tbuckley/cabot-search huggingface dataset:
Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment
Authors: Qi Zhao, Alexandra Eichten, Asma Parveen, Christina Adler, Ying Huang, Wei Wang, Yueming Ding, Alexander Adler, Thomas Nevins, Min Ni, Yi Wei, Gavin Thurston
Journal: Cancer Research (2018)

Abstract Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition, and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell-cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts responded to antiangiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to antiangiogenic therapies. Significance: These findings provide a framework for defining subpopulations of endothelial cells and tumor-associated fibroblasts and their rapid changes in gene expression following antiangiogenic treatment. Cancer Res; 78(9); 2370–82. ©2018 AACR.
Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule
Authors: Gianpiero Manca, Federico Davini, Elisa Tardelli, Annalisa De Liperi, Fabio Falaschi, Franca Melfi, Patrick M. Colletti, Domenico Rubello, Duccio Volterrani, Giuseppe Boni
Journal: Clinical Nuclear Medicine (2018)

Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground-glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa.Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL Tc-labeled human albumin macroaggregates (Tc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm-diameter collimated thoracoscopic gamma probe was resected.From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5-20 mm) with mean distance of 15 mm (range, 6-39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20-90 minutes), with an average time of 3 minutes (range, 1-5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%).This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection.
City-wide electronic health records reveal gender and age biases in administration of known drug–drug interactions
Authors: Rion Brattig Correia, Luciana P. de Araújo Kohler, Mauro M. Mattos, Luis M. Rocha
Journal: npj Digital Medicine (2019)

Abstract The occurrence of drug–drug-interactions (DDI) from multiple drug dispensations is a serious problem, both for individuals and health-care systems, since patients with complications due to DDI are likely to reenter the system at a costlier level. We present a large-scale longitudinal study (18 months) of the DDI phenomenon at the primary- and secondary-care level using electronic health records (EHR) from the city of Blumenau in Southern Brazil (pop. ≈340,000). We found that 181 distinct drug pairs known to interact were dispensed concomitantly to 12% of the patients in the city’s public health-care system. Further, 4% of the patients were dispensed drug pairs that are likely to result in major adverse drug reactions (ADR)—with costs estimated to be much larger than previously reported in smaller studies. The large-scale analysis reveals that women have a 60% increased risk of DDI as compared to men; the increase becomes 90% when considering only DDI known to lead to major ADR. Furthermore, DDI risk increases substantially with age; patients aged 70–79 years have a 34% risk of DDI when they are dispensed two or more drugs concomitantly. Interestingly, a statistical null model demonstrates that age- and female-specific risks from increased polypharmacy fail by far to explain the observed DDI risks in those populations, suggesting unknown social or biological causes. We also provide a network visualization of drugs and demographic factors that characterize the DDI phenomenon and demonstrate that accurate DDI prediction can be included in health care and public-health management, to reduce DDI-related ADR and costs.
Fucoidan/VEGF-based surface modification of decellularized pulmonary heart valve improves the antithrombotic and re-endothelialization potential of bioprostheses
Authors: N. Marinval, M. Morenc, M.N. Labour, A. Samotus, A. Mzyk, V. Ollivier, M. Maire, K. Jesse, K. Bassand, A. Niemiec-Cyganek, O. Haddad, M.P. Jacob, F. Chaubet, N. Charnaux, P. Wilczek, H. Hlawaty
Journal: Biomaterials (2018)
Abstract P2-11-01: Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials
Authors: JC Jayasekera, C Schechter, R Jagsi, J White, J-AW Chapman, T Whelan, JA Sparano, SJ Anderson, A Fyles, W Sauerbrei, RC Zellars, Y Li, J Song, T Julian, D Berry, EJ Feuer, G Luta, JS Mandelblatt
Journal: Cancer Research (2018)

