tbuckley/cabot-search huggingface dataset:
Concordance of Ki-67 with 21-gene expression profile (RS) in early-stage breast cancer.
Authors: Zeina A. Nahleh, Juan Arenas, Salman Otoukesh, Azadeh Nasrazadani, Luis Sanchez, Andres Alvarado, Osvaldo Padilla, Alok kumar Dwivedi
Journal: Journal of Clinical Oncology (2014)

e11510 Background: The RS (Oncotype DX) is widely used in the U.S. to better define risk and help clinical decision-making in breast cancer (BC). However, it is an expensive tool for underinsured patients or in low-resource settings. Ki-67 is a widely available marker for tumor proliferation and could be used to define risk. However, there have been issues with Ki-67 scoring methods and standardization. We sought to determine the clinical validity of Ki 67 in relation with RS at our institution. Methods: After IRB approval, we identified 110 consecutive patients with early stage, ER-and or PR-positive, invasive BC who were recommended RS testing as part of their clinical care (2006-2013). Ki 67 was determined by IHC [rabbit monoclonal (30-9) from Ventana (Tucson, AZ.)], and reported for the nuclear staining as the percentage of positively stained cells . We tested the performance of Ki-67 with RS (low, Intermediate, high) using various cut offs of Ki-67. Raw agreement and weighted Kappa agreement with their 95% confidence interval (CI) were obtained. McNemar’s test was used to compare the proportion of discordant pairs. Stata 12.1 was used for data analysis. Results: 15 patients (16%) of 110 whom RS was recommended were unable to obtain the test due to financial limitations and were excluded. Mean age was 59.6 (SD: 11.2); 93 women and 2 men. 82 (86%) were Hispanic. Majority of patients had Stage I and II BC. 82 patients had HER2 neu negative BC. Overall agreement was found to be 54% when we considered <10% as low risk in Ki-67 but 0.59 (95% CI: 0.48, 0.69) with <20 % while chance corrected Kappa agreement was 0.427 (p<0.01), with no significant difference in proportion of discordant pairs (p=0.676). Highest concordance was found for low group (76%) followed by high group (65%) and intermediate group (40%). The predictive performance for classifying high or intermediate risk group of RS was found to be 60%. Conclusions: Our results suggest that Ki-67 provides fairly good agreement with RS classification, considering less than 20% as cut off for low risk group in Ki-67. The diagnostic measures of Ki-67 were found to be considerably high for our study population. Therefore, the ki-67 can be used reliably for clinical decision making in the absence of Oncotype DX.
Validation of Nu.Q™ colorectal cancer screening triage test to identify FIT positive individuals at low risk of screen relevant neoplasia
Authors: Marielle Herzog, Mark Eccleston, Jake Micallef, Dorian Pamart, Brieuc Cuvelier, Eléonore Josseaux, Jason Terrell, Ib Christensen, Hans Nielsen
Journal: Annals of Oncology (2017)
Longer intervals after neoadjuvant therapy in locally advanced rectal cancer: a monocentric experience
Authors: R. Murialdo, L. Belgioia, S. Scabini, E. Romairone, A. Bacigalupo, L. Tixi, G. Zoppoli, A. Ghiglione, E. Harusha, R. Corvo', A. Ballestrero
Journal: Annals of Oncology (2017)
Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II–III trial
Authors: M.G. Ghi, A. Paccagnella, D. Ferrari, P. Foa, D. Alterio, C. Codecà, F. Nolè, E. Verri, R. Orecchia, F. Morelli, S. Parisi, C. Mastromauro, C.A. Mione, C. Rossetto, M. Polsinelli, H. Koussis, L. Loreggian, A. Bonetti, F. Campostrini, G. Azzarello, C. D’Ambrosio, F. Bertoni, C. Casanova, E. Emiliani, M. Guaraldi, F. Bunkheila, P. Bidoli, R.M. Niespolo, A. Gava, E. Massa, A. Frattegiani, F. Valduga, G. Pieri, T. Cipani, D. Da Corte, F. Chiappa, E. Rulli
Journal: Annals of Oncology (2017)

BackgroundPlatinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3–4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy.Materials and methodsPatients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level).Results414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56–0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF.ConclusionsIC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy.Clinical Trial NumberNCT01086826, www.clinicaltrials.gov
Advances in keratinocyte delivery in burn wound care
Authors: Britt ter Horst, Gurpreet Chouhan, Naiem S. Moiemen, Liam M. Grover
Journal: Advanced Drug Delivery Reviews (2017)

This review gives an updated overview on keratinocyte transplantation in burn wounds concentrating on application methods and future therapeutic cell delivery options with a special interest in hydrogels and spray devices for cell delivery. To achieve faster re-epithelialisation of burn wounds, the original autologous keratinocyte culture and transplantation technique was introduced over 3 decades ago. Application types of keratinocytes transplantation have improved from cell sheets to single-cell solutions delivered with a spray system. However, further enhancement of cell culture, cell viability and function in vivo, cell carrier and cell delivery systems remain themes of interest. Hydrogels such as chitosan, alginate, fibrin and collagen are frequently used in burn wound care and have advantageous characteristics as cell carriers. Future approaches of keratinocyte transplantation involve spray devices, but optimisation of application technique and carrier type is necessary.
Patient preferences for the attributes of a noninvasive treatment for superficial basal cell carcinoma: a discrete choice experiment
Authors: B.A.B. Essers, A.H. Arits, M.R. Hendriks, K. Mosterd, N.W. Kelleners‐Smeets
Journal: British Journal of Dermatology (2017)

To examine which attributes of a non-invasive treatment for superficial BCC (sBCC) are valued by patients, a discrete choice experiment (DCE) was performed alongside a clinical trial in which methylaminolevulinate photodynamic therapy (MAL-PDT), 5-fluorouracil and imiquimod were compared.1

Treatment options were described by the following attributes: effectiveness, cosmetic result, treatment process and side-effects. Effectiveness was defined as the probability that complete tumour clearance is achieved 12 months after treatment with levels of 75%,80%,85% and 90%.2-4

This article is protected by copyright. All rights reserved.
Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices
Authors: Sonal Mazumder, Ashish Kumar Dewangan, Naresh Pavurala
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Polysaccharide-based polymers were used to produce nanoparticles of poorly soluble antiviral drugs using a rapid precipitation process. The structure-property relationships of four novel cellulose acetate-based polymers were studied for their solubility enhancement of poorly soluble drugs. Particles were purified by dialysis, and dried powders were recovered after freeze-drying. The particle diameters were 150–200 nm. The target drug loading in the particles was 25 wt%, and the drug loading efficiencies were 80–96%. The effects of the formulation process and nanoparticle properties on drug solubility were investigated. All nanoparticles afforded increased solubility and faster release compared to pure drugs. Drug release was a function of the relative hydrophobicity (or solubility parameters) of the polymers.
Hypoxia imaging using 18F-FAZA PET/CT to predict radioresistance and guide hypoxic modification with nimorazole in esophageal adenocarcinoma xenografts
Authors: Elodie Melsens, Elly De Vlieghere, Benedicte Descamps, Christian Vanhove, Ken Kersemans, Filip De Vos, Ingeborg Goethals, Boudewijn Brans, Olivier De Wever, Wim Ceelen, Piet Pattyn
Journal: Annals of Oncology (2017)
Comprehensive Detection of Driver Mutations in Acute Myeloid Leukemia Including Internal Tandem Duplications with Anchored Multiplex PCR and Next-Generation Sequencing
Authors: Benjamin Van Deusen, Marc Bessette, Laura Johnson, Aaron Berlin, Michael Banos, Laura Griffin, Erik Reckase, Joshua Stahl, Abel Licon, Brian A. Kudlow
Journal: Blood (2016)
The dynamics of hepcidin‐ferroportin internalization and consequences of a novel ferroportin disease mutation
Authors: Daniel F. Wallace, Cameron J. McDonald, Lesa Ostini, David Iser, Annabel Tuckfield, V. Nathan Subramaniam
Journal: American Journal of Hematology (2017)

