tbuckley/cabot-search huggingface dataset:
Coexistence of Eph receptor B1 and ephrin B2 in port-wine stain endothelial progenitor cells contributes to clinicopathological vasculature dilatation
Authors: W. Tan, J. Wang, F. Zhou, L. Gao, R. Yin, H. Liu, A. Sukanthanag, G. Wang, M.C. Mihm, D.-B. Chen, J.S. Nelson
Journal: British Journal of Dermatology (2017)

Port-wine stain (PWS) is a vascular malformation characterized by progressive dilatation of postcapillary venules, but the molecular pathogenesis remains obscure.To illustrate that PWS endothelial cells (ECs) present a unique molecular phenotype that leads to pathoanatomical PWS vasculatures.Immunohistochemistry and transmission electron microscopy were used to characterize the ultrastructure and molecular phenotypes of PWS blood vessels. Primary culture of human dermal microvascular endothelial cells and in vitro tube formation assay were used for confirmative functional studies.Multiple clinicopathological features of PWS blood vessels during the development and progression of the disease were shown. There were no normal arterioles and venules observed phenotypically and morphologically in PWS skin; arterioles and venules both showed differentiation impairments, resulting in a reduction of arteriole-like vasculatures and defects in capillary loop formation in PWS lesions. PWS ECs showed stemness properties with expression of endothelial progenitor cell markers CD133 and CD166 in non-nodular lesions. They also expressed dual venous/arterial identities, Eph receptor B1 (EphB1) and ephrin B2 (EfnB2). Co-expression of EphB1 and EfnB2 in normal human dermal microvascular ECs led to the formation of PWS-like vasculatures in vitro, for example larger-diameter and thick-walled capillaries.PWS ECs are differentiation-impaired, late-stage endothelial progenitor cells with a specific phenotype of CD133+ /CD166+ /EphB1+ /EfnB2+ , which form immature venule-like pathoanatomical vasculatures. The disruption of normal EC-EC interactions by coexistence of EphB1 and EfnB2 contributes to progressive dilatation of PWS vasculatures.
Abstract P013: Canopy 2 Encodes for a Novel Secreted Proangiogenic Factor that Revascularizes and Regenerates Murine Hearts Post Myocardial Infarction
Authors: Jian Guo, Zhuo Sun, Anton Mihic, Sharon Au, Shu Hong Li, Kota Hatta, Yue Mei Zhang, Sanjiv Dhingra, Jun Wu, Richard D Weisel, Ren-Ke Li
Journal: Circulation Research (2011)

Through genomic screening of 256 novel genes by RT-PCR in human smooth muscle cells, we discovered that Canopy 2 (CNPY2), previously named as MSAP, TMEM4 or ZSIG9, actually encodes for a secreted pro-angiogenic factor, which was differentially regulated by in vitro hypoxia. Tissue distribution profile reveals that CNPY2 has the highest expression levels in the heart, liver and lung. Surprisingly, CNPY2 was dramatically downregulated (∼2–5 fold) in the murine heart at day 1–7 post myocardial infarction. Recombinant CNPY2 proteins were purified both from E.coli to generate rabbit (blocking) antibodies, and from mammalian cells with proper folding and posttranslational modification to study signaling cascades. We demonstrate that recombinant CNPY2 protein binds to the extracellular domain of VEGFR2 and phosphorylates the intracellular Tyr 1175 and Tyr 1214 of VEGFR2, activates FAK and ERK which resulting in pERK nuclear translocation in human endothelial cells. On the other hand, CNPY2 binds to adhesion molecule desmoglein 1, activates Cdc42, PAK1 and FAK in human smooth muscle cells. CNPY2 reorganizes the dynamic vimentin structure in both cell types, resulting in an accelerated cell migration. In vivo delivery of recombination CNPY2 protein enhanced the blood capillary formation in a retinal ischemia/reperfusion mouse model, and dramatically revascularized blood vessel network, reduced infarct size and improved cardiac function in a rat myocardial infarction model. In line with the paracrine mechanism in (stem) cell-based therapy, our data suggests that CNPY2 might be employed as a promising therapeutic protein for ischemic tissue revascularization and regeneration.
Optimization of CSF3R Mutation Detection in Severe Congenital Neutropenia and Cyclic Neutropenia Patients for Routine Diagnostics Using Next Generation Sequencing
Authors: Maksim Klimiankou, Cornelia Zeidler, Sabine Mellor-Heineke, Ingeborg Steiert, Karin Haehnel, Karl Welte, Julia Skokowa
Journal: Blood (2016)
Distribution of receptor tyrosine kinase (RTK) nsSNPs in breast cancer (BC) patients (pts) using next-generation sequencing (NGS).
Authors: Lindsay Kaye Morris, Matthew Stein, Saradasri Karri, Srishti Sareen, Kruti Patel, Gregory A. Vidal, Lee Steven Schwartzberg, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

