tbuckley/cabot-search huggingface dataset:
Abstract 12447: Early Coronary Reperfusion Improves Cerebral and Systemic Hemodynamics After Ischemic Refractory Cardiac Arrest and Extracorporeal Resuscitation in Pigs
Authors: Alice Hutin, Lionel Lamhaut, Fanny Lidouren, Matthias Kohlhauer, Nicolas Mongardon, Pierre Carli, Alain Berdeaux, Bijan Ghaleh, Renaud Tissier
Journal: Circulation (2016)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is widely proposed for the treatment of refractory cardiac arrest. It should be associated to etiologic determination, especially if acute coronary artery occlusion is suspected. However, prioritization of care remains unclear in this situation. Hypothesis: Our goal was to determine whether reperfusion should be instituted as soon as possible during ischemic refractory cardiac arrest treated by extracorporeal cardiopulmonary resuscitation (ECPR) in pigs. Methods: Pigs were instrumented and submitted to coronary artery occlusion prior to ventricular fibrillation. After 5 min of untreated cardiac arrest, life support was started using external chest compression (ECC) during 15 min followed by ECPR during 240 min, respectively. Animals randomly underwent either early or late coronary reperfusion after 20 or 120 min of ECPR, respectively. Return of spontaneous circulation (ROSC) was determined as organized ECG rhythm with systolic blood pressure above 80 mmHg. Results: Hemodynamic parameters were not different between groups at baseline or during ECC. Since the onset of ECPR, carotid blood flow was improved by ≈70% vs ECC in both groups. No animal (0/7) elicited ROSC after late reperfusion vs 4/7 after early reperfusion (p&lt;0.05). Hemodynamic parameters, such as mean arterial pressure and carotid blood flow, were improved in early vs late reperfusion groups (Figure), along with infarct size decrease (71±4 vs 84±2 % of the risk zone, respectively; p&lt;0.05). Conclusions: Early reperfusion improved hemodynamic status and increased ROSC chances after ischemic refractory cardiac arrest treated by ECPR. This supports the need of rapid reperfusion in this situation. Figure: Carotid blood flow after extracorporeal cardiopulmonary resuscitation (ECPR) and successful defibrillation (*, p&lt;0.05 between groups; comparisons were only made at the end of the follow-up).
Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C<sup>+</sup> monocytes
Authors: Li Liu, Yantong Liu, Bocheng Xu, Chuyu Liu, Yanpeng Jia, Ting Liu, Chunju Fang, Wei Wang, Jun Ren, Zhiyao He, Ke Men, Xiao Liang, Min Luo, Bin Shao, Ye Mao, Henyi Xiao, Zhiyong Qian, Jia Geng, Birong Dong, Peng Mi, Yu Jiang, Yuquan Wei, Xiawei Wei
Journal: Theranostics (2018)

Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application.How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown.Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week.Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials.Cell necrosis was detected by flow cytometry.Release of mitochondrial DNA was quantified by qPCR via Taqman probes.Signal proteins were detected by Western blotting.PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA).The infiltrated inflammatory cells were observed in WT mice, Ccr2 -/-mice, Sting -/-mice and Tlr9 -/-mice.Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2 -/-mice presented with more severe pulmonary inflammation.A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model.The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING-or TLR9-dependent pathway.Neutrophil activation was specifically inhibited by PGE2 from Ly6C + inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin.Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C + monocytes and increased PGE2 production through TLR9-or STING-mediated MAPK-NF-κB-COX2 pathways. Conclusion:Our findings suggest that Ly6C + monocytes and mtDNA-induced Ly6C + monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.
Macrophages Promote Circulating Tumor Cell–Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients
Authors: Marjan Rafat, Todd A. Aguilera, Marta Vilalta, Laura L. Bronsart, Luis A. Soto, Rie von Eyben, Meghana A. Golla, Yasaman Ahrari, Stavros Melemenidis, Anosheh Afghahi, Melissa J. Jenkins, Allison W. Kurian, Kathleen C. Horst, Amato J. Giaccia, Edward E. Graves
Journal: Cancer Research (2018)

Abstract Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC. Significance: This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4241/F1.large.jpg. Cancer Res; 78(15); 4241–52. ©2018 AACR.
A randomized phase II study of pembrolizumab, an anti-PD (programmed cell death) 1 antibody, in combination with carboplatin compared to carboplatin alone in breast cancer patients with chest wall disease, with immunologic and genomic correlative studies.
Authors: Neelima Vidula, Andrei Goga, Jimmy Hwang, Minetta C. Liu, Ben Ho Park, Rita Nanda, Paula Raffin Pohlmann, Anna Maria Storniolo, Adam Brufsky, Vandana Gupta Abramson, Hope S. Rugo
Journal: Journal of Clinical Oncology (2018)