Abstract Purpose: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses of radiotherapy benefits pre-dated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis utilized GEP information with individual-level data from seven clinical trials to evaluate the impact of omitting radiotherapy on recurrence and mortality. Patients and Methods: The pooled observational data included women who had undergone breast conservation surgery for stage I, ER+ and/or PR+/HER2- cancers with clinicopathologically estimated 21-Gene Recurrence Scores (RS) of ≤ 18, and did not receive chemotherapy (n= 1,684). The primary endpoint was 10-year invasive or DCIS recurrence free-interval (IRFI-DCIS), including breast cancer death and was estimated using adjusted Cox models. Secondary outcomes were breast-cancer specific and all-cause survival. Covariates included for all models were age, tumor size, grade, hormonal status, type of hormonal therapy, risk score, and trial. Results: Ten-year IRFI-DCIS was high (96.6% with radiotherapy vs. 91.6% without), for an absolute difference of 5%. Omission of radiotherapy (vs. radiotherapy) was associated with an overall adjusted hazard ratio of 2.6 (95% confidence interval 1.5-4.5) for any first event. There was only a significant increase in risk of loco-regional; not, distant recurrence, breast cancer–specific or overall survival. The effect of radiotherapy varied across subgroups, with lower first event rates for those with estimated RS of &amp;lt;11 (vs. 11-18), and women ages 60+ (vs. &amp;lt;60 years). Conclusion: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest absolute increase in loco-regional recurrence, but does not appear to increase risk of distant recurrence or death. Citation Format: Jayasekera JC, Schechter C, Jagsi R, White J, Chapman J-AW, Whelan T, Sparano JA, Anderson SJ, Fyles A, Sauerbrei W, Zellars RC, Li Y, Song J, Julian T, Berry D, Feuer EJ, Luta G, Mandelblatt JS. Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-01.
Abstract P6-11-18: Ten year trends in antiemetic prescribing in cancer patients receiving highly emetogenic chemotherapy (HEC)
Authors: CC O'Sullivan, HK Van Houten, L Sangaralingham, AD Leal, S Shinde, H Liu, D Ettinger, CL Loprinzi, KJ Ruddy
Journal: Cancer Research (2018)

Abstract Purpose: Prevention of chemotherapy-induced nausea and vomiting (CINV) is essential to preserve quality of life in cancer patients receiving highly emetogenic chemotherapy (HEC) such as doxorubicin-cyclophosphamide (AC) or cisplatin. Recently, new drugs (e.g. fosaprepitant and newer neurokinin 1 receptor antagonists [NK1RAs], rolapitant and netupitant) and updated guidelines for antiemetic use (e.g. adding olanzapine) have emerged. However, trends in real world antiemetic use are understudied. Methods: We performed a retrospective study using the OptumLabs Data Warehouse (OLDW), which includes administrative claims for privately insured and Medicare Advantage enrollees in the U.S. We identified 34,236 patients age 18 years or older treated with either AC or cisplatin between January 2006 and June 2016. Data collected included baseline demographics (age, gender, census region and race), chemotherapy administered, and presence/absence of a central intravenous access device. Trends of anti-emetic use were presented overall and separately for 5-HT receptor antagonists (5HT3RAs) and NK1RAs. Results: 23,030 patients (67.3%) received an anthracycline-based regimen (AC with or without docetaxel or paclitaxel), and 11,206 (32.7%) patients received cisplatin. Approximately two thirds of patients were female (n= 23,392). Dexamethasone use was stable over the decade (used by 85-90% in all years). Use of 5HT3RAs, primarily palonosetron and ondansetron, occurred in at least 95% of patients in all study years, consistent with guideline recommendations. NK1RAs were underutilized early on compared with guideline recommendations, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use rose precipitously starting in 2009, preceding a sharp fall in aprepitant use beginning in 2011. The use of olanzapine, rolapitant and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used in the vast majority of patients receiving HEC, in accordance with guideline recommendations. Less compliance with guidelines was seen with NK1RA use. Citation Format: O'Sullivan CC, Van Houten HK, Sangaralingham L, Leal AD, Shinde S, Liu H, Ettinger D, Loprinzi CL, Ruddy KJ. Ten year trends in antiemetic prescribing in cancer patients receiving highly emetogenic chemotherapy (HEC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-18.
Stereotactic body radiotherapy (SBRT) versus high dose rate (HDR) brachytherapy (BT) boost for high-risk (HR) prostate cancer.
Authors: Alejandro Gonzalez-Motta, Mack Roach
Journal: Journal of Clinical Oncology (2018)

