tbuckley/cabot-search huggingface dataset:
TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma
Authors: Matthew J. Reilley, Brittany Morrow, Casey R. Ager, Arthur Liu, David S. Hong, Michael A. Curran
Journal: Journal for ImmunoTherapy of Cancer (2019)

Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. Tumor-resident myeloid cells and selected lymphocyte populations retain expression of Toll-like Receptors (TLR) that sense common features of pathogens and activate innate immunity in response. We explored whether agonists of TLR9 could augment innate immunity to promote tumor regression alone or in combination with T cell checkpoint blockade. In the setting of the immunogenic B16-Ova (Ovalbumin) expressing melanoma model, local injection of the CpG oligonucleotide TLR9 agonist ODN1826 combined with systemic CTLA-4 blockade cured 45% of mice of both their treated and an untreated tumor on the opposite flank demonstrating the synergistic potential of this combination. Next, in the non-immunogenic B16-F10 melanoma model, we showed that only intra-tumoral, but not systemic TLR9 activation augments the therapeutic potential of checkpoint blockade. In this setting, intra-tumoral TLR9 activation cooperated equally with either CTLA-4 or PD-1 blockade co-administered locally or given systemically; however, the uninjected tumor rarely regressed. Anti-CTLA-4 combinations were associated with improved intra-tumoral CD8 to regulatory T cell ratios, while anti-PD-1 combinations elicited improved ratios of CD8 T cells relative to suppressive myeloid stroma. Using both a TLR9 agonist (MGN1703) and a CTLA-4 antibody (9D9-IgG2a) of increased potency cured 50% of bi-lateral B16-F10 melanoma. These findings suggest that intra-tumoral TLR9 agonists can improve sensitivity of poorly immunogenic tumors to T cell checkpoint blockade, and that newer, higher potency TLR agonists and checkpoint antibodies can raise the therapeutic ceiling for this combination therapy.
The role of transposable elements activity in aging and their possible involvement in laminopathic diseases
Authors: Davide Andrenacci, Valeria Cavaliere, Giovanna Lattanzi
Journal: Ageing Research Reviews (2019)

Eukaryotic genomes contain a large number of transposable elements, part of which are still active and able to transpose in the host genome. Mobile element activation is repressed to avoid deleterious effects, such as gene mutations or chromosome rearrangements. Control of transposable elements includes a variety of mechanisms comprising silencing pathways, which are based on the production of small non-coding RNAs. Silencing can occur either through transposable element RNA degradation or through the targeting of DNA sequences by heterochromatin formation and consequent transcriptional inhibition. Since the important role of the heterochromatin silencing, the gradual loss of heterochromatin marks in constitutive heterochromatin regions during the aging process promotes derepression of transposable elements, which is considered a cause of the progressive increase in genomic instability and of the activation of inflammatory responses. This review provides an overview of the effects of heterochromatin loss on the activity of transposable elements during the aging process and the possible impact on genome function. In this context, we discuss the possible role of the nuclear lamina, a major player in heterochromatin dynamics, in the regulation of transposable element activity and potential implications in laminopathic diseases.
Coronary Microvascular Dysfunction, Left Ventricular Remodeling, and Clinical Outcomes in Patients With Chronic Kidney Impairment
Authors: Navkaranbir S. Bajaj, Amitoj Singh, Wunan Zhou, Ankur Gupta, Kana Fujikura, Christina Byrne, Hendrik J. Harms, Michael T. Osborne, Paco Bravo, Efstathia Andrikopolou, Sanjay Divakaran, Courtney F. Bibbo, Jon Hainer, Hicham Skali, Viviany Taqueti, Michael Steigner, Sharmila Dorbala, David M. Charytan, Sumanth D. Prabhu, Ron Blankstein, Rahul C. Deo, Scott D. Solomon, Marcelo F. Di Carli
Journal: Circulation (2019)

Background: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. Methods: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women’s Hospital were studied longitudinally. Patients free of overt coronary (summed stress score &lt;3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e’) and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. Results: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR &lt;60 mL·min −1 ·1.73 m −2 , a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P &lt;0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. Conclusions: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.
Social care: 81 people a day die waiting for support in England, charity claims
Authors: Elisabeth Mahase
Journal: BMJ (2019)

In the 30 months between the last and upcoming election, an estimated 74 000 people will have died waiting for social care in England, according to a new report from Age UK.