The hepcidin-ferroportin axis underlies the pathophysiology of many iron-associated disorders and is a key target for the development of therapeutics for treating iron-associated disorders. The aims of this study were to investigate the dynamics of hepcidin-mediated ferroportin internalization and the consequences of a novel disease-causing mutation on ferroportin function. Specific reagents for ferroportin are limited; we developed and characterized antibodies against the largest extracellular loop of ferroportin and developed a novel cell-based assay for studying hepcidin-ferroportin function. We show that hepcidin-mediated ferroportin internalization is a rapid process and could be induced using low concentrations of hepcidin. Targeted next-generation sequencing utilizing an iron metabolism gene panel developed in our group identified a novel ferroportin p.D84E variant in a patient with iron overload. Wild-type and mutant ferroportin constructs were generated, transfected into HEK293 cells and analysed using an all-in-one flow-cytometry-based assay to study the effects on hepcidin-mediated internalization and iron transport. Consistent with the classical phenotype of ferroportin disease, the p.D84E mutation results in an inability to transport iron and hepcidin insensitivity. These results validate a recently proposed 3D-structural model of ferroportin and highlight the significance of this variant in the structure and function of ferroportin. Our novel ferroportin antibody and assay will be valuable tools for investigating the regulation of hepcidin/ferroportin function and the development of novel approaches for the therapeutic modulation of iron homeostasis.
Air Pollution Still Kills
Authors: Rebecca E. Berger, Ramya Ramaswami, Caren G. Solomon, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2017)

In late October 1948, a dense smog descended over the town of Donora, Pennsylvania. The town was home to a zinc plant and a steel mill, both run by the United States Steel Corporation. Susan Gnora, a 62-year-old resident of Donora, started to gasp and cough as the smog descended.1 She died the next day. Dr. William Rongaus, a physician and a member of the board of health, went door to door, treating patients for their respiratory symptoms and encouraging them to leave town if they could. Many thousands were ill, and at least 20 people died in one of . . .
Abstract P339: The Mechanistic Relationship Between GRK2 and eNOS During Cardiac Ischemia/Reperfusion Injury
Authors: Zheng M Huang, Erhe Gao, Xiying Shang, Xufan Tian, Gang Qiu, J Kurt Chuprun, David J Lefer, Walter J Koch
Journal: Circulation Research (2011)

Background: Previous studies have shown that both cardiac-specific GRK2 transgenic (TG) (αMHC-GRK2) mice and eNOS knockout (KO) mice have larger infarcts after I/R compared to control mice. In contrast, cardiac-targeted eNOS TG mice and cardiac specific GRK2 KO mice show cardioprotection after I/R, suggesting a dynamic interaction between the two proteins. Mechanistically, GRK2 can be inhibited by cellular NO through S-nitrosylation with Cys340 being the major site; meanwhile GRK2 has been shown to directly bind to and inhibit Akt, which is a strong activator of eNOS. Aim: to investigate the potential novel interaction between GRK2 and eNOS, and the consequent functional impact on the protein activity and cardiac phenotype after I/R injury. Methods: αMHC-GRK2 mice were crossed with either eNOS TG or eNOS KO mice. All mice were subjected to sham or 30min myocardial ischemia via coronary artery ligation followed by 24hrs of reperfusion. Infarct size, cardiac function, and tissue apoptosis were examined. Co-IP was used to test the interaction between GRK2 and eNOS, and phosphorylation of eNOS was studied in neonatal myocytes. Results: 1).αMHC-GRK2/eNOS TG hybrid mice showed a significantly reduced infarct size after I/R compared to αMHC-GRK2 mice, accompanied by improved cardiac function measured by echocardiography and hemodynamics, and significantly less apoptosis tested by TUNEL assay, implying a rescue effect by eNOS. 2). αMHC-GRK2/eNOS KO mice exhibited a bigger infarct size compared to either αMHC-GRK2 mice or eNOS KO mice. 3). CO-IP confirmed the interaction between GRK2 and eNOS in cardiac tissue, which was increased upon β-AR agonist treatment. 4). In neonatal ventricular myocytes, GRK2 overexpression significantly decreased eNOS phosphorylation at Ser1177 after exposure to H2O2, while GRK2 knockdown by siRNA led to slight increase in pSer1177. Conclusions: eNOS interacts with and may be a downstream target of GRK2 in the heart. Decreased activation of eNOS may mediate the deleterious effect of GRK2 overexpression during cardiac I/R injury.
Structural basis for potent antibody-mediated neutralization of human cytomegalovirus
Authors: Sumana Chandramouli, Enrico Malito, TuongVi Nguyen, Kate Luisi, Danilo Donnarumma, Yi Xing, Nathalie Norais, Dong Yu, Andrea Carfi
Journal: Science Immunology (2017)

Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and organ transplant rejection. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of humoral responses and thus a key vaccine candidate. We report two structures of Pentamer bound to human neutralizing antibodies, 8I21 and 9I6, at 3.0 and 5.9 Å resolution, respectively. The HCMV gH/gL architecture is similar to that of Epstein-Barr virus (EBV) except for amino-terminal extensions on both subunits. The extension of gL forms a subdomain composed of a three-helix bundle and a β hairpin that acts as a docking site for UL128/UL130/UL131A. Structural analysis reveals that Pentamer is a flexible molecule, and suggests sites for engineering stabilizing mutations. We also identify immunogenic surfaces important for cellular interactions by epitope mapping and functional assays. These results can guide the development of effective vaccines and immunotherapeutics against HCMV.
Drug Delivery: Dendritic Mesoporous Silica Nanoparticles for pH-Stimuli-Responsive Drug Delivery of TNF-Alpha (Adv. Healthcare Mater. 13/2017)
Authors: Arne Kienzle, Sven Kurch, Janine Schlöder, Carsten Berges, Robert Ose, Jonathan Schupp, Andrea Tuettenberg, Henning Weiss, Jennifer Schultze, Svenja Winzen, Meike Schinnerer, Kaloian Koynov, Markus Mezger, Nikolas K. Haass, Wolfgang Tremel, Helmut Jonuleit
Journal: Advanced Healthcare Materials (2017)

In article number 1700012, Helmut Jonuleit and co-workers utilize dendritic mesoporous silica nanoparticles for drug delivery to increase the efficacy of anti-tumor drug TNF-α, while decreasing its side-effects.
Adjuvant radiation for patients (pts) with high-grade serous ovarian cancer (HGSC) and T-cell infiltration.
Authors: Aalok Kumar, Cyril Blake Gilks, Blaise Clarke, Christina Aquino-Parsons, Jessica N. McAlpine, Julian J Lum, Anna Tinker
Journal: Journal of Clinical Oncology (2014)

