tbuckley/cabot-search huggingface dataset:
Abstract LB074: Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro <i>in vitro</i>
Authors: Nagendra Sastry Yarla, Gopal Pathuri, Simon Terzyan, Yuting Zhang, Anil Singh, Marcus T. Scotti, Venkateshwar Madka, Chinthalapally V. Rao
Journal: Cancer Research (2021)

Abstract Lung cancer patients are more vulnerable to COVID-19 infection. Treatment of patients with lung cancer during the current COVID-19 pandemic is challenging and development of drugs for COVID-19 and lung cancer is urgently needed. Cathepsin L plays key role in lung cancer progression, invasion and more so, endocytosis of SARS-Cov-2 virus into the lung epithelial cells. Importantly, patients with KrasG12V mutation show agreessive disease and high-resistance to chemotherapy due to over-expression of Cathepsin L. Thus, Cathepsin L is a common target for lung cancer and COVID-19 infection. Chymostatin is a known cathepsin L inhibitor, here we screened it for dual inhibition of COVID-19 Mpro and lung cancer patients with COVID-19. In vitro COVID-19 Mpro fluorometric assay was performed to evaluate its inhibitory efficacy by chymostatin. Chymostatin showed dose-dependent inhibition of COVID-19 Mpro activity with IC50 of 15.81 µM (P&amp;lt;0.0001). Isothermal titration calorimetry based binding studies determined that chymostatin strongly bound to COVID-19 Mpro (KD=22.45 µM). CD spectrum analysis demonstrated that chymostatin (10 µM)-induced changes in the secondary structure of COVID-19 Mpro. A unit cell crystal parameter COVID-19 Mpro co-crystalized with chymostatin (a = 49.926 Å, b = 108.71 Å, c = 56.49 Å, α = 90.0°, β = 102.7553°, γ = 90.0°; unit cell volume: 299.03 Ao) was determined using X-ray diffractometer. Molecular docking studies demonstrated that chymostatin interacts with active site amino acids (Cys145). Pro-apoptotic effect of chymostatin was evaluated on human H441 lung cancer cells and mouse lung normal epithelial cells using Annexin V/propidium iodide staining. Chymostatin did not show any cytotoxicity on normal mouse lung epithelial cells up to 100 µM, where as it inhibited proliferation of human H441 lung cancer cells (KrasG12V mutant) with IC50 of 1.2 µM. In conclusion, preliminary in vitro studies demonstrated that naturally occurring cathepsin L inhibitor chymostatin is a SARS-CoV-2 Mpro inhibitor and exhibited anticancer activity against lung cancer cells. The results of the study warranted detailed studies to develop as drugs for lung cancer patients during COVID-19 pandemic (supported by VPR-PHF, the University of Oklahoma Health Sciences Centre for financial support through COVID-19 seed grant program). Citation Format: Nagendra Sastry Yarla, Gopal Pathuri, Simon Terzyan, Yuting Zhang, Anil Singh, Marcus T. Scotti, Venkateshwar Madka, Chinthalapally V. Rao. Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB074.
A metabolic inhibitor arms macrophages to kill intracellular fungal pathogens by manipulating zinc homeostasis
Authors: Diego C.P. Rossi, Julio A. Landero Figueroa, William R. Buesing, Kathleen Candor, Logan T. Blancett, Heather M. Evans, Rena Lenchitz, Bradford L. Crowther, Waleed Elsegeiny, Peter R. Williamson, Jan Rupp, George S. Deepe
Journal: Journal of Clinical Investigation (2021)

Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource-poor environment by marshaling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog 2-deoxy-D-glucose (2-DG) armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages, decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This effect promoted the antifungal machinery of macrophages and expanded the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.
