tbuckley/cabot-search huggingface dataset:
Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer
Authors: Marym Mohammad Hadi, Heather Nesbitt, Hamzah Masood, Fabiola Sciscione, Shiv Patel, Bala S. Ramesh, Mark Emberton, John F. Callan, Alexander MacRobert, Anthony P. McHale, Nikolitsa Nomikou
Journal: Journal of Controlled Release (2020)

Nano-formulations that are responsive to tumour-related and externally-applied stimuli can offer improved, site-specific antitumor effects, and can improve the efficacy of conventional therapeutic agents. Here, we describe the performance of a novel stimulus-responsive nanoparticulate platform for the targeted treatment of prostate cancer using sonodynamic therapy (SDT). The nanoparticles were prepared by self-assembly of poly(L-glutamic acid-L-tyrosine) co-polymer with hematoporphyrin. The nanoparticulate formulation was characterized with respect to particle size, morphology, surface charge and singlet oxygen production during ultrasound exposure. The response of the formulation to the presence of cathepsin B, a proteolytic enzyme that is overexpressed and secreted in the tumour microenvironment of many solid tumours, was assessed. Our results showed that digestion with cathepsin B led to nanoparticle size reduction. In the absence of ultrasound, the formulation exhibited greater toxicity at acidic pH than at physiological pH, using the human prostate cells lines LNCaP and PC3 as targets. Nanoparticle cellular uptake was enhanced at acidic pH – a condition that was also associated with greater cathepsin B production. Nanoparticles exhibited enhanced ultrasound-induced cytotoxicity against both prostate cancer cell lines. Subsequent proof-of-concept in vivo studies demonstrated that, when ectopic human xenograft LNCaP tumours in SCID mice were treated with SDT using the systemically-administered nanoparticulate formulation at a single dose, tumour volumes decreased by up to 64% within 24 h. No adverse effects were observed in the nanoparticle-treated mice and their body weight remained stable. The potential of this novel formulation to deliver safe and effective treatment of prostate cancer is discussed.
Brigatinib in Japanese Patients With ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial
Authors: Makoto Nishio, Tatsuya Yoshida, Toru Kumagai, Toyoaki Hida, Ryo Toyozawa, Tadasuke Shimokawaji, Koichi Goto, Kazuhiko Nakagawa, Yuichiro Ohe, Takashi Seto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Nobuyuki Yamamoto
Journal: Journal of Thoracic Oncology (2020)

IntroductionThis phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs).MethodsThis single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)–assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsWe report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%–49%) with median duration of response of 11.8 months (95% CI: 5.5–16.4). Disease control rate was 79% (95% CI: 64%–89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7–9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations.ConclusionsBrigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).
99P Development of a qRT-PCR-based diagnostic test to identify colorectal cancer patients with recurrent R-Spondin gene fusions
Authors: V. Diermayr, S. Sarma, K.F.Y. Lee, P. Ng, C.K. Tong, V. Soon, B.H. Gan, Z.J. Qu, Z. Tan, X. Han, L.Y. Phua, H.M. Poh, A. Gan, D.M. Camat, R. Weng, E.W. Cheong, M. Inoue, A. Lezhava, I.B. Tan, T.K.H. Lim
Journal: Annals of Oncology (2020)
Cardiac Resynchronization Therapy: Are Modern Myths Preventing Appropriate Use?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: John G.F. Cleland, Luigi Tavazzi, Jean-Claude Daubert, Ahmed Tageldien, Nick Freemantle
Journal: Journal of the American College of Cardiology (2009)
Abstract S08-01: Highly sensitive and full-genome interrogation of SARS-CoV-2 using multiplexed PCR enrichment followed by next-generation sequencing
Authors: Chenyu Li, David N. Debruyne, Julia Spencer, Vidushi Kapoor, Lily Y. Liu, Bo Zhou, Utsav Pandey, Moiz Bootwalla, Dejerianne Ostrow, Dennis T. Maglinte, David Ruble, Alex Ryutov, Lishuang Shen, Lucie Lee, Rounak Feigelman, Grayson Burdon, Jeffrey Liu, Alejandra Oliva, Adam Borcherding, Hongdong Tan, Alexander E. Urban, Xiaowu Gai, Jennifer Dien Bard, Guoying Liu, Zhitong Liu
Journal: Clinical Cancer Research (2020)

