tbuckley/cabot-search huggingface dataset:
Association of Ambulance Use in New York City With the Implementation of the Patient Protection and Affordable Care Act
Authors: Charles Courtemanche, Andrew I. Friedson, Daniel I. Rees
Journal: JAMA Network Open (2019)

Expanding insurance coverage may be associated with overuse of medical care because newly insured patients are insulated from having to pay the full cost.To examine the use of ambulance transport before and after the rollout of the Patient Protection and Affordable Care Act (ACA) in New York City (NYC), New York.In this case-control study, the volume of ambulance dispatches in NYC for minor injuries before and after the rollout of the ACA was examined. Data were drawn from a census of all ambulance dispatches in NYC between January 1, 2013, and July 31, 2016. Ambulance dispatches for more severe injuries, which are more difficult to characterize as unnecessary, were used as the control group. Analyses were conducted from August 17, 2017, to May, 10, 2019.The main outcome was the number of ambulance dispatches for minor injuries, defined per month per dispatch zone. The implementation of the ACA was measured using an indicator variable of 1 for dispatches starting January 1, 2014, and 0 for dispatches before January 1, 2014. The number of ambulance dispatches for injuries and major injuries was used to account for secular trends. Injury severity was classified by the dispatchers based on information from the 911 callers with a severity score on a scale of 1 to 8, where 1 is the most severe; minor injuries had a score of 7; injuries, 5; and major injuries, 3.There were 4 787 180 ambulance dispatches in NYC during the study. After the 2014 expansion of insurance coverage under the ACA, there was an increase in ambulance dispatches for minor injuries compared with dispatches for more severe injuries. Compared with the preimplementation mean (SD) of 20.75 (14.24) minor injury dispatches per dispatch zone per month, there were 7.71 (95% CI, 1.23-14.19) additional minor injury dispatches per dispatch zone per month compared with dispatches for other types of injuries, an increase of 37.2%. Given that NYC has 31 dispatch zones, this increase is equivalent to approximately 239 additional dispatches per month or 2868 additional dispatches per year for minor injuries.There was a significant increase in use of ambulance transport for minor injuries in NYC after the ACA insurance expansion, suggesting that the change in health insurance structure was associated with increased use of emergency medical services in nonemergent situations. Future reforms to the US health insurance system should take into account the potential for increased use of emergency medical services in nonemergent situations, which the literature suggests may lead to congestion and slower response times.
PARP-ness in metastatic colorectal cancer
Authors: G. Mauri, K. Kanter, M. Fish, N. Horick, J. Allen, L. Blaszkowsky, J. Clark, D. Ryan, R. Nipp, B. Giantonio, L. Goyal, J. Dubois, J. Murphy, E. Roeland, C. Weekes, J. Wo, T. Hong, A. Zhu, E. Van Seventer, R. Corcoran, A. Parikh
Journal: Annals of Oncology (2019)
Junior doctor contract: dispute with government ends after juniors accept changes
Authors: Abi Rimmer
Journal: BMJ (2019)

Junior doctors in England have voted to accept amendments to their contract, after the terms were agreed between the BMA, NHS Employers, and the Department of Health and Social Care.

Jeeves Wijesuriya, chair of the BMA’s Junior Doctors Committee, announced on 26 June that 82% of junior doctors and final year medical students had accepted the deal, which would see changes leading to a total of £90m (€100m; $115m) worth of investment over four years for junior doctors.

Of the 41 116 BMA members who were eligible to vote on the deal, 9449 voted in favour of the amended contract and 2139 voted …
Abstract 1759: Studying T-cell force activation and DNA repair dynamics at the single-molecule level with optical tweezers and correlated fluorescence microscopy
Authors: Ali Raja, Leif Anderson, Willem Peutz, Andrea Candelli, Gerrit Sitters
Journal: Cancer Research (2019)