In vitro and ex vivo models in inhalation biopharmaceutical research — advances, challenges and future perspectives
Authors: Mohammed Ali Selo, Johannes A. Sake, Kwang-Jin Kim, Carsten Ehrhardt
Journal: Advanced Drug Delivery Reviews (2021)

Oral inhalation results in pulmonary drug targeting and thereby reduces systemic side effects, making it the preferred means of drug delivery for the treatment of respiratory disorders such as asthma, chronic obstructive pulmonary disease or cystic fibrosis. In addition, the high alveolar surface area, relatively low enzymatic activity and rich blood supply of the distal airspaces offer a promising pathway to the systemic circulation. This is particularly advantageous when a rapid onset of pharmacological action is desired or when the drug is suffering from stability issues or poor biopharmaceutical performance following oral administration. Several cell and tissue-based in vitro and ex vivo models have been developed over the years, with the intention to realistically mimic pulmonary biological barriers. It is the aim of this review to critically discuss the available models regarding their advantages and limitations and to elaborate further which biopharmaceutical questions can and cannot be answered using the existing models.
Safety and outcomes of using ureteral access sheaths for treatment of paediatric renal stones: A review of 48 patients across 2 large European endourology centres
Authors: L. Mosquera Seoane, A.E. Brewin, A. Pietropaolo, Y. Quiroz Madarriaga, E. Llorens De Knecht, P. Jones, A. Bujons Tur, S. Griffin, B.K. Somani
Journal: European Urology (2021)
Abstract 2270: Membrane organization of KRas4B with regulatory domain of Raf-1
Authors: Hyunbum Jang, Mingzhen Zhang, Ruth Nussinov
Journal: Cancer Research (2021)

Abstract A major pathway in RAS-driven cell proliferation is the MAPK (Raf/MEK/ERK) pathway. In cancer, membrane-anchored, proximally located, oncogenic Ras isoforms promote Raf dimerization and fully activate MAPK signaling. Among Ras isoforms, KRas4B is frequently mutated in cancer. In the MAPK pathway, active KRas4B dimer or nanocluster can lead to dimerization of Raf kinase domain enhancing the affinity of the KRas4B-Raf interaction. Recently, we modeled the binary KRas4B-Raf-1 complex and its quaternary assembly with the regulatory domain of Raf-1 containing the Ras binding domain (RBD) and cysteine-rich domain (CRD), and suggested that Raf-1 CRD bolsters the high-affinity interaction of Raf-1 with KRas4B by reducing the KRas4B-RBD fluctuations. For the quaternary assembly, recent in silico studies suggested that KRas4B dimer is aligned through the α3 and α4 helical interface, not the α4 and α5 helical interface due to hindrance to the membrane contact of Raf-1 CRD. The Raf-1 regulatory domain contains the N-terminal region (residues 1-55), RBD, and CRD. However, previous modeling efforts were conducted for the KRas4B-Raf-1 complex in the absence of the N-terminal region. Here, computational studies were performed for the KRas4B-Raf-1 complex with full sequence of Raf-l regulatory domain interacting with monomeric and dimeric KRas4B-GTP at the membrane. Increasing experimental evidences suggested that the N-terminal region of Raf plays a significant role in the Ras interaction and the membrane anchorage of Raf. The membrane interaction of isolated N-terminal segment was investigated as the first step toward the complex model construction. Since oncogenic KRas4B mutants form dimers/nanoclusters at the membrane microdomains that provide the signaling platform for Raf, KRas4B in different mutation states interacting with the membrane microdomains with different lipid composition was also studied. The presence of the N-terminal segment of Raf-1 regulatory domain at the membrane can enhance the stability of KRas4B-Raf-1 and thereby relieving Raf's autoinhibition toward a kinase domain-accessible state, providing a complete mechanistic picture of the KRas4B-Raf-1 interaction. Our recent work uncovers the mechanism of Raf-1 activation by KRas4B at atomic resolution and highlight how this may help in elucidating vital mechanistic questions in Ras biology. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Hyunbum Jang, Mingzhen Zhang, Ruth Nussinov. Membrane organization of KRas4B with regulatory domain of Raf-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2270.
Author reply: Do Tunisians have a European ancestry?