12 Background: Declining use of BT has prompted questions regarding the use of SBRT in HR patients. A systematic literature review was conducted to assess toxicity, and biochemical outcomes following SBRT or HDR BT boost in HR patients. Methods: A search was carried out on the PubMed and Embase databases, for studies published between 2007 and 2017, including HR patients treated with SBRT or HDR boost. Results: We identified 11250 articles, with 6 SBRT and 41 HDR boost studies eligible. The median follow-up was 3.5-5.5 and 2.6-10.3 years in SBRT and HDR boost studies, respectively. The five-year bDFS was 41%–96% in HDR and 69%–98% in SBRT boost studies. Toxicity was reported using the Radiation Therapy Oncology Group (RTOG) scale or the Common Terminology Criteria for Adverse Events (CTCAE) scale and/or validated patient reported Quality of Life (QoL) outcomes. Single SBRT and HDR studies reported 1 year IPSS scores &lt; 7, with 2 SBRT reports of excellent outcomes by the EPIC scale. Acute grade 2 (G2) genitourinary (GU) toxicity ranged from 24-46% and 0.4-33% in SBRT and HDR boost studies, respectively. Late G2 GU toxicity occurred in 2.3-25% and 0-22% following SBRT and the HDR boost, respectively. Late grade 3 (G3) GU toxicity was reported in 0-2.3% and 0-10% with SBRT and HDR boost, respectively. Late G3 GU was reported in 0.8% (2/226) and 4% (114/2763) following SBRT and HDR boost, respectively. Acute G2 gastrointestinal (GI) was noted in 8-19% and 0-19% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 0-10% and 0-4.6% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 2% (5/226) and 0.6% (18/2829) of SBRT and HDR boost studies, respectively. Conclusions: SBRT boost may be associated with higher acute G2 but lower late G3 GU toxicity but was not shown by QoL reports, and could be due to selection bias, learning curves or other factors. Randomized trials and validated QoL instruments are needed to accurately compare SBRT to HDR boost.
A Multicenter Retrospective Analysis Evaluating Performance of Synovial Biopsy Techniques in Patients With Inflammatory Arthritis
Authors: Frances Humby, Vasco C. Romão, Antonio Manzo, Andrew Filer, Serena Bugatti, Elsa Vieira‐Sousa, Stephen Kelly, Mihir Wechalekar, Manzoor Ahmed, Vidalba Rocher, Rebecca Hands, Carlomaurizio Montecucco, Joao Fonseca, Costantino Pitzalis
Journal: Arthritis & Rheumatology (2018)

To evaluate whether the choice of synovial biopsy technique (arthroscopy, blind needle [BN] biopsy, ultrasound [US]-guided portal and forceps [P&F], or US-guided needle biopsy [NB]) translates to significant variation in synovial tissue quality and quantity, with the aim of informing recommendations for the choice of synovial sampling technique within clinical trials.In total, 159 procedures from 5 academic rheumatology centers were evaluated. Hematoxylin and eosin-stained, paraffin-embedded synovial tissue sections from patients with inflammatory arthritis were assessed in order to determine the proportion of graded synovial fragments, total area of graded synovial tissue, and synovitis score per procedure. RNA quantity (μg of RNA) and quality (RNA integrity number) per procedure were also assessed in the synovial samples.In this study, 84 of the 159 procedures performed on large joints at baseline (25 arthroscopic, 35 US-P&F, 11 US-NB, and 13 BN biopsies), 41 of the 159 procedures performed on small joints at baseline (11 US-P&F, 20 US-NB, and 10 BN biopsies), and 34 sequential biopsy procedures were evaluated. Compared to all other techniques evaluated in the small and large joints, fewer small joint BN biopsies and a significantly lower proportion of large joint BN biopsies yielded graded synovial tissue. No significant difference in either the proportion of graded tissue samples or total graded synovial tissue area between the US-NB and arthroscopic large joint procedures was demonstrated. Among the sequential biopsy procedures evaluated (small joint US-NB, large joint arthroscopy, US-P&F biopsy, and BN biopsy), no significant difference in the proportion of graded synovial tissue or total graded synovial tissue area was demonstrated. All procedures yielded RNA of significant quality and quantity for subsequent transcriptomic analysis.These data support the integration of US-guided methods along with arthroscopic biopsy for clinical trial protocols in which sequential sampling of synovium from the large and small joints is needed for both histologic and molecular analysis. BN biopsy may be considered if graded synovial tissue is not required for subsequent analyses.
Liposomes and lipid disks traverse the BBB and BBTB as intact forms as revealed by two-step Förster resonance energy transfer imaging
Authors: Tongcheng Dai, Kuan Jiang, Weiyue Lu
Journal: Acta Pharmaceutica Sinica B (2018)

The blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand-mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both in vitro and in vivo. Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.68‰ and 1.67‰, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.31‰ and 8.32‰ at 3 h. Ex vivo imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB in vivo as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma.
Funding must shift from hospitals to primary care, NHS Confederation says
Authors: Tom Moberly
Journal: BMJ (2012)

NHS services need a “fundamental overhaul,” with funding shifting from hospitals to primary care and a reorganisation of staff working patterns, the NHS Confederation believes.