Abstract DNA repair, the collection of highly regulated mechanisms by which a cell identifies and repairs DNA damage, remains one of the most essential processes of human life. Without DNA repair mechanisms cells lose the ability to transcribe important regions of their genome, resulting in harmful mutations, which could eventually jeopardize cellular wellbeing. Sources of DNA damage include double-stranded breaks and DNA intra- and interstrand crosslinks, which can ultimately become malignant tumors, leading to cancer. To study DNA repair, single-molecule studies have proven to greatly enhance understanding at the molecular level. However, it is often challenging to obtain adequate sensitivity and resolution, as well as biological conditions mimicking in vivo environments. The C-Trap™ system allows for realtime visualization of the interaction between DNA and DNA repair proteins, under biologically relevant conditions with high spatial and temporal resolution. The C-Trap™ is the only instrument that integrates optical tweezers, confocal/STED microscopy, and an advanced microfluidics system in a truly correlated manner. It enables live, simultaneous and correlative visualization and manipulation of molecular interactions with sub-picoNewton (pN) force resolution and a kilo-Hz (to mega-Hz) temporal resolution. Previously we have presented applications in: protein (un)folding and conformational changes; DNA-protein interactions and genome modifications; effects of mechanical stress on DNA/RNA structure; motility of cytoskeletal molecular motors; and protein droplet and aggregation dynamics. By culturing or adhering cells to the surface of the flow chamber, single-molecule cell-based studies can also be performed with the C-Trap. Cell-surface bound mechano-receptors can be activated by forming tethers with an optically trapped particle and then creating a controlled tension on the molecule. Correlated fluorescent imaging can elucidate internal protein cascades and other similar reactions to the applied force. Here, we present our experiments visualizing and quantifying the mechanisms of DNA repair and the force activation of T-cells using the C-Trap system. These experiments show that the technological advances in hybrid single-molecule methods can be turned into an easy-to-use and stable instrument that opens up new venues in many research areas. Citation Format: Ali Raja, Leif Anderson, Willem Peutz, Andrea Candelli, Gerrit Sitters. Studying T-cell force activation and DNA repair dynamics at the single-molecule level with optical tweezers and correlated fluorescence microscopy [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 1759.
Abstract 1869: Mechanistic evaluation of ergosterol peroxide on<i>in vitro</i>breast cancer models
Authors: Camille L. Santiago, Fatima Rivas, Taotao Ling, Ivette J. Suarez-Arroyo, Gabriela Ortiz, Mercedes Y. Lacourt, Anibal Valentin, Walter H. Lang, Michelle M. Martínez-Montemayor
Journal: Cancer Research (2019)

Abstract Ganoderma lucidum extract (GLE), an extensively studied mushroom for its anti-cancer and anti-inflammatory properties, has been shown to possess physiologically active compounds such as polysaccharides, triterpenoids and sterols. In our previous studies, we reported that commercially available GLE whole mushroom extract selectively inhibits cancer cell viability, induces apoptosis, reduces invasion, and regulates key signaling molecules in various cell models of breast cancer. Hence, we sought to elucidate the compounds responsible for the observed anti-cancer activity. Among the isolated compounds from GLE, we identified a steroidal compound, Ergosterol Peroxide (EP), which has shown antiproliferative activity against cancer. EP is a member of natural endoperoxides, featuring the peroxy- warhead that can lead to hydroxyperoxy radicals or be activated and react as nucleophile, leading to significant biological cytotoxicity against various cancer models (e.g. ovarian, liver, colon). We hypothesized that EP would promote cell death mechanisms in the aggressive breast cancer phenotype. Thus, in this study, we evaluated EP’s anti-cancer potential using immunoblotting, colony formation, cell motility, cell cycle and reactive oxygen species (ROS) production assays against human breast cancer SUM-149, MCF-7, MDA-MB-231 cellular models. We show that EP displays anti-proliferative effects through cell arrest in G1 phase, and apoptosis induction via caspase 3/7 activation. EP induced ROS and decreased the migratory and invasive phenotype of these cancer cells. Moreover, it inhibited the expression of total AKT1, AKT2, BCL-2, BCL-XL, Cyclin D1 and c-Myc. Our combined results indicate that EP from GLE is a promising molecular scaffold for further exploration as an anti-cancer agent,particularly in aggressive breast cancer models. Citation Format: Camille L. Santiago, Fatima Rivas, Taotao Ling, Ivette J. Suarez-Arroyo, Gabriela Ortiz, Mercedes Y. Lacourt, Anibal Valentin, Walter H. Lang, Michelle M. Martínez-Montemayor. Mechanistic evaluation of ergosterol peroxide onin vitrobreast cancer models [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 1869.
Detection of Expiratory Flow Limitation by Forced Oscillations during Noninvasive Ventilation
Authors: Emanuela Zannin, Biswajit Chakrabarti, Leonardo Govoni, Pasquale P. Pompilio, Robert Romano, Peter M. A. Calverley, Raffaele L. Dellacà
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc
Authors: Ruifang Liang, Rosebeth Kagwiria, Ariella Zehender, Clara Dees, Christina Bergmann, Andreas Ramming, Dorota Krasowska, Małgorzata Michalska-Jakubus, Alexander Kreuter, Max E Kraner, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc. Methods Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models. Results The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-β (TGFβ)/SMAD-dependent manner. Knockdown of HHAT reduced TGFβ-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis. Conclusion HHAT is regulated in SSc in a TGFβ-dependent manner and in turn stimulates TGFβ-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.
Galectin-3 and S100A9: Novel Diabetogenic Factors Mediating Pancreatic Cancer–Associated Diabetes
Authors: Wei-Chih Liao, Bo-Shih Huang, Ya-Han Yu, Hsin-Hua Yang, Peng-Ruei Chen, Cheng-Chieh Huang, Hsin-Yi Huang, Ming-Shiang Wu, Lu-Ping Chow
Journal: Diabetes Care (2019)