Abstract Many detection methods have been used or reported for the diagnosis and/or surveillance of COVID-19. Among them, reverse transcription polymerase chain reaction (RT-PCR) is the most commonly used because of its high sensitivity, typically claiming detection of about 5 copies of viruses. However, it has been reported that only 47-59% of the positive cases were identified by some RT-PCR methods, probably due to low viral load, timing of sampling, degradation of virus RNA in the sampling process, or possible mutations spanning the primer binding sites. Therefore, alternative and highly sensitive methods are imperative. With the goal of improving sensitivity and accommodating various application settings, we developed a multiplex-PCR-based method comprising 343 pairs of specific primers and demonstrated its efficiency at detecting SARS-CoV-2 at low copy numbers. The assay produced clean characteristic target peaks of defined sizes, which allowed for direct identification of positives by electrophoresis. We further amplified the entire SARS-CoV-2 genome from 8 to half a million viral copies purified from 13 COVID-19 positive specimens and detected mutations through next-generation sequencing. Finally, we developed a multiplex-PCR-based metagenomic method in parallel that required modest sequencing depth for uncovering SARS-CoV-2 mutational diversity and potentially novel or emerging isolates. Citation Format: Chenyu Li, David N. Debruyne, Julia Spencer, Vidushi Kapoor, Lily Y. Liu, Bo Zhou, Utsav Pandey, Moiz Bootwalla, Dejerianne Ostrow, Dennis T. Maglinte, David Ruble, Alex Ryutov, Lishuang Shen, Lucie Lee, Rounak Feigelman, Grayson Burdon, Jeffrey Liu, Alejandra Oliva, Adam Borcherding, Hongdong Tan, Alexander E. Urban, Xiaowu Gai, Jennifer Dien Bard, Guoying Liu, Zhitong Liu. Highly sensitive and full-genome interrogation of SARS-CoV-2 using multiplexed PCR enrichment followed by next-generation sequencing [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S08-01.
Evolution of Hominin Detoxification: Neanderthal and Modern Human Ah Receptor Respond Similarly to TCDD
Authors: Jac M M J G Aarts, Gerrit M Alink, Henk J Franssen, Wil Roebroeks
Journal: Molecular Biology and Evolution (2020)

Abstract In studies of hominin adaptations to fire use, the role of the aryl hydrocarbon receptor (AHR) in the evolution of detoxification has been highlighted, including statements that the modern human AHR confers a significantly better capacity to deal with toxic smoke components than the Neanderthal AHR. To evaluate this, we compared the AHR-controlled induction of cytochrome P4501A1 (CYP1A1) mRNA in HeLa human cervix epithelial adenocarcinoma cells transfected with an Altai-Neanderthal or a modern human reference AHR expression construct, and exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We compared the complete AHR mRNA sequences including the untranslated regions (UTRs), maintaining the original codon usage. We observe no significant difference in CYP1A1 induction by TCDD between Neanderthal and modern human AHR, whereas a 150–1,000 times difference was previously reported in a study of the AHR coding region optimized for mammalian codon usage and expressed in rat cells. Our study exemplifies that expression in a homologous cellular background is of major importance to determine (ancient) protein activity. The Neanderthal and modern human dose–response curves almost coincide, except for a slightly higher extrapolated maximum for the Neanderthal AHR, possibly caused by a 5′-UTR G-variant known from modern humans (rs7796976). Our results are strongly at odds with a major role of the modern human AHR in the evolution of hominin detoxification of smoke components and consistent with our previous study based on 18 relevant genes in addition to AHR, which concluded that efficient detoxification alleles are more dominant in ancient hominins, chimpanzees, and gorillas than in modern humans.
A model to identify individuals with a high probability of a SARS-CoV-2 infection
Authors: B. Kowall, M. Nonnemacher, B. Brune, M. Brinkmann, M. Dudda, J. Böttcher, B. Schmidt, F. Standl, S. Stolpe, U. Dittmer, KH Jöckel, A. Stang
Journal: Journal of Infection (2020)
Worsening Heart Failure Hospitalization Epidemic: We Do Not Know How to Prevent and We Do Not Know How to Treat!⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Javed Butler, Andreas Kalogeropoulos
Journal: Journal of the American College of Cardiology (2008)
Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate
Authors: Timothy J. Poterucha, Pierre Elias, Sabahat Bokhari, Andrew J. Einstein, Albert DeLuca, Mona Kinkhabwala, Lynne L. Johnson, Kathleen R. Flaherty, Sunil E. Saith, Jan M. Griffin, Adler Perotte, Mathew S. Maurer
Journal: JACC. Cardiovascular imaging (2020)
112P Pembrolizumab vs chemotherapy in patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: Asia subgroup results of the phase III KEYNOTE-177 study
Authors: T. Yoshino, T.W. Kim, W.P. Yong, K-K. Shiu, B. Vittrup Jensen, L. Henrik Jensen, D. Smith, R. Garcia-Carbonero, J. Alcaide-Garcia, P. Gibbs, C. de la Fouchardiere, F. Rivera, E. Elez, J. Bendell, D.T. Le, P. Yang, M. Farooqui, P. Marinello, L.A. Diaz, T. Andre
Journal: Annals of Oncology (2020)
16937 Evaluation of construct validity and inter-rater reliability of the Objective Structured Assessment of Technical Skills (OSATS) tool for assessment of surgical skills of dermatology trainees
Authors: Kristina Navrazhina, Murad Alam, Rebecca Tung, David Surprenant, Brienne D. Cressey, Ashley Decker, Cindy E. Parra, Emily Poon, Wendy Kim, Kira Minkis
Journal: Journal of the American Academy of Dermatology (2020)
Loss of Fbxw7 Impairs Development of and Induces Heterogeneous Tumor Formation in the Mouse Mammary Gland
Authors: Ichiro Onoyama, Shogo Nakayama, Hideyuki Shimizu, Keiichi I. Nakayama
Journal: Cancer Research (2020)