Authors: Sanja Stanojevic, Graham L. Hall, Nicole Filipow, Gregg Ruppel, Tolu Okitika, Bruce Thompson, Jane Kirkby, Irene Steenbruggen, Brendan G. Cooper
Journal: European Respiratory Journal (2021)

H. Ben Saad's summary of the Tunisian population and use of the "European" label in our recent Global Lung Function Initiative (GLI) lung volume paper [1] highlights that we live in a diverse world and using a limited number of labels to define populations and ancestral groups is fraught with bias and historical artefact. We recognise that no single reference equation for lung function outcomes can be generalisable globally. Until we have more comprehensive data from all regions in the world, we must be careful not to apply GLI equations indiscriminately. It is imperative that we continue to conduct research to better understand how ancestry, as well as social and environmental determinants, impacts lung health. The GLI is reviewing the factors that explain observed population differences and will work towards developing more broadly applicable reference equations in the future. Until we have more comprehensive data from all regions in the world, we must be careful not to apply GLI equations indiscriminately <https://bit.ly/3g1r9Q5>
超音波脳治療のための音響窓としてのイットリア安定化ジルコニアの新しい頭蓋インプラント【Powered by NICT】
Authors: I Gutierrez Mario, H Penilla Elias, Leija Lorenzo, Vera Arturo, E Garay Javier, Aguilar Guillermo
Journal: Advanced Healthcare Materials (2017)
Abstract 1571: Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1
Authors: Changbo Sun, Koji Nagaoka, Akihiro Hosoi, Yukari Kobayashi, Jun Nakajima, Kazuhiro Kakimi
Journal: Cancer Research (2021)

Abstract Immune checkpoint inhibitors are now the mainstay for the treatment of lung cancer. However, so-called cold tumors are known to be resistant to checkpoint inhibitors. Neoantigens associated with genetic mutations of the tumor have the potential to stimulate a potent and highly specific immune response. To develop effective immunotherapy for cold lung cancer, we examined whether neoantigen-based immunotherapy can develop immune responses and display anti-tumor effects on the cold lung cancer model, Lewis lung carcinoma cells (LLC1) resistant to anti-CTLA-4 or anti-PD-1 therapy. LLC1 cells were subjected to whole-exome and RNA sequencing. Mutation-associated neoantigens were predicted and prioritized by their affinity to MHC class I molecules and their expression. Using netMHCpan, sixty mutated peptides with IC50 &amp;lt;200 nM and 68 mutated peptides with IC50&amp;gt;200 nM, but the wild to corresponding mutated peptide ratio of binding affinity&amp;gt;10 were selected as candidate neoantigens. C57BL/6 mice were immunized with dendritic cells pulsed with these neoantigen short peptides (8-10mer). Twenty-five out of 128 short mutated peptides induced peptide-specific CD8+ T cell response to some extent. Next, 25 long peptides (21mer), which incorporated corresponding immunogenic short peptide sequences, were synthesized and used to immunize mice. DC vaccines pulsed with neoantigen in long peptide format (LP) induced both CD4+ and CD8+ T cell response ex vivo. Of them, DC pulsed with LP82 partly delayed the LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed in LLC1. Thereby, an anti-CD38 antibody was administered in LLC1-bearing mice immunized with DC pulsed with LP82. The tumor growth was suppressed in the combination treatment. Although CD38 plays an important role in converting nicotinamide adenine dinucleotide (NAD+) to adenosine, adenosine receptor antagonist could not inhibit the tumor growth in mice immunized with LP82. Alternatively, NAD+ accumulation due to CD38 blockade decreased regulatory T cells in the tumor immune microenvironment, consistent with the decreased Foxp3+ transcription and increased IFNg and IL2 production of CD4+ T cells sorted from tumor immune microenvironment. Our study suggested that the prioritization of neoantigens that can induce anti-tumor response is critical for developing neoantigen-targeting immunotherapy. Combining an effective neoantigen vaccine and precise immune modulator could enhance anti-tumor activities even in cold lung tumors. Citation Format: Changbo Sun, Koji Nagaoka, Akihiro Hosoi, Yukari Kobayashi, Jun Nakajima, Kazuhiro Kakimi. Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1571.