TPS1113 Background: Chest wall disease from breast cancer has limited treatments. Given the inflammatory nature of this disease and the increased expression of PD-1 seen with lymphocytic infiltration, we hypothesize that pembrolizumab may be effective. Combining immunotherapy with platinum chemotherapy may facilitate anti-tumor immunity, as demonstrated in lung cancer. This study is evaluating the combination of pembrolizumab and carboplatin in breast cancer patients with chest wall disease. Methods: This is a randomized phase II multicenter trial in the Translational Breast Cancer Research Consortium. Eighty-four patients with breast cancer (hormone resistant, triple negative, or refractory HER2+) with chest wall disease will be enrolled. Patients may have had prior surgery but prior radiation is not required, and patients may have distant metastases. Patients will be randomized 2:1 to treatment with pembrolizumab 200 mg IV and carboplatin AUC 5 every 3 weeks for at least 6 cycles followed by pembrolizumab 200 mg IV alone (n = 56, Arm A) or carboplatin AUC 5 every 3 weeks (n = 28, Arm B) until progression. Patients in Arm B may cross over to pembrolizumab 200 mg IV every 3 weeks (Arm Bx) on progression. After 18 patients are enrolled in Arm B, an interim analysis for futility will be performed, to allow for early closure if lack of efficacy. The primary objective is to determine the disease control rate in both arms at 18 weeks of treatment; the study is powered to detect a 20% difference between arms, with a hazard ratio of 0.52 (α = 0.10, β = 0.20). The secondary objectives are to determine toxicity, progression free survival, and response based on irRECIST and PD-L1 expression. Exploratory objectives, using tumor biopsy and peripheral blood testing before and after treatment, include correlations of response with biomarkers including tumor PD-L1 expression, tumor and peripheral blood immune composition, circulating tumor cells, circulating tumor DNA, soluble PD-L1 and tumor MYC expression. This study is open to accrual; the first patient was enrolled in 11/17. Clinical trial information: NCT03095352.
Doctors urge prime minister to intervene in case of surgical trainee denied right to stay in UK
Authors: Abi Rimmer
Journal: BMJ (2018)

A doctors’ campaign group has written to the prime minister to intervene in the case of a surgical trainee who has been unable to renew his visa to stay in the UK.

The Doctors’ Association UK wrote to Theresa May on 28 May highlighting the case of Nnaemeka Chidumijie, a core surgical trainee from Nigeria who has been working in the NHS since moving to the UK …
Androgen receptor expression in patients with triple negative breast cancer treated with neoadjuvant chemotherapy: A single institution experience.
Authors: Chad Glisch, Zeeshan Ali Jawa, Talha Badar, Alexis Visotcky, Lubna Chaudhary, Sailaja Kamaraju, John D. Burfeind, John A. Charlson, Christopher R. Chitambar, Valentina Lagunova, Irene Aguilera-Barrantes, Julie Jorns, Yee Chung Cheng
Journal: Journal of Clinical Oncology (2018)

e12662 Background: Androgen receptor (AR) expression has recently emerged as a potential prognostic and predictive marker in patients with triple negative breast cancer (TNBC). We conducted a retrospective analysis in our institution to evaluate pathologic complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS) in both AR positive and AR negative TNBC patients treated with neoadjuvant chemotherapy over 10 years. Methods: 107 patients with TNBC subtype, treated between June 2006 and March 2016 were evaluated for AR expression. Fifty-eight tumor specimens were available, and stained immunohistochemically, with twenty being AR-positive (⩾10% nuclear stained cells) and thirty-eight being AR negative. Correlation of AR expression was examined with various prognostic factors and outcomes. Results: For the cohort of 58 patients, median age was 49 years. Median follow up was 49 months. All patients received anthracycline based chemotherapy with 23% receiving an additional platinum chemotherapy. BRCA positivity was 7% for the entire group. No differences were observed based on age, menopausal status, BMI, tumor grade, race, lymph node involvement, and tumor size between the two groups. Median DFS has not been reached in the AR positive group (60% at 60 months) vs 131 months for AR negative group,p = 0.912. Median OS has not been reached in either group (75% vs 62% at 84 months, p = 0.39). Overall pCR rate was 34% with no difference between the two groups (35% vs 27%, p = 0.557). Conclusions: Our study did not find AR status to correlate with various clinicopathological factors and the pCR rate.
Quantum Dot–Dye Conjugates for Biosensing, Imaging, and Therapy
Authors: Sungwook Jung, Xiaoyuan Chen
Journal: Advanced Healthcare Materials (2018)