Fbxw7 is an F-box protein that contributes to regulation of cell proliferation and cell fate determination as well as to tumor suppression in various tissues. In this study, we generated mice with mammary gland-specific ablation of Fbxw7 (Blg-Cre/Fbxw7F/F mice) and found that most neonates born to mutant dams die soon after birth as a result of defective maternal lactation. The mammary gland of mutant dams was markedly atrophic and manifested both excessive cell proliferation and apoptosis in association with the accumulation of Notch1 and p63. Despite the hypoplastic nature of the mutant mammary gland, Blg-Cre/Fbxw7F/F mice spontaneously developed mammary tumors that resembled basal-like carcinoma with marked intratumoral heterogeneity. Additional inactivation of Trp53 in Blg-Cre/Fbxw7F/F mice further promoted onset and development of mammary tumors, suggesting that spontaneous mutation of Trp53 may facilitate transition of hypoplastic mammary lesions to aggressive cancer in mice lacking Fbxw7. RNA-sequencing analysis of epithelial- and mesenchymal-like cell lines from a Blg-Cre/Fbxw7F/F mouse tumor revealed an increased mutation rate and structural alterations in the tumor and differential expression of upstream transcription factors including known targets of Fbxw7. Together, our results implicate Fbxw7 in the regulation of cell differentiation and in tumor suppression in the mammary gland. Loss of Fbxw7 increases mutation rate and chromosome instability, activates signaling pathways governed by transcription factors regulated by Fbxw7, and triggers the development of mammary tumors with prominent heterogeneity. SIGNIFICANCE: Mammary gland-specific ablation of Fbxw7 in mice results in defective gland development and spontaneous mammary tumor formation reminiscent of human basal-like carcinoma with intratumoral heterogeneity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5515/F1.large.jpg.
Abstract 1962: Quantification of Longitudinal Right Ventricular Systolic Function and Its Coupling to Left Ventricular Global Function Using Speckle-Tracking Strain Imaging in Patients with Old Myocardial Infarction
Authors: Kaoru Dohi, Katsuya Onishi, Shinya Kato, Takeshi Takamura, Naoki Fujimoto, Tairo Kurita, Norikazu Yamada, Mashio Nakamura, Naoki Isaka, Masaaki Ito
Journal: Circulation (2007)