1080 Background: Non-synonymous SNPs (nsSNPs) discovered by NGS occurring in RTKs’ conserved topology in pts with BC may promote oncogenic signaling and hence may be actionable. Methods: We analyzed BC pts for nsSNPs in 29 RTKs identified by tumor profiling with NGS from Caris during 2013-2015. Mutations were classified by location including the tyrosine kinase domain (TKD), extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM) and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to determine pathogenicity. Results: 79 pts were identified with a median age of 58 years (range 32-83); 99% female; 60% white, 38% black and 2% other. 77 pts were classifiable with 8 (10%) triple-positive, 35 (46%) ER+/PR+/HER2- (ER/PR+), 10 (13%) ER-/PR-/HER2+ (HER2+) and 24 (31%) triple-negative. 78 nsSNPs and 1 Caris-reported pathogenic substitution of ERBB3 (TKD S846I) were found. 52/79 (66%) pts had ≥1 RTK nsSNP (range 0-4); 28/29 RTKs had ≥1 nsSNP with median of 2 (range 0-15). In 28 pts (35%), 40% of nsSNPs were predicted to be damaging (pnsSNP) and 3 pts had 2 pnsSNPs. 17/29 RTKs had pnsSNPs, median 1 (range 0-9). The most commonly mutated RTKs were ROS1 (9/15 variants were pnsSNPs), ALK (3/4), EPHA5 (3/3), FLT4 (2/5), cKIT (2/4) and ERBB4 (2/3). ROS1 and ALK nsSNPs were most-frequently seen in ER/PR+ (9/15 pnsSNPs), triple-positive (3/3) and HER2+ (0/2) pts; no triple-negative pts had such variants. 100% triple-positive pts (6/8 pnsSNP), 69% ER/PR+ (18/35), 60% HER2+ (2/10) and 58% triple-negative (3/24) had RTK nsSNP. nsSNP were spread in all 5 RTK regions: 58% localized to the ECD (20/45 pnsSNPs), 17% TKD (8/13), 9% CT (2/7), 9% TM (1/7) and 8% JM (1/6) lesions were found. Of 9 ROS1 pnsSNPs, 7 were ECD, 1 CT and 1 TKD. Conclusions: 35% of BC pts had pnsSNP in RTKs across various phenotypes including frequent mutations in potentially actionable genes such as ROS1 and ALK. 26% of ER/PR+ pts had pnsSNPs in ROS1 or ALK. nsSNPs in the ECD or TKD were most likely to be damaging.
HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia
Authors: S Tharkar-Promod, D P Johnson, S E Bennett, E M Dennis, B G Banowsky, S S Jones, J R Shearstone, S N Quayle, C Min, M Jarpe, T Mosbruger, A D Pomicter, R R Miles, W Y Chen, K N Bhalla, P A Zweidler-McKay, D C Shrieve, M W Deininger, M B Chandrasekharan, S Bhaskara
Journal: Leukemia (2017)

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11–Rad51–DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.
Tips on…Leading a team
Authors: Mark Griffiths
Journal: BMJ (2003)

Be a role model for your team --Being the team leader means you are the designated role model. Lead by example. If you take long lunches or cut corners, they will too.