Adding value to the intrinsic properties of quantum dots (QDs), a strategy to conjugate dyes on the surface of QDs offers new opportunities, since the coupling between QD and dyes can be designed to allow Förster resonance energy transfer (FRET) and/or electron transfer (eT). These processes are accompanied by the change of QD and/or dye fluorescence and subsequent photochemical reactions (e.g., generation of 1 O2 ). Based on the change of fluorescence signals by the interaction with biomolecules, QD-dye conjugates are exploited as biosensors for the detection of pH, O2 , nicotinamide adenine dinucleotide (phosphate), ions, proteases, glutathione, and microRNA. QD-dye conjugates also can be modulated by the irradiation of external light; this concept is demonstrated for fluorescence super-resolution imaging as photoactivatable or photoswitchable probes. When QDs are conjugated with photosensitizing dyes, the QD-dye conjugates can generate 1 O2 in a repetitive manner for better cancer treatment, and can also be available for approaches using two-photon excitation or bioluminescence resonance energy transfer mechanisms for deep tissue imaging. Here, the recent advances in QD-dye conjugates, where FRET or eT produces fluorescence readouts or photochemical reactions, are reviewed. Various QD-dye conjugate systems and their biosensing/imaging and photodynamic therapeutics are summarized.
Double intrahepatic bile duct puncture: a pitfall during endoscopic ultrasound-guided hepaticogastrostomy
Authors: Takeshi Ogura, Atsushi Okuda, Akira Miyano, Rieko Kamiyama, Nobu Nishioka, Kazuhide Higuchi
Journal: Endoscopy (2018)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) has emerged as an alternative technique to endoscopic retrograde cholangiopancreatography (ERCP) [1] [2]. During EUS-HGS, the process of fistula dilation is technically challenging. To date, various dilation devices and techniques have been reported [3] [4] [5]. However, despite improvements in dilation devices, challenging cases are still sometimes encountered. We herein describe a pitfall of EUS-HGS, which may be one of the reasons for the challenges encountered in some cases.
Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish
Authors: Angel-Carlos Román, Julián Vicente-Page, Alfonso Pérez-Escudero, Jose M. Carvajal-González, Pedro M. Fernández-Salguero, Gonzalo G. de Polavieja
Journal: Genome biology (2018)

Animals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior. We find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors. We suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic-independent behavioral inter-individual variability.
3D‐Ridge Stocked Layers of Nitrogen‐Doped Mesoporous Carbon Nanosheets for Ultrasensitive Monitoring of Dopamine Released from PC12 Cells under K<sup>+</sup> Stimulation
Authors: Mohammed Y. Emran, Mohamed A. Shenashen, Hiromi Morita, Sherif A. El‐Safty
Journal: Advanced Healthcare Materials (2018)

Abstract 3D‐ridge nanosheets of N‐doped mesoporous carbon (NMCS)‐based electrodes are fabricated as ultrasensitive biosensors for in vitro monitoring of dopamine (DA) released from living cells. The large‐scale ranges of dense‐layered sheets are arranged linearly with a thickness of &lt;10 nm, soft tangled edges, stocked layer arrangements, and tunable mesoporous frameworks with 3D orientations. The intrinsic features of the active interfacial surface of the electrode based on NMCS along with polarized surfaces, dense surface‐charged matrices, fast electron transfer, and easy molecular diffusion, are present in the highly active electrode for biosensing applications. The designed electrode based on the NMCS shows high sensitivity and selectivity for DA sensing even in the presence of physiological interference molecules, such as ascorbic acid and/or uric acid, at a low applied potential of 0.25 V versus Ag/AgCl. The large‐scale NMCS‐based electrode shows low detection limits as low as 10 nmol L −1 , wide linear range up to 0.5 mmol L −1 , long‐term stability for more than 15 d (relative standard deviation (RSD)= 5.8%), and a low cytotoxicity with high biocompatibility. The findings demonstrated that the NMCS‐based electrode is a reliable modified electrode for ultratrace sensitivity of DA, which is secreted normally from dopaminergic cells (PC12) or under a stimulating agent (K + ).
Excess mortality among people with mental disorders: a public health priority
Authors: Shekhar Saxena
Journal: The Lancet Public Health (2018)

