tbuckley/cabot-search huggingface dataset:
Abstract 17683: LCZ696 vs. ACEI/ARB for Hypertension: A Meta-analysis of Randomized Controlled Trials
Authors: Abdulah Alrifai, shadi Al Halabi, Robert Chait
Journal: Circulation (2015)

Introduction: LCZ696 is a first-in-class inhibitor of the angiotensin II receptor and Neprilysin. The use of LCZ696 in Heart Failure is promising compared to ACEI or ARB. The use of LCZ696 for blood pressure has been studied but controversial. We performed a meta-analysis of randomized controlled trials (RCTs) comparing LCZ696 to ACEI/ARB for lowering systolic blood pressure effect. Objectives: To assess the efficacy of LCZ696 on systolic blood pressure in comparison to angiotensin-converting-enzyme inhibitor (ACEI)/Angiotensin II receptor antagonist (ARB). Methods: We searched PubMed, Medline, Embase and Cochrane for prospective RCTs that compared LCZ696 versus ACEI or ARB in patients with established diagnosis of essential hypertension. Trials that included patients with essential hypertension with or without heart failure were randomized to either LCZ696 or ACEI or ARB, and that also reported at least one of the studied outcomes were included. Study quality was assessed using the Jadad score. Heterogeneity of the studies was analyzed by Cochran’s Q statistics. Mean differences were calculated using the random effect model. Results: Three RCTs met our inclusion criteria and included 8996 patients who had mild-moderate essential hypertension and were between18-75 years. They were randomized to LCZ696 versus ACEI or ARB. The use of LCZ696 was associated with improved systolic blood pressure control when compared to the control group (MD -3.89; 95% CI -7.75, -0.04; P=0.05). Conclusions: Our findings suggest that the use of LCZ696 in hypertensive patients provides better reduction of blood pressure when compared to an ACEI or an ARB.
Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma
Authors: Rodabe N. Amaria, Sangeetha M. Reddy, Hussein A. Tawbi, Michael A. Davies, Merrick I. Ross, Isabella C. Glitza, Janice N. Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K. Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y. Lai, Richard Ehlers, Jorge Blando, Denái R. Milton, Scott Woodman, Robin Kageyama, Daniel K. Wells, Patrick Hwu, Sapna P. Patel, Anthony Lucci, Amy Hessel, Jeffrey E. Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M. Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J. Lazar, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C. Andrews, Christine N. Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T. Tetzlaff, Jennifer A. Wargo
Journal: Nature Medicine (2018)
3D Deep Learning from CT Scans Predicts Tumor Invasiveness of Subcentimeter Pulmonary Adenocarcinomas
Authors: Wei Zhao, Jiancheng Yang, Yingli Sun, Cheng Li, Weilan Wu, Liang Jin, Zhiming Yang, Bingbing Ni, Pan Gao, Peijun Wang, Yanqing Hua, Ming Li
Journal: Cancer Research (2018)

: Identification of early-stage pulmonary adenocarcinomas before surgery, especially in cases of subcentimeter cancers, would be clinically important and could provide guidance to clinical decision making. In this study, we developed a deep learning system based on 3D convolutional neural networks and multitask learning, which automatically predicts tumor invasiveness, together with 3D nodule segmentation masks. The system processes a 3D nodule-centered patch of preprocessed CT and learns a deep representation of a given nodule without the need for any additional information. A dataset of 651 nodules with manually segmented voxel-wise masks and pathological labels of atypical adenomatous hyperplasia (AAH), adenocarcinomas in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive pulmonary adenocarcinoma (IA) was used in this study. We trained and validated our deep learning system on 523 nodules and tested its performance on 128 nodules. An observer study with 2 groups of radiologists, 2 senior and 2 junior, was also investigated. We merged AAH and AIS into one single category AAH-AIS, comprising a 3-category classification in our study. The proposed deep learning system achieved better classification performance than the radiologists; in terms of 3-class weighted average F1 score, the model achieved 63.3% while the radiologists achieved 55.6%, 56.6%, 54.3%, and 51.0%, respectively. These results suggest that deep learning methods improve the yield of discriminative results and hold promise in the CADx application domain, which could help doctors work efficiently and facilitate the application of precision medicine. SIGNIFICANCE: Machine learning tools are beginning to be implemented for clinical applications. This study represents an important milestone for this emerging technology, which could improve therapy selection for patients with lung cancer.
Abstract P294: The Chinese Great Famine and Major Depression Disorder: the CHARLS study
Authors: Luqi Shen, Cheng Huang, Changwei Li
Journal: Circulation (2017)