Don't be afraid to delegate --One of the advantages of having a team around you is that you can delegate some tasks. There's little point in having a team if you don't let them get …
冲突与灾害知识（一）——灾后的公共卫生问题
Authors: Eric, Nofi, 张民（译）, 周元国（校）
Journal: BMJ (2005)

灾难发生后，公共卫生机构必须详细地分析内乱、武装冲突、人口迁徙、经济崩溃和饥荒所产生的影响。在现代战争中，平民常常被当作攻击的目标，他们即使没有背井离乡，也会面临严重的公共卫生问题，其健康水平、医疗设施、供水系统、居住条件和农业生产等遭受严重的破坏，将导致营养不良性疾病和传染性疾病的急速增加。但是，只要提供充足的饮用水和卫生设施，及时接种麻疹疫苗，对腹泻脱水患者进行简单的治疗，为营养不良的人补充足够的营养和微量元素，并建立一套完善的保健监护系统，就可以极大地减少难民营中与严峻环境相关的疾病危险因素。
Antibodies to Cyclic Citrullinated Peptides in Patients With Juvenile Idiopathic Arthritis and Patients With Rheumatoid Arthritis: Shared Expression of the Inherently Autoreactive 9G4 Idiotype
Authors: Hannah Peckham, Geraldine Cambridge, Lauren Bourke, Debajit Sen, Anna Radziszewska, Maria Leandro, Yiannis Ioannou
Journal: Arthritis & Rheumatology (2017)

Antibodies to cyclic citrullinated peptides (anti-CCP) in rheumatoid arthritis (RA) can express the inherently autoreactive gene VH 4-34, detected using the rat monoclonal antibody 9G4. Patients with the polyarticular subtype of juvenile idiopathic arthritis (JIA) share some but not all of the features of adult patients with RA. This study was undertaken to compare serologic findings for rheumatoid factor (RF), anti-CCP, and 9G4-expressing anti-CCP in a large JIA cohort with a cohort of adult RA patients.Serum from 88 patients with polyarticular JIA, 29 patients with enthesitis-related arthritis, 38 patients with extended oligoarthritis, 31 adolescent controls, 35 patients with RA, and 30 adult controls were tested for RF, for IgG, IgA, and IgM anti-CCP, and for 9G4-expressing anti-CCP by enzyme-linked immunosorbent assay. Total serum 9G4-positive IgM was also measured.Of 65 patients with RF-negative polyarticular JIA, 4 (6.2%) were IgG anti-CCP positive. Sera from 20 of 23 patients with RF-positive polyarticular JIA (87.0%), 24 of 35 patients with RA (68.6%), and 1 patient with extended oligoarthritis contained IgG anti-CCP. IgA and IgM anti-CCP levels were lower in the adolescent group (P < 0.01). Levels of 9G4-expressing anti-CCP were higher in patients with RF-positive polyarticular JIA than in those with RF-negative polyarticular JIA (P < 0.0001). Median levels of 9G4-expressing anti-CCP in patients with RF-positive polyarticular JIA and those with RA did not differ. Expression of 9G4 on serum total IgM was greater in patients with RF-positive polyarticular JIA than other adolescent groups (P < 0.01), but similar to adult RF-positive RA.In healthy individuals, 9G4-positive B cells comprise 5-10% of the peripheral blood pool but serum immunoglobulins utilizing VH 4-34 are disproportionately low. The idiotope recognized by 9G4 was detected on anti-CCP antibodies in >80% of patients with RF-positive polyarticular JIA. VH 4-34 usage by anti-CCP in both JIA and RA patients suggest elicitation of these autoantibodies through shared pathogenic B cell selection processes.
A phase II study of eribulin mesylate in combination with trastuzumab and pertuzumab in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC).
Authors: Ines Maria Vaz Duarte Luis, Hao Guo, William Thomas Barry, Ian E. Krop, Nikhil Wagle, Alarice Lowe, Danielle Gore, Chelsea Andrews, Wafa Osmani, Steven J. Isakoff, Nadine M. Tung, Eric P. Winer, Nancy U. Lin, Rachel A. Freedman
Journal: Journal of Clinical Oncology (2017)