Pancreatic cancer-associated diabetes (PCDM) is a paraneoplastic phenomenon accounting for 1% of new-onset diabetes. We aimed to identify the mediators of PCDM and evaluate their usefulness in distinguishing PCDM from type 2 diabetes.Secreted proteins of MIA PaCa-2 cells were identified by proteomics, and those with ≥10-fold overexpression in transcriptome analysis were assessed by bioinformatics and glucose uptake assay to identify candidate factors. Expression of factors was compared between tumors with and without PCDM by immunohistochemistry. Serum levels were measured in a training set including PC with and without PCDM, type 2 diabetes, pancreatitis, other pancreatic/peripancreatic tumors, and control subjects (n = 50 each). Cutoff values for differentiation between PCDM and type 2 diabetes from the training set were validated in a test set (n = 41 each).Galectin-3 and S100A9 were overexpressed in tumors with PCDM and dose-dependently suppressed insulin-stimulated glucose uptake in C2C12 myotubes. In the training set, serum galectin-3 and S100A9 levels were exclusively increased in patients with PCDM and distinguished PCDM from type 2 diabetes (area under the curve [AUC] galectin-3: 0.73 [95% CI 0.64-0.83]; S100A9: 0.79 [95% CI 0.70-0.87]). Similar results were observed in the test set (AUC galectin-3: 0.83 [95% CI 0.74-0.92]; S100A9: 0.77 [95% CI 0.67-0.87]), with sensitivity and specificity 72.1% and 86.1%, respectively, for galectin-3 and 69.8% and 58.1% for S100A9 in differentiating between PCDM and type 2 diabetes.Galectin-3 and S100A9 are overexpressed in PCDM tumors and mediate insulin resistance. Galectin-3 and S100A9 distinguish PCDM from type 2 diabetes in subjects with new-onset diabetes.
HPV vaccine: adverse event signals were minimised or ignored
Authors: Manuel Martínez-Lavín
Journal: BMJ (2019)

Chandler discusses the difficulties in the pharmacovigilance of HPV vaccines due to the non-specific nature of dysautonomia symptoms reported to surveillance agencies.1

In our critical review, we found that serious adverse event signals were already present in the largest randomised trials of HPV vaccines. These signals were ignored or minimised.2 The group of 2881 women injected with the …
A nomogram to predict neutropenia in metastatic pancreatic cancer patients treated with gemcitabine/nab-paclitaxel
Authors: C. Morelli, V. Formica, A. Nardecchia, J. Lucchetti, G. Tisone, A. Anselmo, G. Del Vecchio Blanco, M. Benassi, G. Palmieri, R. Argiró, M. Roselli
Journal: Annals of Oncology (2019)
Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells
Authors: Eric R. Bray, Benjamin J. Yungher, Konstantin Levay, Marcio Ribeiro, Gennady Dvoryanchikov, Ana C. Ayupe, Kinjal Thakor, Victoria Marks, Michael Randolph, Matt C. Danzi, Tiffany M. Schmidt, Nirupa Chaudhari, Vance P. Lemmon, Samer Hattar, Kevin K. Park
Journal: Neuron (2019)
Abstract 19137: Association of Pulmonary Hypertension and Left Ventricular Dysfunction: Impact of Demographics
Authors: Roozbeh Sharif, Arnav Kumar, Adnan Khan, Trisha Parekh, Anjali Kohli, Van Hoang, Mohammad Morsy, Wissam Khalife
Journal: Circulation (2013)

