISL) as a potent bone-bioresponsive nanoencapsulation system for prevention of osteoclast-mediated bone loss in vitro and in vivo. Methods: We synthesized MSNs-ISL and then investigated the drug loading and release characteristics of the resulting nanoparticles. In vitro experiments on osteoclast differentiation and bone resorption were performed using mouse primary bone marrow-derived macrophages (BMMs). In vivo animal experiments were conducted using a lipopolysaccharide (LPS)-mediated calvarial bone erosion model. Results: The resulting MSNs-ISL were spherical and highly monodispersed; they possessed a large specific surface area and superior biocompatibility, and allowed acid-sensitive sustained drug release. Compared with free ISL and MSNs alone, MSNs-ISL significantly and additively inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast generation, decreased the size and quantity of sealing zones, and reduced the osteolytic capacity of osteoclasts in vitro. MSNs-ISL treatment also downregulated RANKL-stimulated mRNA expression of osteoclast-associated genes and transcription factors. Mechanistically, MSNs-ISL remarkably attenuated the RANKL-initiated expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of mitogen-activated protein kinases (MAPKs), and phosphorylation and degradation of inhibitor of κBα (IκBα), together with the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the activator protein (AP)-1 component c-Fos. Moreover, MSNs-ISL almost completely restrained the expression of nuclear factor of activated T cells (NFATc1). Consistent with the in vitro results, MSNs-ISL could block osteoclast activity; relieve inflammation-related calvarial bone destruction in vivo; and suppress c-Fos, NFATc1, and cathepsin K expression levels. Conclusion: Licorice ISL-encapsulated MSNs exhibit notable anti-osteoclastogenetic effects and protect against inflammatory bone destruction. Our findings reveal the feasibility of applying MSNs-ISL as an effective natural product-based bone-bioresponsive nanoencapsulation system to prevent osteoclast-mediated bone loss.
Activated M2 Macrophages Contribute to the Pathogenesis of IgG4‐Related Disease via Toll‐like Receptor 7/Interleukin‐33 Signaling
Authors: Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A. S. M. Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun‐Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka Yamamoto, Kensuke Miyake, Seiji Nakamura
Journal: Arthritis & Rheumatology (2019)

IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD.SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist.In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05).TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.
Neuroinflammation in frontotemporal dementia
Authors: Fiona Bright, Eryn L. Werry, Carol Dobson-Stone, Olivier Piguet, Lars M. Ittner, Glenda M. Halliday, John R. Hodges, Matthew C. Kiernan, Clement T. Loy, Michael Kassiou, Jillian J. Kril
Journal: Nature Reviews Neurology (2019)
More women found to have missed cervical screening invitations in new Capita “administrative error”
Authors: Ingrid Torjesen
Journal: BMJ (2019)

The BMA has reiterated its call for Capita be stripped of its contract to provide GP support services after the company admitted more administrative errors related to its contract to invite women for cervical screening.

NHS England previously stripped Capita of its contract to provide administration services for the NHS cervical screening programme and brought it back in-house following a series of blunders by the private sector company.1 Last year it came to light that some 43 220 women had not had invitation letters for cervical screening, and a further 4508 were not sent their results. …
Cannabinoid hyperemesis syndrome
Authors: Yaniv Chocron, Jean-Philippe Zuber, Julien Vaucher
Journal: BMJ (2019)

### What you need to know 

A 26 year old man attends the emergency department with a four week history of diffuse abdominal pain and nausea, along with vomiting every 30 minutes. Laboratory test results show a sodium level of 124 mmol/L (reference range 135-145) and a creatinine level of 348 µmol/L (62-106). During the last six years he has sought medical care several times for similar episodes, but no precise diagnosis was made, despite multiple investigations (including abdominal ultrasound and computed tomography scan and upper and lower endoscopies). He admits smoking cannabis about 4-6 times a day for 13 years. His symptoms are only alleviated by taking hot showers and baths, which he takes 10 to 15 times a day. After rehydration and normalisation of renal function, he is discharged home with a psychiatric follow-up to support cannabis abstinence. Three years after cessation of cannabis consumption, he does not report any symptoms. 

Cannabinoid hyperemesis syndrome (CHS) was first described in 20041 and associates cyclic nausea and vomiting with abdominal pain in regular cannabis users (defined, in the most comprehensive systematic review on CHS, as at least weekly cannabis use2). Typically, patients report compulsive hot showering or bathing to alleviate symptoms (encountered in 90-100% of reported cases and it has been proposed as a diagnostic criteria).123

Different mechanisms have been proposed to explain how, in certain individuals, the established anti-emetic properties of cannabis are overridden and CHS develops.24 Approximately 100 cannabinoids have been identified,5 and …
Diagnosis of elevated intracranial pressure in critically ill adults: systematic review and meta-analysis
Authors: Shannon M Fernando, Alexandre Tran, Wei Cheng, Bram Rochwerg, Monica Taljaard, Kwadwo Kyeremanteng, Shane W English, Mypinder S Sekhon, Donald E G Griesdale, Dar Dowlatshahi, Victoria A McCredie, Eelco F M Wijdicks, Saleh A Almenawer, Kenji Inaba, Venkatakrishna Rajajee, Jeffrey J Perry
Journal: BMJ (2019)