In his New Year message the confederation’s chief executive, Mike Farrar, said that the NHS needed to change to cope with the changing demands placed on it. “NHS leaders know that a fundamental overhaul …
设立针对脱发(斑秃除外)预防、诊断和治疗的研究问题并安排优先顺序:脱发优先设定合作伙伴关系
Authors: A. Macbeth, J. Tomlinson, A. Messenger, K. Moore-Millar, C. Michaelides, A. Shipman, J. Kassim, J. Brockley, W. Szczecinska, P. Farrant, R. Robinson, J. Rodgers, J. Chambers, S. Upadhyaya, M. Harries
Journal: British Journal of Dermatology (2018)

头发和头皮问题相当常见。有多种情况可能导致脱发,可能表现为头发脱落、稀疏或斑驳,进而形成脱发。有些情况下头发会重新生长,而其他情况的秃头症(脱发)则是永久性的。经常性疏于打理是人们脱发的心理影响因素。脱发的表现以及对进一步发展的恐惧可能会导致患者自尊心下降、焦躁和沮丧。遗憾的是,治疗脱发的最有效疗法尚有许多不确定因素。这项由英国脱发慈善组织资助的研究旨在识别脱发管理、预防、诊断和治疗中的不确定因素,这对有脱发烦恼的人们和专业医护人员而言十分重要。研究人员在患者、其看护者和亲属以及专业医护人员之间设立了脱发“优先设定合作伙伴关系”(PSP),以识别最重要的脱发不确定因素。此项研究展示了10大脱发(斑秃除外)研究优先项,以指导研究人员和资助单位支持对患者和临床医生而言十分重要的研究。
Abortion rates are similar in countries where procedure is legal or restricted
Authors: Jacqui Wise
Journal: BMJ (2018)

Abortion rates have declined globally over the past 25 years according to a comprehensive new report, although most of the change has occurred in developed regions with no significant change occurring in developing regions.1

The report from the Guttmacher Institute—a research organisation that focuses on sexual and reproductive health—shows that abortion rates are similar in countries where abortion is highly restricted and where it is broadly legal.

The abortion rate is 37 per 1000 women in those countries where abortion is banned or permitted only to save the life of the pregnant woman, and 34 per 1000 women in countries where abortion …
ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism
Authors: Maxime W.C. Rousseaux, Tyler Tschumperlin, Hsiang-Chih Lu, Elizabeth P. Lackey, Vitaliy V. Bondar, Ying-Wooi Wan, Qiumin Tan, Carolyn J. Adamski, Jillian Friedrich, Kirk Twaroski, Weili Chen, Jakub Tolar, Christine Henzler, Ajay Sharma, Aleksandar Bajić, Tao Lin, Lisa Duvick, Zhandong Liu, Roy V. Sillitoe, Huda Y. Zoghbi, Harry T. Orr
Journal: Neuron (2018)
Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma
Authors: Presha Rajbhandari, Gonzalo Lopez, Claudia Capdevila, Beatrice Salvatori, Jiyang Yu, Ruth Rodriguez-Barrueco, Daniel Martinez, Mark Yarmarkovich, Nina Weichert-Leahey, Brian J. Abraham, Mariano J. Alvarez, Archana Iyer, Jo Lynne Harenza, Derek Oldridge, Katleen De Preter, Jan Koster, Shahab Asgharzadeh, Robert C. Seeger, Jun S. Wei, Javed Khan, Jo Vandesompele, Pieter Mestdagh, Rogier Versteeg, A. Thomas Look, Richard A. Young, Antonio Iavarone, Anna Lasorella, Jose M. Silva, John M. Maris, Andrea Califano
Journal: Cancer Discovery (2018)

Abstract High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module—centered around a TEAD4–MYCN positive feedback loop—emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas. Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4–MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582–99. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 517