The charity said this is equivalent to 81 people a day or three an hour between 8 June 2017 to 12th December 2019.

It also estimated that a total of 1 725 000 unmet requests will have been made by …
Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment
Authors: Noemi Puig, Maria-Victoria Mateos, Teresa Contreras, Bruno Paiva, María Teresa Cedena, José J Pérez, Irene Aires, Cristina Agullo, Joaquin Martinez-Lopez, Paula Rodriguez Otero, Veronica Gonzalez De La Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Rafael Rios, Laura Rosiñol, Miguel Angel Alvarez, Maria Jose Calasanz, Joan Bargay, Ana Pilar Gonzalez, Adrián Alegre, Fernando Escalante, Rafael Martínez, Javier de la Rubia, Ana Isabel Teruel, Felipe De Arriba, Luis Palomera, Miguel-Teodoro Hernández, Javier López, Jesús Martín, Aránzazu García Mateo, Ramón García-Sanz, Enrique M. Ocio, Joan Bladé, Juan-José Lahuerta, Jesus F. San-Miguel
Journal: Blood (2019)
Conservative oxygen therapy for mechanically ventilated adults with sepsis: a post hoc analysis of data from the intensive care unit randomized trial comparing two approaches to oxygen therapy (ICU-ROX)
Authors: Paul Young, Diane Mackle, Rinaldo Bellomo, Michael Bailey, Richard Beasley, Adam Deane, Glenn Eastwood, Simon Finfer, Ross Freebairn, Victoria King, Natalie Linke, Edward Litton, Colin McArthur, Shay McGuinness, Rakshit Panwar
Journal: Intensive Care Medicine (2019)
Graft-Versus-Host Disease (GVHD)-Free Relapse-Free Survival (GRFS) and Chronic Gvhd (CRFS) in Alternative Donor Hematopoietic Cell Transplantation (HCT) in Pediatric Patients
Authors: Rohtesh S. Mehta, Shernan G. Holtan, Tao Wang, Michael T. Hemmer, Stephen R. Spellman, Mukta Arora, Daniel R. Couriel, Amin M. Alousi, Joseph Pidala, Daniel J. Weisdorf
Journal: Blood (2017)
Pensions crisis: leaders call for long term solutions
Authors: Abi Rimmer
Journal: BMJ (2019)

NHS leaders have warned that the latest scheme to tackle doctors’ pension problems may not have much uptake and does not offer a workable solution for many of those facing unexpected tax bills.

The scheme is designed to allow doctors in England to pick up extra shifts this winter with the promise that the NHS will reimburse them for any additional tax they accrue as a result. Under the temporary scheme proposed by NHS England, hospital doctors and GPs who reach the annual allowance limit in 2019-20 will be able to choose a “scheme pay” option, meaning that they can pay their tax bill from their existing pension pot.