Abstract Objectives To summarise and compare the accuracy of physical examination, computed tomography (CT), sonography of the optic nerve sheath diameter (ONSD), and transcranial Doppler pulsatility index (TCD-PI) for the diagnosis of elevated intracranial pressure (ICP) in critically ill patients. Design Systematic review and meta-analysis. Data sources Six databases, including Medline, EMBASE, and PubMed, from inception to 1 September 2018. Study selection criteria English language studies investigating accuracy of physical examination, imaging, or non-invasive tests among critically ill patients. The reference standard was ICP of 20 mm Hg or more using invasive ICP monitoring, or intraoperative diagnosis of raised ICP. Data extraction Two reviewers independently extracted data and assessed study quality using the quality assessment of diagnostic accuracy studies tool. Summary estimates were generated using a hierarchical summary receiver operating characteristic (ROC) model. Results 40 studies (n=5123) were included. Of physical examination signs, pooled sensitivity and specificity for increased ICP were 28.2% (95% confidence interval 16.0% to 44.8%) and 85.9% (74.9% to 92.5%) for pupillary dilation, respectively; 54.3% (36.6% to 71.0%) and 63.6% (46.5% to 77.8%) for posturing; and 75.8% (62.4% to 85.5%) and 39.9% (26.9% to 54.5%) for Glasgow coma scale of 8 or less. Among CT findings, sensitivity and specificity were 85.9% (58.0% to 96.4%) and 61.0% (29.1% to 85.6%) for compression of basal cisterns, respectively; 80.9% (64.3% to 90.9%) and 42.7% (24.0% to 63.7%) for any midline shift; and 20.7% (13.0% to 31.3%) and 89.2% (77.5% to 95.2%) for midline shift of at least 10 mm. The pooled area under the ROC (AUROC) curve for ONSD sonography was 0.94 (0.91 to 0.96). Patient level data from studies using TCD-PI showed poor performance for detecting raised ICP (AUROC for individual studies ranging from 0.55 to 0.72). Conclusions Absence of any one physical examination feature is not sufficient to rule out elevated ICP. Substantial midline shift could suggest elevated ICP, but the absence of shift cannot rule it out. ONSD sonography might have use, but further studies are needed. Suspicion of elevated ICP could necessitate treatment and transfer, regardless of individual non-invasive tests. Registration PROSPERO CRD42018105642.
Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis
Authors: Guido Carpino, Lorenzo Nevi, Diletta Overi, Vincenzo Cardinale, Wei‐Yu Lu, Sabina Di Matteo, Samira Safarikia, Pasquale Bartolomeo Berloco, Rosanna Venere, Paolo Onori, Antonio Franchitto, Stuart J. Forbes, Domenico Alvaro, Eugenio Gaudio
Journal: Hepatology (2019)

Mechanisms underlying the repair of extrahepatic biliary tree (EHBT) after injury have been scarcely explored. The aims of this study were to evaluate, by using a lineage tracing approach, the contribution of peribiliary gland (PBG) niche in the regeneration of EHBT after damage and to evaluate, in vivo and in vitro, the signaling pathways involved.Bile duct injury was induced by the administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 14 days to Krt19Cre TdTomatoLSL mice. Human biliary tree stem/progenitor cells (BTSC) within PBGs were isolated from EHBT obtained from liver donors. Hepatic duct samples (n = 10) were obtained from patients affected by primary sclerosing cholangitis (PSC). Samples were analyzed by histology, immunohistochemistry, western blotting, and polymerase chain reaction. DDC administration causes hyperplasia of PBGs and periductal fibrosis in EHBT. A PBG cell population (Cytokeratin19- /SOX9+ ) is involved in the renewal of surface epithelium in injured EHBT. The Wnt signaling pathway triggers human BTSC proliferation in vitro and influences PBG hyperplasia in vivo in the DDC-mediated mouse biliary injury model. The Notch signaling pathway activation induces BTSC differentiation in vitro toward mature cholangiocytes and is associated with PBG activation in the DDC model. In human PSC, inflammatory and stromal cells trigger PBG activation through the up-regulation of the Wnt and Notch signaling pathways.We demonstrated the involvement of PBG cells in regenerating the injured biliary epithelium and identified the signaling pathways driving BTSC activation. These results could have relevant implications on the pathophysiology and treatment of cholangiopathies.
Gene loci associated with insulin secretion in islets from nondiabetic mice
Authors: Mark P. Keller, Mary E. Rabaglia, Kathryn L. Schueler, Donnie S. Stapleton, Daniel M. Gatti, Matthew Vincent, Kelly A. Mitok, Ziyue Wang, Takanao Ishimura, Shane P. Simonett, Christopher H. Emfinger, Rahul Das, Tim Beck, Christina Kendziorski, Karl W. Broman, Brian S. Yandell, Gary A. Churchill, Alan D. Attie
Journal: Journal of Clinical Investigation (2019)

Genetic susceptibility to type 2 diabetes is primarily due to β-cell dysfunction. However, a genetic study to directly interrogate β-cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged >1,000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion QTL from mouse are associated with diabetes-related SNPs in human genome-wide association studies. We report on three genes, Ptpn18, Hunk and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These three genes encode a non-receptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in non-diabetic individuals.
Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin
Authors: Christian Orlik, Daniel Deibel, Johanna Küblbeck, Emre Balta, Sabina Ganskih, Jüri Habicht, Beate Niesler, Jutta Schröder-Braunstein, Knut Schäkel, Guido Wabnitz, Yvonne Samstag
Journal: Cellular and Molecular Immunology (2019)

The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating self-reactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graft-versus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell–keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.