tbuckley/cabot-search huggingface dataset:
A Radical Approach to Ebola: Saving Humans and Other Animals
Authors: Sarah J. L. Edwards, Charles H. Norell, Phyllis Illari, Brendan Clarke, Carolyn P. Neuhaus
Journal: The American Journal of Bioethics (2018)

As the usual regulatory framework did not fit well during the last Ebola outbreak, innovative thinking still needed. In the absence of an outbreak, randomised controlled trials of clinical efficacy in humans cannot be done, while during an outbreak such trials will continue to face significant practical, philosophical, and ethical challenges. This article argues that researchers should also test the safety and effectiveness of novel vaccines in wild apes by employing a pluralistic approach to evidence. There are three reasons to test vaccines in wild populations of apes: i) protect apes; ii) reduce Ebola transmission from wild animals to humans; and iii) accelerate vaccine development and licensing for humans. Data obtained from studies of vaccines among wild apes and chimpanzees may even be considered sufficient for licensing new vaccines for humans. This strategy will serve to benefit both wild apes and humans.
P3.12-12 Genomic Profiling of Pulmonary Large-Cell Neuroendocrine Carcinoma (LCNEC) Reveals Distinct Mutational Landscape
Authors: L. Wu, G. Lin, X. Hu, L. Chen, Y. Lin, S. Zhang, Z. Han, J. Ye, X. Mao, W. Peng, M. Jiang
Journal: Journal of Thoracic Oncology (2018)
Gesicle-Mediated Delivery of CRISPR/Cas9 Ribonucleoprotein Complex for Inactivating the HIV Provirus
Authors: Lee A. Campbell, Lamarque M. Coke, Christopher T. Richie, Lowella V. Fortuno, Aaron Y. Park, Brandon K. Harvey
Journal: Molecular Therapy (2018)

Investigators have utilized the CRISPR/Cas9 gene-editing system to specifically target well-conserved regions of HIV, leading to decreased infectivity and pathogenesis in vitro and ex vivo. We utilized a specialized extracellular vesicle termed a "gesicle" to efficiently, yet transiently, deliver Cas9 in a ribonucleoprotein form targeting the HIV long terminal repeat (LTR). Gesicles are produced through expression of vesicular stomatitis virus glycoprotein and package protein as their cargo, thus bypassing the need for transgene delivery, and allowing finer control of Cas9 expression. Using both NanoSight particle and western blot analysis, we verified production of Cas9-containing gesicles by HEK293FT cells. Application of gesicles to CHME-5 microglia resulted in rapid but transient transfer of Cas9 by western blot, which is present at 1 hr, but is undetectable by 24 hr post-treatment. Gesicle delivery of Cas9 protein preloaded with guide RNA targeting the HIV LTR to HIV-NanoLuc CHME-5 cells generated mutations within the LTR region and copy number loss. Finally, we demonstrated that this treatment resulted in reduced proviral activity under basal conditions and after stimulation with pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). These data suggest that gesicles are a viable alternative approach to deliver CRISPR/Cas9 technology. Investigators have utilized the CRISPR/Cas9 gene-editing system to specifically target well-conserved regions of HIV, leading to decreased infectivity and pathogenesis in vitro and ex vivo. We utilized a specialized extracellular vesicle termed a "gesicle" to efficiently, yet transiently, deliver Cas9 in a ribonucleoprotein form targeting the HIV long terminal repeat (LTR). Gesicles are produced through expression of vesicular stomatitis virus glycoprotein and package protein as their cargo, thus bypassing the need for transgene delivery, and allowing finer control of Cas9 expression. Using both NanoSight particle and western blot analysis, we verified production of Cas9-containing gesicles by HEK293FT cells. Application of gesicles to CHME-5 microglia resulted in rapid but transient transfer of Cas9 by western blot, which is present at 1 hr, but is undetectable by 24 hr post-treatment. Gesicle delivery of Cas9 protein preloaded with guide RNA targeting the HIV LTR to HIV-NanoLuc CHME-5 cells generated mutations within the LTR region and copy number loss. Finally, we demonstrated that this treatment resulted in reduced proviral activity under basal conditions and after stimulation with pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). These data suggest that gesicles are a viable alternative approach to deliver CRISPR/Cas9 technology.
Abstract 16190: Myocardial Deformation as Provided by CMR Based Feature Tracking is Related to Exercise Capacity and Outcome in Patients with Repaired Tetralogy of Fallot
Authors: Gerhard-Paul Diller, Stefan Orwat, Aleksander Kempny, Robert Radke, Brigitte Peters, Philipp B Beerbaum, Samir Sarikouch, Helmut Baumgartner
Journal: Circulation (2012)