The association between left ventricular diastolic dysfunction (LVDD) and pulmonary hypertension (PH) is shown in the literature, studies on the linear association between LVDD and PH severity and effect of demographics on this association are lacking. We aimed to investigate the correlation of LVDD with presence and/or severity of PH and to examine whether patient’s demographics modifies this association. Methods: Study population included 2702 randomly selected patients with ejection fraction (EF) ≥ 50%, who presented to the echocardiographic lab at a tertiary care academic center between 2008 and 2011. Diastolic function was assessed based on echocardiographic characteristics. PH was diagnosed if right ventricle systolic pressure (RSVP) was ≥ 40 mmHg. Using logistic regression analysis, the association between diastolic function and presence and severity of PH was examined after adjusting for potential demographic and clinical confounders. Then, we examined the interaction term of demographics (age, sex and combination of age and sex) in regards to the association between LVDD and PH. Results: Among 2702 patients, 1301 (48.4%) were female, 842 (31.2%) had normal LVDD and 694 (25.7%) had PH. Patients with LVDD had higher frequency of PH compared to those with normal diastolic function (28.1% vs. 18.6%, OR: 1.7; 95%CI: 1.4, 2.1; p&lt; 0.0001). RVSP increases at higher stages of LVDD (p&lt;0.0001). Among patients with LVDD, PH was found in 24.7% patients with impaired relaxation, 44.5% of pseudonormal, and 52.5% of those with restrictive. Subgroup analysis showed that in patients 60 (OR: 1.9 vs. 0.9, p&lt;0.0001 and 0.8820, respectively). Besides, the association of LVDD and PH was higher among female patients &lt; 60, compared to males &lt;60 (OR: 2.5 vs 1.5, p&lt;0.0001 and 0.0800, respectively). Sex did not modify the association between LVDD and PH. Conclusion: Patients with LVDD have higher risk of PH, compared to those patients with normal diastolic function. The severity of PH also increases with higher stages of the LVDD. In addition, these findings were more pronounced in middle age females.
Abstract 1153: Hypoxic microenvironments promote stemness and enhance the directed migration of glioma stem cells
Authors: Nitya V. Sharma, Monica Chau, Subhas Mukherjee, James Ross, Brandon Miller, Changming Zhang, Jun Kong, Carol Tucker-Burden, Emily Kaissi, John W. Reitnauer, Bilge Dundar, Cheryl L. Olson, Gregory Bix, Daniel J. Brat
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is a highly malignant primary brain tumor and has a poor prognosis and is resistant to the most advanced therapies. The development of highly hypoxic centrally located necrotic regions is strongly associated with accelerated GBM progression, yet mechanistic explanations are not complete. Hypoxic regions within GBM are highly enriched for glioma stem cells (GSC), which are critical for tumor initiation, recurrence and therapeutic resistance due to their self-renewing capabilites. While most GBM cells migrate outward, away from hypoxia, GSCs accumulate there, forming a hypercellular border called pseudopalisades that promote their survival. Mechanisms that mediate GSC accumulation within pseudopalisades are unknown. We hypothesize that GSCs are enriched in the pseudopalisades due to the homing of a subpopulation towards the supportive hypoxic microenvironment. This in turn activates critical hypoxia-induced drivers to promote stemness, survival and migratory behavior encouraging the recruitment of more GSCs. Using two genetically distinct patient-derived GBM cell lines, we found that exposure to hypoxia in vitro led to enrichment of GSCs among a heterogeneous population of GSCs and non-GSCs. We found that hypoxia enhanced the expression of stem cell, pro-survival and pro-migratory factors in GSCs, such as the pro-migratory chemokine SDF-1α, and its cognate receptor CXCR4. Importantly, we found hypoxia also induced upregulation of OLIG2, one of four core transcription factors necessary and sufficient to induce stemness, in GSCs and non-GSCs exposed to hypoxia. We determined that OLIG2 was necessary for the expression of stem cell markers, and that its knockdown reduced cellular migration in hypoxia vs normoxia in GSCs. This suggests a critical role for OLIG2 in both hypoxia-induced stemness and homing behavior. We also generated a unique model of localized hypoxia in one brain hemisphere through vaso-cclusion and observed the homing of xenografted GBM cells towards hypoxia, regulated by OLIG2 in vivo. These data shed light on how hypoxic tumor microenvironments facilitate mechanisms vital to GBM progression and therapeutic resistance. Citation Format: Nitya V. Sharma, Monica Chau, Subhas Mukherjee, James Ross, Brandon Miller, Changming Zhang, Jun Kong, Carol Tucker-Burden, Emily Kaissi, John W. Reitnauer, Bilge Dundar, Cheryl L. Olson, Gregory Bix, Daniel J. Brat. Hypoxic microenvironments promote stemness and enhance the directed migration of glioma stem cells [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 1153.
Targeting hypoxia downstream signaling protein, CAIX, for CAR T-cell therapy against glioblastoma
Authors: Jing Cui, Qi Zhang, Qi Song, Herui Wang, Pauline Dmitriev, Mitchell Y Sun, Xiaoyu Cao, Yang Wang, Liemei Guo, Iris H Indig, Jared S Rosenblum, Chunxia Ji, Dongqing Cao, Kaiyong Yang, Mark R Gilbert, Yu Yao, Zhengping Zhuang
Journal: Neuro-Oncology (2019)

Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to (i) develop chimeric antigen receptor (CAR) T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and (ii) demonstrate its efficacy with limited off-target effects.First we demonstrated expression of CAIX in patient-derived glioblastoma samples and available databases. CAR T cells were generated against CAIX and efficacy was assessed in 4 glioblastoma cell lines and 2 glioblastoma stem cell lines. Cytotoxicity of anti-CAIX CAR T cells was assessed via interferon gamma, tumor necrosis factor alpha, and interleukin-2 levels when co-cultured with tumor cells. Finally, we assessed efficacy of direct intratumoral injection of the anti-CAIX CAR T cells on an in vivo xenograft mouse model using the U251 luciferase cell line. Tumor infiltrating lymphocyte analyses were performed.We confirm that CAIX is highly expressed in glioblastoma from patients. We demonstrate that CAIX is a suitable target for CAR T-cell therapy using anti-CAIX CAR T cells against glioblastoma in vitro and in vivo. In our mouse model, a 20% cure rate was observed without detectable systemic effects.By establishing the specificity of CAIX under hypoxic conditions in glioblastoma and highlighting its efficacy as a target for CAR T-cell therapy, our data suggest that anti-CAIX CAR T may be a promising strategy to treat glioblastoma. Direct intratumoral injection increases anti-CAIX CAR T-cell potency while limiting its off-target effects.
Assessment of a Multi-Cytokine Profile By a Novel Biochip-Based Assay Reveals Unique Correlation Patterns with Immune Reconstitution after Cord Blood Transplantation in Adults
Authors: Theodoros Karantanos, Haesook T Kim, Lequn Li, Corey Cutler, Joseph H. Antin, Karen Ballen, Jerome Ritz, Ioannis Politikos, Vassiliki A Boussiotis
Journal: Blood (2017)
Phase 3 (COSMIC-312) study of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy
Authors: L. Rimassa, A. Cheng, F. Braiteh, F. Benzaghou, S. Hazra, A. Borgman, R. Sinha, Z. Kayali, A. Zhu, R. Kelley
Journal: Annals of Oncology (2019)
Image Gallery: Swelling of the upper eyelid with trichomegaly revealing neurofibromatosis type 1
Authors: C. Berthin, C. Hugny‐Larroque, F. Heran, L. Misery, C. Abasq‐Thomas
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, A 3‐week‐old boy with primary congenital glaucoma presented with a congenital swelling of the left upper eyelid (a) with trichomegaly and inconspicuous hypertrichosis of the left cheek (b). One month later, café au lait spots and naevus anaemicus were revealed over the trunk, while brain magnetic resonance imaging showed trigeminal nerve neurofibroma, left buphthalmos and orbital plexiform neurofibroma. A diagnosis of sporadic neurofibromatosis type 1 with an orbital plexiform neurofibroma was made. Congenital glaucoma with plexiform neurofibroma located on the eyelid is uncommon in neurofibromatosis type 1.1,2 This case highlights the importance of ophthalmological signs, which can reveal neurofibromatosis type 1 early on.