Background: We tested the hypothesis that speckle-tracking strain imaging can quantify longitudinal right ventricular (RV) function and its association with left ventricular (LV) function in patients with myocardial infarction (MI). Methods: To quantify longitudinal RV function, 39 patients with old MI (OMI: LV ejection fraction 17 – 77 %, 45 ±16 %) and 29 age matched normal controls (Control: LV ejection fraction 65 ± 5 %) were studied with echocardiography. Longitudinal RV global peak systolic strain was assessed from apical four-chamber view using speckle-tracking imaging (EchoPAC, GE Electronic). RV fractional area change was also analyzed. Results: Longitudinal RV global peak systolic strain was significantly impaired in OMI compared to Control (−18 ± 5* and −25 ± 4 %, *p &lt; 0.05 vs. Control) whereas RV fractional area change failed to discriminate from normal to impaired RV function (OMI: 48 ± 11 vs. Control: 52 ± 6 %, p = NS). When divided OMI into three groups regarding to plasma BNP level (Group A: BNP &lt; 100 pg/ml; n = 14, Group B: 100 pg/ml ≤ BNP &lt; 500 pg/ml; n = 14, and Group C; BNP ≥ 500 pg/ml; n = 11), Group A had no significant relations between longitudinal RV global peak systolic strain and LV ejection fraction (y = −0.07x − 11, r = 0.30, p = NS) whereas those were significantly correlated in Group B (y = −0.18x − 11, r = 0.59*, *p &lt; 0.05). Furthermore, the strongest correlation between longitudinal RV global peak systolic strain and LV ejection fraction was observed in Group C (y = −0.58x + 5, r = 0.90*, *p &lt; 0.05). Conclusion: Speckle tracking strain imaging quantified longitudinal RV global systolic function and exhibited its BNP-related dependency to LV systolic function in patents with OMI.
Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
Authors: Premal D. Lulla, Swati Naik, Spyridoula Vasileiou, Ifigeneia Tzannou, Ayumi Watanabe, Manik Kuvalekar, Suhasini Lulla, George Carrum, Carlos A. Ramos, Rammurti Kamble, LaQuisa Hill, Jasleen Randhawa, Stephen Gottschalk, Robert Krance, Tao Wang, Mengfen Wu, Catherine Robertson, Adrian P. Gee, Betty Chung, Bambi Grilley, Malcolm K. Brenner, Helen E. Heslop, Juan F. Vera, Ann M. Leen
Journal: Blood (2020)
436P Clinicopathological characteristics and outcomes of adolescent and young adult (AYA) melanoma: Results from an Asian perspective
Authors: W.L. Goh, J. Hong, E.Y.T. Wong, E.W.Y. Chang, V.S. Yang, J. Chiang, J.Y. Chan, N. Somasundaram, M. Farid, E.Y.L. Poon
Journal: Annals of Oncology (2020)
15325 Effects of guselkumab on musculoskeletal features in patients with active psoriatic arthritis by baseline skin disease: Results from the phase 3 DISCOVER-1 and DISCOVER-2 studies
Authors: Alice B. Gottlieb, Philip Mease, Proton Rahman, Alexa P. Kollmeier, Bei Zhou, Iain B. McInnes, Atul Deodhar, Philip Helliwell, Christopher T. Ritchlin, Wolf-Henning Boehncke
Journal: Journal of the American Academy of Dermatology (2020)
The FABRIC Cancer Portal: A Ranked Catalogue of Gene Selection in Tumors Over the Human Coding Genome
Authors: Guy Kelman, Nadav Brandes, Michal Linial
Journal: Cancer Research (2020)

Abstract Contemporary catalogues of cancer driver genes rely primarily on high mutation rates as evidence for gene selection in tumors. Here, we present The Functional Alteration Bias Recovery In Coding-regions Cancer Portal, a comprehensive catalogue of gene selection in cancer based purely on the biochemical functional effects of mutations at the protein level. Gene selection in the portal is quantified by combining genomics data with rich proteomic annotations. Genes are ranked according to the strength of evidence for selection in tumor, based on rigorous and robust statistics. The portal covers the entire human coding genome (∼18,000 protein-coding genes) across 33 cancer types and pan-cancer. It includes a selected set of cross-references to the most relevant resources providing genomics, proteomics, and cancer-related information. We showcase the portal with known and overlooked cancer genes, demonstrating the utility of the portal via its simple visual interface, which allows users to pivot between gene-centric and cancer type views. The portal is available at fabric-cancer.huji.ac.il. Significance: A new cancer portal quantifies and presents gene selection in tumor over the entire human coding genome across 33 cancer types and pan-cancer.
Methods for improving thermal tolerance in military personnel prior to deployment
Authors: Edward Tom Ashworth, James David Cotter, Andrew Edward Kilding
Journal: Military Medical Research (2020)

Acute exposure to heat, such as that experienced by people arriving into a hotter or more humid environment, can compromise physical and cognitive performance as well as health. In military contexts heat stress is exacerbated by the combination of protective clothing, carried loads, and unique activity profiles, making them susceptible to heat illnesses. As the operational environment is dynamic and unpredictable, strategies to minimize the effects of heat should be planned and conducted prior to deployment. This review explores how heat acclimation (HA) prior to deployment may attenuate the effects of heat by initiating physiological and behavioural adaptations to more efficiently and effectively protect thermal homeostasis, thereby improving performance and reducing heat illness risk. HA usually requires access to heat chamber facilities and takes weeks to conduct, which can often make it impractical and infeasible, especially if there are other training requirements and expectations. Recent research in athletic populations has produced protocols that are more feasible and accessible by reducing the time taken to induce adaptations, as well as exploring new methods such as passive HA. These protocols use shorter HA periods or minimise additional training requirements respectively, while still invoking key physiological adaptations, such as lowered core temperature, reduced heart rate and increased sweat rate at a given intensity. For deployments of special units at short notice (< 1 day) it might be optimal to use heat re-acclimation to maintain an elevated baseline of heat tolerance for long periods in anticipation of such an event. Methods practical for military groups are yet to be fully understood, therefore further investigation into the effectiveness of HA methods is required to establish the most effective and feasible approach to implement them within military groups.
Covid-19: Should the UK mandate more stringent workplace protection for older people?
Authors: Stephen T Green, Lorenzo Cladi
Journal: BMJ (2020)

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