Premature and excess mortality among people with mental illness is an issue that has implications for not only mental health and overall health services but also for equity and human rights. It has been called a scandal that contravenes international conventions for the "right to health".1 WHO considers excess morbidity and mortality among people with mental disorders as a high public health priority; these aspects are also included within WHO's Comprehensive Mental Health Action Plan.2 In 2017, WHO led an initiative on this issue and published a multilevel model of risk factors that lead to excess morbidity and mortality among people with severe mental disorders, and a framework for interventions.
Ontogeny and Biology of Human Small Airway Epithelial Club Cells
Authors: Wu-Lin Zuo, Sushila A. Shenoy, Sheng Li, Sarah L. O’Beirne, Yael Strulovici-Barel, Philip L. Leopold, Guoqing Wang, Michelle R. Staudt, Matthew S. Walters, Christopher Mason, Robert J. Kaner, Jason G. Mezey, Ronald G. Crystal
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Little is known about human club cells, dome-shaped cells with dense cytoplasmic granules and microvilli that represent the major secretory cells of the human small airways (at least sixth-generation bronchi).To define the ontogeny and biology of the human small airway epithelium club cell.The small airway epithelium was sampled from the normal human lung by bronchoscopy and brushing. Single-cell transcriptome analysis and air-liquid interface culture were used to assess club cell ontogeny and biology.We identified the club cell population by unbiased clustering using single-cell transcriptome sequencing. Principal component gradient analysis uncovered an ontologic link between KRT5 (keratin 5)+ basal cells and SCGB1A1 (secretoglobin family 1A member 1)+ club cells, a hypothesis verified by demonstrating in vitro that a pure population of human KRT5+ SCGB1A1- small airway epithelial basal cells differentiate into SCGB1A1+KRT5- club cells on air-liquid interface culture. Using SCGB1A1 as the marker of club cells, the single-cell analysis identified novel roles for these cells in host defense, xenobiotic metabolism, antiprotease, physical barrier function, monogenic lung disorders, and receptors for human viruses.These observations provide novel insights into the molecular phenotype and biologic functions of the human club cell population and identify basal cells as the human progenitor cells for club cells.
A proposed multidisciplinary model providing comprehensive breast cancer care.
Authors: Lauren Cornell, Sandhya Pruthi, Dawn Mussallem
Journal: Journal of Clinical Oncology (2018)

43 Background: Strategies to detect and treat breast cancer continue to improve, and as such, the number of survivors has grown dramatically. To date, there has not been a well-established model to provide cohesive care for breast cancer survivors. Care often feels fragmented and important issues are overlooked due to lack of continuity. The adoption of Survivorship Care Plans has aimed to fill this gap in care, but the literature still demonstrates that our patients’ needs are not being met. Methods: We present a comprehensive model for breast cancer care, within a multidisciplinary breast center, which incorporates consistent management from time of diagnosis through survivorship. This model utilizes the appointment of a dedicated breast internist that meets with each patient at the time of diagnosis and again assumes care at time of survivorship. The breast internists or “onco-generalists” have specialized training in breast cancer/survivorship and work alongside the entire multidisciplinary team. This unique approach incorporates individualized surveillance, integrative management of late treatment effects, and appropriate risk reducing lifestyle education. Results: The inclusion of a dedicated breast internist into survivorship care has been the standard within our center for over 10 years. With this model, we have found that survivorship care is more holistic with a focus on the patients’ overall needs. There is dedicated time to individualized risk assessment, appropriate surveillance, and modifiable risk factor education. The model also allows for incorporation of integrative medicine including mindfulness, acupuncture, and massage therapy to improve quality of life for patients. With this model, patients do not feel the abandonment that is so often experienced by survivors, but rather they feel empowered to enter their new life as a survivor. Conclusions: Continuity of care during and after breast cancer treatment remains a significant issue. By designating an internist with specialized breast training who initially meets with patients upfront, we have been able to create a more integrative approach to survivorship care, which encompasses the patients’ needs both surrounding and outside of their cancer diagnosis.
Progress in Primary Biliary Cholangitis
Authors: Elizabeth J. Carey
Journal: New England Journal of Medicine (2018)

Primary biliary cholangitis remains an incurable disease. The first medical treatment for this disease was ursodeoxycholic acid, which was approved in 1997 after it was shown to delay the progression of liver disease and improve transplantation-free survival.1 In the past two decades, it has become apparent that approximately 40% of patients with primary biliary cholangitis do not have an adequate biochemical response to ursodeoxycholic acid.2 This group remains at risk for progression of liver disease and development of liver failure. Primary biliary cholangitis is a rare disease with a slow rate of progression; these factors complicate the effort to design . . .