1034 Background: As a single agent, eribulin is an active agent among MBC pts. In the first-line setting, pertuzumab improves progression free and overall survival when added to trastuzumab and chemotherapy (CT); however there are limited data in the second line or beyond. The primary aim of this study was to evaluate the activity of eribulin in combination with trastuzumab and pertuzumab in pts with HER2+ MBC whose cancers are refractory to trastuzumab containing regimens. Safety and toxicity were examined and correlative studies are also planned. Methods: Single center, single-arm, phase II, 2 cohorts study planned to enroll up to 81 pts. The studied combination would be of clinical interest if the true overall response rate (ORR) was 40% among those without prior pertuzumab exposure (Cohort A) and 30% among those with prior pertuzumab exposure (Cohort B). The trial was stopped prematurely due to low accrual. Prior to the start of the phase II study, a run-in established dose of eribulin with standard dose of trastuzumab and pertuzumab (1.4mg/m2 days 1, 8 /21 days). Results: Of 32 pts enrolled, 6 were in the run-in, 19 in Cohort A and 7 in Cohort B. Most pts were heavily pre-treated (median [range] lines of CT for metastatic disease, run-in: 4[2-11], cohort A: 2.5 [0-7], cohort B: 3[1-8]). In cohort A, 5 pts had partial responses (ORR = 26% [95% CI 9-51%]), 1 (5%) experienced stable disease (SD) lasting ≥ 6 months and 11 (58%) had a SD lasting &lt; 6 months. In cohort B, the ORR was 0% [95% CI 0-41%]), 1(14%) experienced SD lasting ≥ 6 months and 5 (75%) had a SD lasting &lt; 6 months. The combination was well tolerated, most adverse events (AE) were mild to moderate. Hematologic toxicity was the most frequent grade 3-4 AE. Analyses looking at tissue genomic markers and cell free DNA will be presented. Conclusions: We observed modest activity of the treatment combination in those without prior pertuzumab exposure but limited activity in unselected pts with HER2+ MBC. The study was limited by small sample size. Correlative studies may help us to understand resistance and response to eribulin with anti-HER2 therapy and the interplay between CT and targeted therapy. Clinical trial information: NCT01912963.
A quarter of Scottish general practices report vacancies
Authors: Bryan Christie
Journal: BMJ (2017)

Action is being demanded to tackle recruitment problems in general practice in Scotland, as a new survey shows that vacancies exist in at least one in four practices.

More than half of Scotland’s 963 practices took part in the survey, and 26% of responding practices reported at least one GP vacancy. Of the 171 unfilled posts that were reported, almost three quarters had been vacant for six months or more.

The survey, carried …
Right ventricular dysfunction in left‐sided heart failure with preserved versus reduced ejection fraction
Authors: Lena Bosch, Carolyn S.P. Lam, Lingli Gong, Siew Pang Chan, David Sim, Daniel Yeo, Fazlur Jaufeerally, Kui Toh Gerard Leong, Hean Yee Ong, Tze Pin Ng, Arthur Mark Richards, Fatih Arslan, Lieng H. Ling
Journal: European Journal of Heart Failure (2017)
Fetal Outcomes After Diabetic Ketoacidosis During Pregnancy
Authors: Fritha J.R. Morrison, Maryam Movassaghian, Ellen W. Seely, Ashley Curran, Maria Shubina, Emma Morton-Eggleston, Chloe A. Zera, Jeffrey L. Ecker, Florence M. Brown, Alexander Turchin
Journal: Diabetes Care (2017)

Historical literature reports risk of fetal demise after diabetic ketoacidosis (DKA) in pregnancy as high as 25–60% (1,2). However, estimates have generally been based on small sample sizes, with limited investigation of other fetal outcomes or risk factors associated with poor fetal outcomes. We aimed to provide an updated assessment of the incidence and risk factors for fetal demise and other adverse outcomes in women with DKA during pregnancy.