Background: Parameters of myocardial deformation have been suggested to be superior to conventional measures of ventricular function in pts. with repaired tetralogy of Fallot (rToF). We assessed biventricular myocardial function using CMR cine-based feature tracking (FT) in a large cohort of rToF pts. to study its relation to clinical parameters and outcome. Methods and Results: Pts. with rToF undergoing standardized CMR imaging were recruited as part of a nationwide, prospective study between 2005 and 2008. In addition to conventional parameters of ventricular volumes and function, myocardial deformation was assessed by CMR based FT (TomTec, Unterschleissheim, Germany). FT analysis was performed for the left (LV) and right ventricle (RV), providing longitudinal (LS), circumferential (CS) and radial global strain (RS). Cardiopulmonary exercise data at the time of CMR were available in 95% of pts. A composite endpoint of death, successful cardiopulmonary resuscitation, documented ventricular tachycardia (V...
A phase III, randomized, placebo-controlled trial of adjuvant nivolumab plus ipilimumab in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after radical or partial nephrectomy (CheckMate 914)
Authors: A. Bex, V. Grünwald, P. Russo, Y. Tomita, E. Berghorn, M.B. McHenry, R.J. Motzer
Journal: Annals of Oncology (2018)
Efficacy of second-line nivolumab after early time to progression on first-line cytotoxic chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)
Authors: T. Ota, K. Kirita, H. Udagawa, S. Umemura, S. Matsumoto, K. Yoh, S. Niho, K. Goto
Journal: Annals of Oncology (2018)
Intracranial activity of ensartinib in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC)
Authors: H. Wakelee, K.L. Reckamp, T.A. Leal, S.P. Patel, G. Blumenschein, E. Shum, J. Nieva, G. Oxnard, R.E. Sanborn, S. Waqar, K. Zeman, G. Dukart, K. Harrow, C. Liang, A. Holzhausen, L. Horn
Journal: Annals of Oncology (2018)
Long-term Follow-up of Autologous Fat Transfer vs Conventional Breast Reconstruction and Association With Cancer Relapse in Patients With Breast Cancer
Authors: Todor Krastev, Arjen van Turnhout, Eline Vriens, Luc Smits, René van der Hulst
Journal: JAMA Surgery (2018)

Autologous fat transfer (AFT or fat grafting) has become an invaluable tool for the correction of disfiguring deformities after breast cancer surgery. However, clinical and animal studies have shown conflicting results regarding its oncologic safety.To determine whether exposure to AFT vs conventional breast reconstruction is associated with increased rates of cancer relapse in patients with breast cancer.This matched cohort study involved retrospective medical record review to identify all patients in a local patient database receiving AFT between 2006 and 2014. Each AFT case was matched with a nonexposed control patient with similar baseline characteristics. The mean (SD) follow-up of patients receiving AFT was 9.3 (4.9) years including 5.0 (1.7) years following AFT. Control patients were followed up for a mean (SD) of 8.6 (1.8) years from the primary surgery. Patients were identified through the local patient database of the Tergooi Hospital in Hilversum, the Netherlands. A total of 287 patients with breast cancer (300 affected breasts) who received AFT for breast reconstruction after cancer were included in the intervention group. Each AFT case was matched with a respective control patient based on age, type of oncologic surgery, tumor invasiveness, and disease stage. In addition, individual AFT-control pairs were selected to have the same locoregional recurrence-free interval at baseline. Data were analyzed between 2016 and 2017.Reconstruction with AFT vs conventional breast reconstruction or none.Primary end points were the cumulative incidences of oncologic events in AFT and control patients and their respective hazard ratios.Of the 587 total patients, all were women and the mean age was 48.1 years for the patients undergoing AFT and 49.4 years for the control patients. Eight locoregional recurrences were observed in the treatment group (287 patients) and 11 among the control group (300 patients), leading to an unadjusted hazard ratio of 0.63 (95% CI, 0.25-1.60; P = .33). No increased locoregional recurrence rates were seen in relevant subgroups based on the type of oncological surgery, tumor invasiveness, or pathological stage. In addition, no increased risks with AFT were detected with respect to distant recurrences or breast cancer-specific mortality.No significant differences in the locoregional recurrence rates between the AFT and control groups were observed after 5 years of follow-up. These findings confirm the results of previous studies; therefore, clinical evidence suggesting that AFT is associated with increased risk for cancer relapse is still lacking.
Enlisting commensal microbes to resist antibiotic-resistant pathogens
Authors: James W. Keith, Eric G. Pamer
Journal: The Journal of Experimental Medicine (2018)