The NHS will …
SAT0559 IMPACT OF BLOCK SWITCH TO BIOSIMILAR ETANERCEPT IN PRACTICE – AN EXPERIENCE FROM ONE TERTIARY RHEUMATOLOGY DEPARTMENT
Authors: Luisa Brites, Flavio Costa, João Dinis de Freitas, Mariana Luis, Margarida Coutinho, Mariana Santiago, Maria Joao Salvador, Catia Duarte, P José Antonio, Da Silva
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Biosimilars of biotechnological agents represent an important opportunity to increase accessibility to these medications. Clinicians still maintain reservations regarding the similarity of their efficacy and safety in practice. <h3>Objectives</h3> To evaluate the clinical consequences of a non-medical switch of etanercept (ETN) original to biosimilar in a clinical practice setting. <h3>Methods</h3> The study included all patients aged 18+ treated in a Tertiary Rheumatology Department with original ETN who were switched to his biosimilar following a decison by the hospital administration, accepted by rheumatologists. Patients were informed of the switch prior to its occurrence, in simple terms underlining the similarity in terms of regulatory issues and scientific evidence. Disease activity, adverse events and adaptation to the drug delivery system were evaluated at each visit. Disease activity at baseline (time of switch), 3 and 6 months after was compared using Paired samples T-test or Wilcoxon test as adequate. A p≤0.05 was considered statistically significant. Continuous variables are presented as means and categorical variables as proportions. <h3>Results</h3> From 98 patients treated with original ETN in our department, 89 were switched to his biosimilar. The remaining ones maintained the treatment with the reference biological product for several reasons. Eight patients were excluded from this analysis due to poor adherence to treatment (n=4) and early interruption of treatment [n=4: due to surgery (n=1), respiratory infection (n=1), suspected allergic reaction to biosimilar (n=1) and own initiative (n=1)]. Of the remaining 81 patients (58% female, mean age 56.2±12.1 years), 38.3% had RA, 40.7% SpA, 18.5% PsA and 2.5% JIA. Disease activity was stable over the follow up in patients with RA, PsA and SpA as no statistically significant differences were observed in acute phase reactants, patient or physician global assessment between the three time points. Minor adverse events were reported by 2 patients (pain and local cutaneous reaction), 2 reported sense of disease exacerbation in the first three months that was not confirmed by clinical and analytical evaluation and 2 patients reported minor infections. Good adaptation to the drug delivery instrument was reported by 93.8% of patients (n=76). <h3>Conclusion</h3> The switch from ETN to his biosimilar in this group of patients followed in routine care did not affect the overall efficacy and safety of treatment. We did not observe a significant impact of nocebo effect. <h3>Disclosure of Interests</h3> None declared
Experience with Axicabtagene Ciloleucel (Axi-cel) in Patients with Secondary CNS Involvement: Results from the US Lymphoma CAR T Consortium
Authors: N. Nora Bennani, Matthew J. Maurer, Loretta J. Nastoupil, Michael D. Jain, Julio C. Chavez, Amanda F Cashen, Saurabh Dahiya, Lazaros J. Lekakis, Patrick M Reagan, Olalekan O. Oluwole, Joseph P. McGuirk, Abhinav Deol, Alison R. Sehgal, Andre Goy, Brian T. Hill, Khoan Vu, Charalambos Andreadis, Javier Munoz, Aaron P. Rapoport, Julie M Vose, David B Miklos, Frederick L. Locke, Sattva S Neelapu, Yi Lin
Journal: Blood (2019)
The Adult Sprague-Dawley Sugen-Hypoxia Rat Is Still “the One:” A Model of Group 1 Pulmonary Hypertension: Reply to Le Cras and Abman
Authors: Harm J. Bogaard, Ekaterina Legchenko, Maximilian Ackermann, Mark P. Kühnel, Danny D. Jonigk, Ketul R. Chaudhary, Xiaoqing Sun, Duncan J. Stewart, Georg Hansmann
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
PACIFIC-5: Phase III study of durvalumab after either concurrent or sequential chemoradiotherapy (CRT) in patients with stage III NSCLC
Authors: Y.-L. Wu, L. Wang, M.A.N. Sendur, Y.-C. Kim, Z. Zhu, Y. Cheng, P. Li, Y. Qin, E. Macpherson, P.A. Dennis, S. Lu
Journal: Annals of Oncology (2019)
Mapping MALT1 Signaling Connectivity Unveils Novel B-Cell Feedback Mechanisms Directing Assembly of Potent Anti-Lymphoma Regimens
Authors: Lorena Fontan, Matthew Durant, Rebecca Goldstein, Matthew R Teater, Gabriella Casalena, Min Xia, Jimmy Wilson, Ilkay Us, Giorgio Inghirami, Ari Melnick
Journal: Blood (2019)
Recombinant Protein Infusion and Hydrodynamic Plasmid Delivery Strategies Provide Distinct and Complementary Approaches to the Characterization of Variant Forms of Von Willeband Factor (VWF) in VWF Knockout Mice.
Authors: Cynthia M. Pruss, Carol A. Hegadorn, Andrea Labelle, Erin Burnett, Mia Golder, David Lillicrap
Journal: Blood (2008)
Metformin in Gynecologic Cancers: Opening a New Window for Prevention and Treatment?
Authors: Ainhoa Madariaga, Pamela J. Goodwin, Amit M. Oza
Journal: Clinical Cancer Research (2019)