Objectives: To estimate the prevalence of major depression and experience severe famine during the Chinese Great Famine in middle-aged and older Chinese population, and to evaluate the impact of famine experience on risk of major depression in late adulthood. Methods: We estimated the prevalence of major depression and severe famine in participants of the China Health and Retirement Longitudinal Study (CHARLS). CHARLS surveyed a representative sample of 17,708 middle-aged and older Chinese adults. SAS PROCFREQ procedure was applied to estimate famine and depression prevalence taking into account the survey design and responding rate. Depression was measured using Center for Epidemiological Studies Depression Scale (CES-D) short form. Famine was based on self-report, and was categorized into none, slight, moderate, and severe. We evaluated famine experience and major depression risk in late adulthood in cohorts of different development stages when famine occurred, using logistic regression adjusting for important demographic, socioeconomic, biomedical, and chronic comorbidities. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) are presented. Results: A total of 11.60% of the middle-aged and older Chinese adults experienced severe famine in 1959-1961. Famine significantly increased risk of major depression in late adulthood among those who experienced famine during fetal, mid-childhood, young teens, and adulthood. Compared to those who did not experience famine, those with severe famine experience were 3.00 (95% CI: 1.53-5.89), 1.94 (95% CI: 1.39-2.71), 1.89 (95% CI: 1.15-3.10), and 2.32 (95% CI: 1.62-3.32) times more likely to have major depression in late adulthood among the fetal, mid-childhood, young teens, and adulthood cohorts, respectively. Even adjusting for all variables, there are still significant trends between famine severity and risk of major depression. However, famine experience was not associated with late adulthood depression risk among infant, toddler, preschool, or teenagers cohorts. Conclusion: More than 11.6% of the Chinese population experienced severe famine. Exposure to famine during fetal, mid-childhood, young teens, and adulthood stages increased risk of depression in late adulthood.
Detection of mixed-strain infections by FACS and ultra-low input genome sequencing
Authors: Mária Džunková, Andrés Moya, Xinhua Chen, Ciaran Kelly, Giuseppe D’Auria
Journal: Gut Microbes (2018)

The epidemiological tracking of a bacterial outbreak may be jeopardized by the presence of multiple pathogenic strains in one patient. Nevertheless, this fact is not considered in most of the epidemiological studies and only one colony per patient is sequenced. On the other hand, the routine whole genome sequencing of many isolates from each patient would be costly and unnecessary, because the number of strains in a patient is never known a priori. In addition, the result would be biased by microbial culture conditions.Herein we propose an approach for detecting mixed-strain infection, providing C. difficile infection as an example. The cells of the target pathogenic species are collected from the bacterial suspension by the fluorescence activated cell sorting (FACS) and a shallow genome sequencing is performed. A modified sequencing library preparation protocol for low-input DNA samples can be used for low prevalence gut pathogens (< 0.1% of the total microbiome). This FACS-seq approach reduces diagnostics time (no culture is needed) and may promote discoveries of novel strains. Methodological details, possible issues and future directions for the sequencing of these natural pan-genomes are herein discussed.
Abstract 14284: Temporal Evolution of Renal Markers for Personalized Risk Assessment in Chronic Heart Failure
Authors: Milos Brankovic, K. Martijn Akkerhuis, Alina Constantinescu, Kadir Caliskan, Olivier Manintveld, Jan Hein Cornel, Sara Baart, Dimitris Rizopoulos, Hans Hillege, Eric Boersma, Victor Umans, Isabella Kardys
Journal: Circulation (2016)