The emergence of antibiotic-resistant bacterial pathogens is an all-too-common consequence of antibiotic use. Although antibiotic resistance among virulent bacterial pathogens is a growing concern, the highest levels of antibiotic resistance occur among less pathogenic but more common bacteria that are prevalent in healthcare settings. Patient-to-patient transmission of these antibiotic-resistant bacteria is a perpetual concern in hospitals. Many of these resistant microbes, such as vancomycin-resistant
A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adults: Epithelioid sarcoma cohort (NCT02601950)
Authors: M. Gounder, P. Schöffski, V. Villalobos, G. Cote, R. Chugh, T.W.-W. Chen, T. Jahan, E.T. Loggers, A. Italiano, A. Gupta, M. Agulnik, S. Attia, R.L. Jones, B.A. van Tine, G.D.D. Demetri, M. Roche, I. Sapir, S. Daigle, A. Clawson, S. Stacchiotti
Journal: Annals of Oncology (2018)
The Majority of CD45– Ter119– CD31– Bone Marrow Cell Fraction Is of Hematopoietic Origin and Contains Erythroid and Lymphoid Progenitors
Authors: Philip E. Boulais, Toshihide Mizoguchi, Samuel Zimmerman, Fumio Nakahara, Judith Vivié, Jessica C. Mar, Alexander van Oudenaarden, Paul S. Frenette
Journal: Immunity (2018)
Clinical Impact of Tumor Mutational Burden in Neuroblastoma
Authors: William L Hwang, Rachel L Wolfson, Andrzej Niemierko, Karen J Marcus, Steven G DuBois, Daphne Haas-Kogan
Journal: JNCI Journal of the National Cancer Institute (2018)

Neuroblastoma is the most common pediatric extracranial solid tumor. Within conventional risk groups, there is considerable heterogeneity in outcomes, indicating the need for improved risk stratification.In this study we analyzed the somatic mutational burden of 515 primary, untreated neuroblastoma tumors from three independent cohorts. Mutations in coding regions were determined by whole-exome/genome sequencing of tumor samples compared to matched blood leukocytes. Survival data for 459 patients were available for analysis of 5-year overall survival using the Kaplan-Meier method and log-rank test. All statistical tests were two-sided.Despite a low overall somatic mutational burden (mean = 3, range = 0-56), 107 patients were considered to have high mutational burden (>3 mutations). Unfavorable histology and age 18 months and older were associated with high mutational burden. Patients with high mutational burden had inferior 5-year overall survival (29.0%, 95% confidence interval [CI] = 17.2 to 41.8%) vs those with three or fewer somatic mutations (76.2%, 95% CI = 71.5 to 80.3%) (log-rank P < .001) and this association persisted when limiting the analysis to genes included on a 447-gene panel commonly used in clinical practice. On multivariable analysis, mutational burden remained prognostic independent of age, stage, histology and MYCN status.This study demonstrates that mutational burden of primary neuroblastoma may be useful in combination with conventional risk factors to optimize risk stratification and guide treatment decisions, pending prospective validation.
Low risk cancer: recalibrate rather than just rename?
Authors: Murali Varma
Journal: BMJ (2018)

The controversy about renaming some low risk cancers1 is partly related to the perception of “benign” and “malignant” as biologically distinct conditions, when there is a continuum of increasing risk from benign to “good cancer” and “bad cancer.”2

The distinction between good and bad cancer is generally accepted to be arbitrary, with any risk of metastasis …
EVIDENS: An observational study of nivolumab-treated patients in advanced non-small cell lung cancer (NSCLC) in a real-world setting: Initial results on 1394 patients
Authors: A. Dixmier, D. Debieuvre, C. Raspaud, J.B. Auliac, N. Benoit, P. Bombaron, B. Asselain, A. Dumont, P. Lamoureux, N. Goyard, D. Moro-Sibilot, M. Perol, F. Barlesi, C. Audigier Valette
Journal: Annals of Oncology (2018)
Abstract IA14: Circulating tumor DNA in early-stage NSCLC: A lung TRACERx study
Authors: Christopher Abbosh
Journal: Clinical Cancer Research (2018)