Metformin is an affordable and well-tolerated drug used in type 2 diabetes. Potential anticancer effects of metformin in gynecologic malignancies include inhibition of the PI3K-mTOR pathway, hormone receptor regulation, and reduction of fibrosis and inflammation. Multiple studies are currently assessing its role in cancer prevention and as a treatment enhancer.See related articles by Soliman et al., p. 581, and McCloskey et al., p. 632.
Interrogation of Individual CLL Loss-of-Function Lesions By CRISPR In Vivo Editing Reveals Common and Unique Pathway Alterations
Authors: Elisa Ten Hacken, Shanye Yin, Kendell Clement, Robert A. Redd, Maria Hernandez-Sanchez, Shuqiang Li, Michaela Gruber, Heather Joyal, Geoffrey Fell, Shu Wang, Jose Jacob, James Flynn, David Ruff, Keith W. Jones, Lili Wang, Donna S Neuberg, Luca Pinello, Kenneth J. Livak, Ruben D. Carrasco, Catherine J. Wu
Journal: Blood (2019)
A Solitary Nodular Vulvar Lesion
Authors: Xavier Cubiró, Fernando Javier Pinedo-Moraleda, Cristina Galván
Journal: JAMA Dermatology (2019)

A girl in her teens presented with a unilateral itchy nodule on her right labium majus of 4 months’ duration. The patient was born and lived in a rural village in Malawi. Her medical and family history were unremarkable. What is your diagnosis?
Effect of inpatient palliative care on supportive care measures in patients undergoing hematopoietic cell transplantation (HCT).
Authors: Areej El-Jawahri, Harry VanDusen, Alyssa L. Fenech, Alison Kavanaugh, Vicki A. Jackson, Lara Traeger, Joseph Greer, Thomas R. Spitzer, Yi-Bin Albert Chen, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2019)

70 Background: Inpatient palliative care integrated with transplant care has been shown to improve patient-reported quality of life (QOL), symptom burden, and psychological distress during hospitalization for HCT. However, the impact of palliative care on supportive care practices during HSCT remains unknown. Methods: This secondary analysis is based on a single-site randomized clinical trial of 160 patients with hematologic malignancies undergoing HSCT between 8/2014 and 1/2016. Participants received either inpatient palliative care integrated with transplant care (n = 81) or transplant care alone (n = 79). We used the electronic health record to obtain data on supportive care measures during HSCT including the use of patient-controlled analgesia (PCA), intravenous pain medications, atypical antipsychotics (used to treat nausea/anxiety), psychostimulants, antidepressants, hypnotics, and the use of standing orders (as opposed to as needed ‘PRN’) for supportive care medications. We compared the proportion of subjects in each group receiving these supportive care measures using Fisher’s exact test. Results: Patients randomized to the palliative care intervention were more likely to use PCA (32.1% vs. 15.19%, P = 0.015), and atypical antipsychotics (35.8% vs. 17.7%, P = 0.012) compared to those receiving transplant care alone. Intervention participants were also more likely to have standing orders for their supportive care medications (74.1% vs. 56.9%, P = 0.030) compared to those receiving transplant care alone. Study groups did not differ in the of intravenous pain medications, psychostimulants, antidepressants, or hypnotics. Conclusions: Patients receiving inpatient integrated palliative and transplant care were more likely to utilize PCA and atypical antipsychotics during HCT compared to those receiving transplant care alone. Future work should examine whether these differences in supportive care practices mediate the effect of the palliative care intervention on patient-reported outcomes. Clinical trial information: NCT02207322.
Encodingism is not just a bad metaphor
Authors: Robert Mirski, Mark H. Bickhard
Journal: Behavioral and Brain Sciences (2019)