Abstract 639: Analysis of DNA minimal residual disease markers in pediatric solid cancers using quantitative real time PCR and droplet digital PCR
Authors: Vinod Vijay Subhash, Alvin Kamili, Marie-Wong Erasmus, Dan Chen, Libby Huang, Vanessa Tyrell, Caroline Atkinson, Nicola Venn, Mark Cowley, Glenn Marshall, Paul Ekert, Michelle Henderson, Rosemary Sutton, Murray Norris, Michelle Haber, Jamie Fletcher, Toby Trahair
Journal: Cancer Research (2021)

Abstract Background: Minimal Residual Disease (MRD) detection is vital for therapy monitoring and relapse prediction in cancers. While RNA-based MRD assays are shown to be effective at diagnostic time-points, serial response monitoring does not provide additional predictive value.DNA-based assays may be more sensitive and allow longitudinal monitoring of the disease trajectory. This study aimed to develop MRD assays based on whole genome sequencing (WGS) data for high-risk neuroblastoma (HRNB) and Ewing sarcoma (ES) patients, to establish their sensitivity in quantitative PCR (qPCR) anddroplet digital PCR (ddPCR) formats, and to directly compare against RNA-based MRD assays. Methodology: We analyzed WGS data to identify patient-specific chromosomal breakpoints in HRNB (N=6) and ES (N=6) patients, then established qPCR and ddPCR assays. Assay performance was validated using patient-derived cells spiked into bone marrow samples and in serially collected clinical samples as available. The DNA-MRD markers were compared against a panel of RNA-MRD markers for HRNB (TH/DCX/PHOX2B) and ES (EWS-FLI1/ERG/ETV1). Results: DNA-MRD markers showed high sensitivity and quantitation ranging from 10-4(0.01%) to 10-5(0.001%) in qPCR assays and ddPCR assays. In clinical samples of HRNB and ES, DNA-MRD markers were detected in diagnosis specimens and predicted disease trajectory. Among RNA-MRD markers, TH &amp; EWS-FLI1 transcripts showed the maximum detection sensitivity (0.01%), however was less sensitive than the patient specific DNA-MRD markers. Conclusion: This study identifies DNA-MRD analysis as a reliable complimentary approach to RNA-MRD assays and highlights its enhanced sensitivity and clinical utility for monitoring treatment response and disease progression in solid pediatric tumors. Citation Format: Vinod Vijay Subhash, Alvin Kamili, Marie-Wong Erasmus, Dan Chen, Libby Huang, Vanessa Tyrell, Caroline Atkinson, Nicola Venn, Mark Cowley, Glenn Marshall, Paul Ekert, Michelle Henderson, Rosemary Sutton, Murray Norris, Michelle Haber, Jamie Fletcher, Toby Trahair. Analysis of DNA minimal residual disease markers in pediatric solid cancers using quantitative real time PCR and droplet digital PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 639.
Lower bowel tract symptoms before and after mesh robotic sacro (Hystero) colpopexy
Authors: V. Li Marzi, S. Morselli, F. Di Maida, S. Musco, L. Gemma, F. Bracco, R. Tellini, A. Vittori, A. Mari, N. Mormile, R. Campi, M. Carini, S. Serni, A. Minervini
Journal: European Urology (2021)
Variability in expenses in the treatment of recurrent urinary infection due to the costs of concomitant medication according to the prophylaxis protocol received
Authors: J.E. Hernández-Sánchez, P. Eguíluz-Lumbreras, A. Noya-Mourullo, S. Valverde-Martínez, M.T. Márquez-Sánchez, G. Márquez-Sánchez, B.Y. Padilla Fernandez, A. Miralles-Puente, M.B. García-Cenador, C. González-Enguita, M.F. Lorenzo Gomez
Journal: European Urology (2021)
Two-yr oncologic outcomes of ORC vs. RARC: Focus on recurrence sites from a prospective-randomized study
Authors: M.C. Ferriero, R. Mastroianni, G. Tuderti, U. Anceschi, A. Brassetti, L. Misuraca, S. Guaglianone, A. Bove, M. Gallucci, G. Simone
Journal: European Urology (2021)
Abstract 71: The immunocytokine PD1-IL2v overcomes immune checkpoint resistance, and combination with an anti-PD-L1 antibody further enhances its anti-tumor activity
Authors: Stephan Wullschleger, Mélanie Tichet, Laura Codarri-Deak, Pablo Umana, Christian Klein, Douglas Hanahan
Journal: Cancer Research (2021)