Introduction: Single ‘baseline’ assessments of glomerular filtration and tubular damage independently predict clinical outcome in patients with chronic heart failure (CHF). However, the temporal relationship is not known. We investigated whether temporal patterns of renal markers predict adverse clinical outcome in patients with CHF. Methods: In 263 CHF patients, we repeatedly assessed markers of glomerular function: cystatin C (CysC), creatinine, estimated glomerular filtration rate (eGFR); and tubular damage markers: urinary N-acetyl-beta-d-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). We investigated the associations between temporal patterns of renal markers and the composite endpoint of HF hospitalizations, cardiovascular death, LVAD placement and heart transplantation. We used time to first event and applied joint modeling, which combines mixed models for subject-specific marker evolution and Cox regression for occurre...
A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma
Authors: Jacob P. Laubach, Chia-Jen Liu, Noopur S. Raje, Andrew J. Yee, Philippe Armand, Robert L. Schlossman, Jacalyn Rosenblatt, Jacquelyn Hedlund, Michael Martin, Craig Reynolds, Kenneth H. Shain, Ira Zackon, Laura Stampleman, Patrick Henrick, Bradley Rivotto, Kalvis T.V. Hornburg, Henry J. Dumke, Stacey Chuma, Alexandra Savell, Damian R. Handisides, Stew Kroll, Kenneth C. Anderson, Paul G. Richardson, Irene M. Ghobrial
Journal: Clinical Cancer Research (2018)

The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined.The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months.Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
Pineal region glioblastoma: report of two long term survivors
Authors: Dr Pankaj Nanda, Prof Philip Kane, Mr Anil Varma
Journal: Neuro-Oncology (2018)

Pineal region glioblastoma (GBM) is an rare entity and is considered to have a poor prognosis similar to cerebral GBM. The current literature describes approximately 28 cases of pineal region GBM reported worldwide with no case series of more than 3 patients. Even with radical treatment the median survival is reported as 6 months (range 6–24 months) with occasional reports describing survival in the range of 24–38 months. Retrospective audit of all cases of GBM treated in our unit between 2008 and 2018. Data were collected from pathology reports, case notes, clinic letters and MDT outcomes. We identified only two cases of pineal region GBM in male patients, aged 21 years and 50 years at the time of diagnosis (in 2013 and 2011 respectively), who are alive at 53 and 75 months since diagnosis. They are still under follow-up, maintaining a good performance status with no radiological evidence of tumour recurrence till date. Both patients had a biopsy, CSF diversion procedure, radical radiotherapy with concomitant temozolomide chemotherapy and 6 cycles of adjuvant temozolomide. Although the overall survival for GBM following only a biopsy and chemoradiotherapy is considered poor, our experience of these tumours in the pineal region show a longer survival with similar treatment, when compared to GBM in cortical location. A larger study including detailed molecular genetic analysis may help in better understanding of the tumour behaviour and whether the location in the pineal region may be of prognostic value. Due to the rarity of GBM in the pineal region, this may only be possible if multiple centres collaborate in such studies.
More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations
Authors: Evelyn Lilly, Christopher G. Bunick, Alexander M. Maley, Shali Zhang, Mary K. Spraker, Amy J. Theos, Karina L. Vivar, Lucia Seminario-Vidal, Adam E. Bennett, Robert Sidbury, Yasushi Ogawa, Masashi Akiyama, Barbara Binder, Smail Hadj-Rabia, Raffaella A. Morotti, Earl J. Glusac, Keith A. Choate, Gabriele Richard, Leonard M. Milstone
Journal: Journal of the American Academy of Dermatology (2018)
Comparing neurosurgical intervention survival outcomes for intracranial metastases in patients with known or unknown primary tumours
Authors: Ms Melissa Gough, Ms Molly Nielsen, Mr Khalil ElGendy, Mr Damian Holliman
Journal: Neuro-Oncology (2018)

INTRODUCTION:There is an urgent need to expedite the development of new or repurposed drugs for children's cancer.An additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non-toxic concentrations for sufficient duration to achieve the biological effect.Children's brain tumours account for over 20% of childhood cancers and differ significantly in their biological characteristics from their adult counterparts.METHODS: The authors participated in an international CNS drug delivery workshop funded by the charity Children with Cancer UK in February 2016, where different experimental techniques aimed at optimising CNS drug delivery in children's brain tumours were discussed.RESULTS: The workshop was reported by e-cancer (http://ecancer.org/journal/10/full/630-highlights-of-children-with-cancer-uk-s-workshop-on-drug-delivery-in-paediatric-brain-tumours.php;http://ecancer.org/conference/831-drug-delivery-in-paediatric-brain-tumours.php).We were encouraged to develop a proposal to establish an international research consortium to raise awareness and promote collaboration in the field.This is now funded for two years by Children with Cancer UK.The Children's Brain Tumour Drug Delivery Consortium seeks to strengthen collaborative developments by working closely with the international children's brain tumour community, encouraging and facilitating discussions between a multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders.As of March 2018, we have 94 individuals from 11 nations registered as members, with diverse stakeholders represented by academics, clinical academics, charities, public/ patient groups, industry and regulatory bodies.CONCLUSION: We present this abstract to the BNOS conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event, and to extend our invitation for collaborators to join the consortium.
COMMANDER HF — A Trial and an Answer
Authors: Marc A. Pfeffer, Jean-Claude Tardif
Journal: New England Journal of Medicine (2018)