Abstract Brette's criticism of the coding metaphor focuses on its presence in neurosciences. We argue that this problematic view, which we call “encodingism,” is pernicious in any model of cognition that adopts it . We discuss some of the more specific problems it begets and then elaborate on Brette's action-based alternative to the coding framework.
ReorientExpress: reference-free orientation of nanopore cDNA reads with deep learning
Authors: Angel Ruiz-Reche, Akanksha Srivastava, Joel A. Indi, Ivan de la Rubia, Eduardo Eyras
Journal: Genome biology (2019)

Abstract We describe ReorientExpress, a method to perform reference-free orientation of transcriptomic long sequencing reads. ReorientExpress uses deep learning to correctly predict the orientation of the majority of reads, and in particular when trained on a closely related species or in combination with read clustering. ReorientExpress enables long-read transcriptomics in non-model organisms and samples without a genome reference without using additional technologies and is available at https://github.com/comprna/reorientexpress .
Bone Marrow Versus Mobilized Peripheral Blood Stem Cells for Non T Depleted Haploidentical Transplantations with Post Transplantation Cyclophosphamide in Acute Lymphoblastic Leukemia: On Behalf of the ALWP of the EBMT
Authors: Arnon Nagler, Myriam Labopin, Emanuele Angelucci, Yener Koc, Mutlu Arat, Pietro Pioltelli, Simona Sica, Zafer Gülbas, Johanna Tischer, Paolo Bernasconi, Jiri Pavlu, Gerard Socie, Didier Blaise, Luigi Rigacci, Massimo Martino, José Luis Díez-Martín, Zinaida Peric, Sebastian Giebel, Mohamad Mohty
Journal: Blood (2019)
Air pollution report shows health impact
Authors: Jacqui Wise
Journal: BMJ (2019)

Living near a busy road can stunt lung growth in children by as much as 14%, warns a new report backed by health and environmental groups that calls for tougher air pollution laws in the UK.1

Researchers from King’s College, London analysed 13 health outcomes in people living in high pollution areas and compared them with the general population in nine cities in the UK and four in Poland. They pooled data from previously published studies and meta-analyses, together with air pollution measurements from roadside monitoring stations.

Most previous reports have concentrated on deaths, life expectancy, and broad types of hospital admissions, whereas this report includes symptoms that affect many people, such as acute bronchitis in …
Sixty seconds on . . . stents
Authors: Nigel Hawkes
Journal: BMJ (2019)

So you might think if your acquaintances include a lot of interventional cardiologists. The clue’s in the name.

Exactly

A big new study suggests that in some cases they may be. The ISCHEMIA trial randomised more than 5000 patients with stable heart disease to either invasive therapy (stenting or a bypass) or to drugs, …
NHS and drug prices could be included in US-UK trade deal, leaked documents suggest
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The NHS and drug patents have been part of ongoing post-Brexit trade negotiations between the US and the UK, leaked unredacted documents obtained and shared by the Labour Party have shown.

The six documents outline “secret talks” held between US trade representatives and the UK Department for International Trade from July 2017 to July 2019. They include discussions on a variety of trade topics including drug pricing, longer patents for US drug companies, and the potential to discuss the NHS “further down the line.”

Earlier this month academics warned that, if the UK loses its ability to negotiate drug prices or to import generic drugs under a trade agreement with the US after Brexit, the NHS’s drug bill could soar from £18bn (€21bn; $23.2bn) to £45bn a year.1

The news that the talks between the UK and the US included drug pricing and the NHS comes after England’s health secretary, Matt Hancock, repeatedly said that “the NHS is not for sale and never will be under this Conservative administration.”2 Less than two hours before the documents were released, the prime …