This retrospective cohort study included pregnancies between 1996 and 2015 with at least one DKA event in women with type 1 diabetes at one of three teaching hospitals in Boston. Data were collected through medical record review. Pregnancies were excluded if information on birth status (live or demise) and gestational age at birth or demise were unknown.

Among the 77 DKA events in 64 pregnancies in 62 women included in the study, fetal demise, preterm …
The long term survival benefit of salvage chemoradiotherapy for local recurrence of esophageal cancer after curative surgery.
Authors: Takashi Ichimura, Keisho Chin, Eiji Shinozaki, Mitsukuni Suenaga, Mariko Ogura, TOMOHIRO MATSUSHIMA, Nobuyuki Mizunuma
Journal: Journal of Clinical Oncology (2015)

e15041 Background: Some retrospective reports suggests that the Chemoradiotherapy (CRT) for local recurrence of esophageal cancer after curative surgery is effective salvage therapy. However, the long term survival benefit has not well known. Methods: Thirty-one patients who were treated with salvage CRT of esophageal cancer after curative surgery between September 2005 and May 2014 at the Cancer Institute Hospital were retrospectively analyzed. All patients were treated with 5-fluorourasil (5-FU) and cisplatin (CDDP) with concurrent radiotherapy (60Gy/30fr). Results: The median follow-up period was 18.8 months. The 1-, 3-, and 5-year survival rates were 69%, 42.9%, and 23.8%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 5.9 months (95% CI 3.0-7.7 months) and 23.9 months (95% CI 10.3-54.6 months) respectively. Performance status before CRT was significantly associated with prognosis. Complete response and partial response were observed in 26% and 42% of the patients respectively. Conclusions: Salvage chemoradiotherapy for local recurrence of esophageal cancer after curative surgery could have a chance of long-term survival especially for the good performance status patients.
Towards omitting breast cancer surgery in select patient groups: Assessment of pathologic complete response after neoadjuvant systemic therapy using biopsies—The MICRA trial.
Authors: Marieke Van Der Noordaa, Frederieke van Duijnhoven, Claudette Loo, Koen van der Vijver, Gabe S. Sonke, Carmen Van Der Pol, Anne Brecht Francken, Marie-Jeanne Vrancken Peeters
Journal: Journal of Clinical Oncology (2017)

TPS593 Background: Improvements in systemic treatments for breast cancer patients has led to increasing rates of pathologic complete response (pCR). In addition, the identification of a pCR has been greatly improved with magnetic resonance imaging (MRI). In patients with a pCR, surgical resection of (part of) the original tumor area is performed to confirm the absence or presence of pCR and is not likely to contribute to locoregional control. With the MICRA trial (Minimally Invasive Complete Response Assessment) we aim to omit breast surgery in breast cancer patients achieving pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) using biopsies, thus preventing overtreatment and improving quality of life. Methods: The MICRA trial is a multi-center observational prospective cohort study. In all breast cancer patients receiving NST, a marker is placed in the center of the tumor area before NST. 440 patients with radiologic complete response or partial response (0.1-2.0 cm residual contrast enhancement, ≥30% decrease in tumor size according to RECIST criteria) on contrast enhanced MRI will be included in the MICRA trial. Patients with hormone receptor positive, triple negative and Human Epidermal growth factor Receptor 2 tumors are eligible. After NST, 8 ultrasound-guided biopsies are obtained in the region surrounding the marker, while the patient is under general anesthesia. Immediately hereafter, breast surgery is performed and pathology results of the biopsies and resected specimens are compared. The primary endpoint is specificity of post-NST biopsies. In addition, sensitivity and positive and negative predictive value will be calculated. We will perform a multivariable analysis using data on MRI and ultrasound findings, pre-NST pathology parameters and post-NST biopsy results to determine what the most reliable method is to assess pCR and how many biopsies are needed for this purpose. Conclusion: With the MICRA-trial we aim to select a group of breast cancer patients in whom surgery of the breast after NST can be omitted, by predicting the presence of a pCR on biopsies. Clinical trial information: NTR6120.
Dopaminergic Imaging and Prodromal Parkinson Disease
Authors: Ronald B. Postuma
Journal: JAMA Neurology (2017)

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