Abstract The Cancer Research UK-funded study TRACERx (TRAcking Cancer Evolution through therapy [Rx]) aims to recruit patients undergoing surgery for early-stage non-small cell lung cancer (NSCLC). Patients donate blood pre- and postoperatively alongside multi-region sampled primary tumor tissue. Up to 40% of patients undergoing surgery for NSCLC experience relapse of their disease. At this point patients are approached for relapse tissue sampling. TRACERx therefore provides a strong platform for evaluating circulating tumor DNA (ctDNA) in early-stage NSCLC and a minimal residual disease (MRD) setting. In this presentation we will describe data arising from a phylogenetic, patient-specific approach to ctDNA evaluation in the first 100 patients analyzed as part of TRACERx. We will discuss clinicopathologic factors associated with ctDNA detection in early-stage NSCLC and suggest the existence of distinct tumor phenotypic characteristics that predict the presence of ctDNA at measurable quantities in plasma. Additionally, we will discuss tumor volume limit of detection analyses and highlight potential implications of our findings within the context of early cancer detection. We will then examine data arising from the ctDNA profiling of postoperative plasma samples taken in the adjuvant setting. These data demonstrate that ctDNA detection is specific for NSCLC relapse and that ctDNA detection precedes clinical diagnosis of NSCLC relapse (median lead-time of 77 days, range 10 to 346 days). We will provide examples of using phylogenetic ctDNA profiling to characterize the subclonal nature of relapsing NSCLC as a potential method to personalize relapse therapeutic intervention. Finally, we will highlight potential advantages of patient-specific ctDNA profiling in an adjuvant MRD setting and suggest ways that this technology can be used to fuel adjuvant drug development in NSCLC by driving novel study designs. Citation Format: Christopher Abbosh. Circulating tumor DNA in early-stage NSCLC: A lung TRACERx study [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA14.
68Ga-PSMA Uptake in Anal Fistula on PET/CT Scan
Authors: Søren Klingenberg, Mads Ryø Jochumsen, Tomas Frahm Nielsen, Kirsten Bouchelouche
Journal: Clinical Nuclear Medicine (2018)

Ga-prostate-specific membrane antigen (PSMA) PET/CT scan for primary staging discovered increased Ga-PSMA uptake in a known anal fistula in a recently diagnosed high-risk prostate cancer patient. The patient had an ongoing history of surgical revisions of complex fistulas in the perianal region, contributing to active inflammation and infection. Recently, reports have demonstrated increased Ga-PSMA uptake in different benign inflammatory conditions. This case demonstrates another case of a benign condition associated with increased Ga-PSMA uptake.
Stephen Charles Wyndham Rowlands
Authors: Megan Rowlands
Journal: BMJ (2018)

Stephen Charles Wyndham Rowlands (“Steve”) went to St Mary’s medical school as a promising scrum half, hoping to play a high level of rugby. Alongside his studies he did just that and qualified as a doctor in 1976. He started a career in anaesthetics, but he soon realised he liked his patients to be awake, and made the change to general practice in 1980.

His first training post to this end was in obstetrics at Northwick Park Hospital. Here he met Chris, a midwife, who was to become his wife of 36 years and mother to their three children. Ever one to seek adventure, Steve took a …
Therapeutic potential of pteridine derivatives: A comprehensive review
Authors: Violeta Carmona‐Martínez, Antonio J. Ruiz‐Alcaraz, María Vera, Antonio Guirado, María Martínez‐Esparza, Pilar García‐Peñarrubia
Journal: Medicinal Research Reviews (2018)

Abstract Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state‐of‐the‐art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine‐based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation‐related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.
Pamiparib, a novel PARP 1/2 inhibitor, monotherapy for gBRCAm patients with recurrent ovarian, fallopian, and primary peritoneal cancer: An open-label, multicenter, phase II trial in China
Authors: X. Wu, J. Wang, Q. Zhou, T. Gu, K. Zhang, J. Liang, S. Mu, R. Ge, H. Yang, V. Huang, R. Brachmann, L. Wang, M. Li
Journal: Annals of Oncology (2018)
Reducing the back overuse-related risks in alpine ski racing: let’s put research into sports practice
Authors: Jörg Spörri, Josef Kröll, Matej Supej, Erich Müller
Journal: British Journal of Sports Medicine (2018)