Abstract Cancer immunotherapies have shown therapeutic benefits in the clinic, but treatments involving immuno-stimulatory agents such as interleukin 2 (IL-2) are typically accompanied by severe adverse events. One strategy to limit the systemic toxicity of IL-2 is to target it specifically to the tumor microenvironment. Here we evaluated the therapeutic efficacy of the bi-specific immunocytokine PD1-IL2v in the genetically engineered, spontaneous RIP1-Tag5 (RT5) mouse model of pancreatic neuroendocrine tumors (PanNETs). PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody to which a single IL2 variant (IL2v) is fused. PD-1 serves as a targeting moiety to deliver IL2v in cis to PD-1-positive T cells located in the immune tumor microenvironment, and IL2v has been engineered to lack binding to CD25 in order to selectively expand effector T cells but not immuno-suppressive regulatory T cells (Tregs). Although RT5 mice are capable of mounting an adaptive immune response against the tumor-driving oncoprotein, PanNETs developing in RT5 are resistant to immune checkpoint inhibitors. In comparing the untargeted version of IL2v combined with an anti-PD-1 antibody vs. the PD-1 targeted immunocytokine PD1-IL2v, we found that PD1-IL2v, but not the mixture, produced significant anti-tumor activity. PD1-IL2v treatment resulted in a substantial infiltration of CD8+ T cells into the pancreatic islet tumors, which in the context of sustained treatment with PD1-IL2v resulted in tumor regression. Interestingly, following tumor shrinkage, the PanNETs appeared to stabilize and eventually relapsed. Notably, we identified up-regulation of PD-L1 on the tumor vasculature in relapsing tumors as a potential factor in the observed adaptive resistance, which encouraged combining an anti-PD-L1 antibody with PD1-IL2v, leading to enhanced therapeutic benefit. The data obtained in this spontaneous de novo tumor model motivate consideration of evaluating the PD1-IL2v/anti-PD-L1 combination therapy in the clinical setting, in particular in anti-PD-1/anti-PD-L1 resistant tumors infiltrated with PD1+CD8+ T cells. Citation Format: Stephan Wullschleger, Mélanie Tichet, Laura Codarri-Deak, Pablo Umana, Christian Klein, Douglas Hanahan. The immunocytokine PD1-IL2v overcomes immune checkpoint resistance, and combination with an anti-PD-L1 antibody further enhances its anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 71.
Covid-19: Rapid testing cuts cases in pilot but questions remain over use of lateral flow tests
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: Rapid testing cuts cases in pilot but questions remain over use of lateral flow tests An evaluation has found that community testing in Liverpool reduced cases of covid-19, but experts say more evidence is needed on the use of rapid tests, reports Jacqui Wise Jacqui WiseA full evaluation of the community testing pilot scheme in Liverpool concluded that it led to a reduction of around a fifth in covid-19 cases compared with control areas. 1 Researchers who carried out the study said mass testing of asymptomatic people using rapid lateral flow tests (LFTs) gave a significant time advantage over polymerase chain reaction (PCR) testing so that those who tested positive could self-isolate promptly.But some experts said the results do not provide justification for the government's national mass testing programme, and said more evidence was required to understand how best to use rapid LFTs in the community.Between 6 November 2020 and 30 April 2021, 283 338 (57%) of Liverpool residents took a test using the Innova SARS-CoV-2 rapid antigen lateral flow device.Of these, 47% had more than one test and in the same period 152 609 residents were tested by PCR.During this time 6300 people who declared no symptoms tested positive by LFT-a case positivity of 2.1%.Of these, 3547 received a confirmatory PCR test within five days.The study, by the University of Liverpool and the Department of Health and Social Care, concluded that community testing led to an 18% increase in case detection (95% confidence interval 7% to 29%) and a 21% reduction in cases (95% CI 12% to 27%) compared with control areas up to mid-December 2020, after which the surge of the Kent variant made it difficult to compare areas.