Patients with heart failure and a reduced left ventricular ejection fraction are at high risk for complications and death, despite the proven benefits of established medications and devices. Several newer medications that have been tested in this context have not yielded positive results or have even caused harm. Therefore, the search continues for additional therapeutic avenues to improve the fate of patients who have this highly prevalent condition. COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following . . .
Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution
Authors: Jonathan D. Proto, Amanda C. Doran, Galina Gusarova, Arif Yurdagul, Erdi Sozen, Manikandan Subramanian, Mohammad N. Islam, Christina C. Rymond, Jasper Du, Jaime Hook, George Kuriakose, Jahar Bhattacharya, Ira Tabas
Journal: Immunity (2018)
Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment
Authors: Jessica L.F. Teh, Andrew E. Aplin
Journal: Clinical Cancer Research (2018)

The uncontrolled proliferation of cancer cells has led to the development of small-molecule inhibitors to target cell-cycle progression. Palbociclib, ribociclib, and abemaciclib are ATP-competitive inhibitors of cyclin-dependent kinases 4/6 (CDK4/6), which function early within the G1 phase of the cell cycle. Recently, CDK4/6 inhibitors have gained FDA approval in postmenopausal estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer and testing in other cancer types is underway. However, resistance to CDK4/6 inhibitors frequently develops. In addition, targeting CDK4/6 may augment the action of immune checkpoint blockade agents. Here, we review recent studies that provide the preclinical rationale for treatment combinations and schedules that include CDK4/6 inhibitors. Furthermore, we discuss inhibitor effects on tumor-infiltrating lymphocytes as a preclinical rationale for targeting CDK4/6 in combination with anti-PD-1 or anti-CTLA-4 antibodies.
Management of antiphospholipid syndrome
Authors: Imad Uthman, Mohammad Hassan A Noureldine, Guillermo Ruiz-Irastorza, Munther Khamashta
Journal: Annals of the Rheumatic Diseases (2018)

Antiphospholipid syndrome, also known as ‘Hughes Syndrome’, is an autoimmune disease characterised by a set of clinical manifestations, almost all of which are direct or indirect sequelae of a hypercoagulable state involving the venous, and to a lesser extent the arterial vasculature. The incidence and prevalence of antiphospholipid syndrome are estimated at approximately 5 de novo cases per 100 000 per year and 40–50 cases per 100 000 individuals, respectively. The clinical spectrum of antiphospholipid syndrome involves haematological (thrombocytopaenia, venous thrombosis), obstetrical (recurrent pregnancy loss), neurological (stroke, transient ischaemic attack, migraine, seizures, cognitive dysfunction, chorea, transverse myelitis, multiple sclerosis), cardiovascular (cardiac valve disease), dermatological (livedo reticularis and racemosa, skin ulceration and necrosis), renal (glomerulonephritis, renal thrombotic microangiopathy) and orthopaedic (avascular necrosis of bones, non-traumatic fractures) manifestations, among others. In addition to the classical antiphospholipid antibodies, namely anticardiolipin antibodies and lupus anticoagulant, new autoantibodies and antibody complexes of different immunoglobulin subtypes (IgA, IgG, IgM) are now recognised as significant contributors to the pathogenesis of antiphospholipid syndrome. Anticoagulation remains the cornerstone in the management of antiphospholipid syndrome; nevertheless, new drugs and therapeutic strategies are being tested, and some have been found effective for the primary and secondary thromboprophylaxis in antiphospholipid syndrome.
Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes
Authors: A. Scott McCall, Gautam Bhave, Vadim Pedchenko, Jacob Hess, Meghan Free, Dustin J. Little, Thomas P. Baker, William F. Pendergraft, Ronald J. Falk, Stephen W. Olson, Billy G. Hudson
Journal: Journal of the American Society of Nephrology (2018)

Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur via disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP.We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score.We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production in vitro. The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.