It is well recognised in alpine ski racing (ASR) that the risk of traumatic injuries is high.1 Yet, so far the nature and causation of ASR-related back overuse injuries have received little attention.2 During adolescence, competitive alpine skiers are already suffering from more prevalent spinal disc degeneration and more severe back pain than age-matched controls.3 Factors previously suggested as being important components of mechanisms leading to overuse injuries of the back are: (1) adverse trunk kinematics including a combined occurrence of frontal bending, lateral bending and torsion,4 (2) high ground reaction forces,4 and (3) excessive exposure to low-frequency whole-body vibrations (WBV) (~4–10 Hz; ie, frequencies close to resonant frequency of the spine; known to be the most damaging to spinal structures).5 6 All of these factors have been demonstrated to be inherent parts of ASR and occur in different combinations and intensities.4 5 Despite applying quite radical equipment and course modifications, previous studies discovered the ASR-specific overall trunk kinematics to be unchangeable.7 8 

Regarding low-frequency WBV exposure in combination with high ground reaction forces, recent studies revealed significant differences in the power spectral density (ie, the signal’s power distribution over frequency) and the root mean square of low-frequency weighted vibrations …
Intratumoral (IT) Injection of the TLR9 agonist tilsotolimod (IMO-2125) in combination with ipilimumab (ipi) triggers durable responses in PD-1 inhibitor refractory metastatic melanoma (rMM): Results from a multicenter, phase I/II study
Authors: A. Diab, C. Haymaker, C. Bernatchez, R.H.I. Andtbacka, M. Shaheen, D. Johnson, J. Markowitz, I. Puzanov, R. Murthy, D.H. Johnson, M. James, S. Chunduru, J. Geib, S. Swann, S. Rahimian, P. Hwu
Journal: Annals of Oncology (2018)
Impact of an increase in the inhaled corticosteroid dose on blood eosinophils in asthma
Authors: Marek Lommatzsch, Maria Klein, Paul Stoll, Johann Christian Virchow
Journal: Thorax (2018)

Here, we report that increasing treatment with inhaled corticosteroids (ICS) in patients with not well-controlled asthma from a medium to a high dose results in a profound reduction of blood eosinophils (median fall in blood eosinophil concentrations from 560 to 320 cells/µL). Therefore, 'normal values' of blood eosinophils in patients with asthma need to be considered in view of the individual ICS doses of the patients. In addition, increases in the dose of ICS may result in blood eosinophil concentrations which would formally preclude treatment with biologics targeting the interleukin-5 pathway.
Sites of metastasis and association with clinical outcome (CO) in advanced stage cancer patients (pts) treated with immunotherapy (IO)
Authors: M.A. Bilen, J.M. Shabto, D.J. Martini, Y. Liu, C. Lewis, H.H. Collins, M. Akce, H. Kissick, B.C. Carthon, W.L. Shaib, O.B. Alese, C.E. Steuer, C. Wu, D.H. Lawson, R. Kudchadkar, V. Master, B. El-Rayes, S.S. Ramalingam, T.K. Owonikoko, R.D. Harvey
Journal: Annals of Oncology (2018)
Karen Kotila #SportsPhysio
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

International School Sport Federation Under 18 World Basketball Championship in Cyprus 2013. Despite the country being on the brink of financial collapse, the organisers and the local community managed to pull off a fantastic tournament. Their genuine and indomitable optimism was inspirational.

As part of the Danish Society of Sports Physiotherapy, I aim to close the gap between scientific research and clinical practice. We need more of a research approach in clinical practice in other to evaluate our own practice and we need more of a clinical approach to research in other to make scientific research applicable. It is a key to create forums for researchers and clinicians to network and interact both in social-related and work-related settings.

Perseverance.

A young man was part of a team that secured areas in Iceland from rockfalls and landslides. Unfortunately, a rock the size of a camper broke loose and came tumbling down the mountain. He managed to detach his teammates from the rope that tied them together and had them escape to the left and right of the path of the rock. He jumped straight down, fracturing both …