5543 Background: CD8 positive intra-epithelial tumor infiltrating T cells (TIL) are associated with improved outcomes in ovarian cancer, particularly in HGSC. Radiotherapy (XRT) has immunologic effects including tumour necrosis, activation of antigen presenting cells and T cell recruitment. Adjuvant XRT in ovarian cancer was historically used at the BC Cancer Agency (BCCA). We hypothesized that adjuvant XRT for HGSC may have a beneficial impact on outcomes within the TIL+ subgroup. Methods: Stage I and II and optimally debulked (no visible residual disease) stage III HGSC pts treated at the BCCA from 1984to 2004 were included in this analysis. All cases underwent pathologic review to confirm histology and to score for TIL, either present (≥1 CD8 cell / 6mm core) or absent via immunohistochemistry. Treatment was platinum based chemotherapy (3-6 cycles) and abdominal-pelvic radiotherapy (45 Gy and 32 fractions to pelvis and whole abdomen). Kaplan-Meier and Cox proportional hazards methods were used to correlate XRT use (yes vs. no) with overall survival (OS) and disease free survival (DFS). Results: We identified 205 pts, of whom 174 scored positive for TIL. Of the 174, 76 (44%) were treated with XRT and 98 (56%) no XRT. Most pts (97%) also received adjuvant chemotherapy. Median follow up was 6.5 years. Pts who received XRT were younger (mean age 56.6 vs. 63.5 years, p<0.001) and had lower stage disease (p=0.0008). On univariate analysis, XRT was associated with an increased median OS (10 vs. 6 years, p=0.03) and a non significant increased DFS. On multivariate analysis, adjuvant XRT did not impact OS or DFS (HR 0.99, 95CI 0.66-1.49,p=0.97 and HR 1.05,95CI 0.67-1.67,p=0.82 respectively). Stage 3 disease was associated with worse OS and DFS (HR 1.71, 95CI 1.03-2.85, p=0.04 and HR 2.26, 95CI 1.26-4.04,p=0.006 respectively). Older age was associated with decreased OS (HR 1.03, 95CI 1.01-1.04,p=0.005). Conclusions: In this population based cohort study, adjuvant XRT for early stage or microscopic residual stage III HGSC with TIL was not associated with an OS or DFS advantage. Adjuvant XRT has no defined role in the treatment of HGSC.
Exclusion of Kaposi Sarcoma From Analysis of Cancer Burden—Reply
Authors: Christina Fitzmaurice, Mohsen Naghavi
Journal: JAMA Oncology (2017)

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Comparable Outcomes of Therapy-Related and De Novo Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Orhan Kemal Yucel, Rima M Saliba, Gabriela Rondon, Sairah Ahmed, Amin M. Alousi, Borje S. Andersson, Qaiser Bashir, Stefan O. Ciurea, Issa F. Khouri, Yago Nieto, Uday R. Popat, David Marin, Katy Rezvani, Partow Kebriaei, Nina Shah, Amanda L. Olson, Elizabeth J. Shpall, Richard E. Champlin, Betul Oran
Journal: Blood (2016)
Landing-related ankle injuries do not occur in plantarflexion as once thought: a systematic video analysis of ankle injuries in world-class volleyball
Authors: Christopher Skazalski, Jacek Kruczynski, Martin Aase Bahr, Tone Bere, Rod Whiteley, Roald Bahr
Journal: British Journal of Sports Medicine (2017)

Ankle injuries are prevalent in elite volleyball and suggested to result from player contact at the net. Traditionally, ankle sprains are thought to happen in a plantarflexed position, but case studies suggest plantarflexion may not be involved.Describe the injury situations and mechanisms of ankle injuries in world-class volleyball based on systematic video analysis of injuries reported through the Fédération Internationale de Volleyball (FIVB) Injury Surveillance System.Videos of 24 injuries from major FIVB tournaments were included for analysis (14 men, 10 women). Five analysts reviewed the videos to determine specific situations and mechanisms leading to injuries.The majority of injuries occurred during two volleyball situations, blocking (n=15) and attacking (n=6). Injuries to blockers were the result of landing on an opponent (n=11) or teammate (n=4). Attacking injuries most frequently occurred when a back-row player landed on a front-row teammate (n=4 of 6). When landing on an opponent under the net, the attacker landed into the opponent's court in 11 of 12 situations but without violating the centre line rule. Injuries mostly resulted from rapid inversion without any substantial plantarflexion.The majority of injuries occur while blocking, often landing on an opponent. The attacker is overwhelmingly to blame for injuries at the net secondary to crossing the centre line. Injuries while attacking often result from a back-row player landing on a front-row teammate. Landing-related injuries mostly result from rapid inversion with the absence of plantarflexion.