tbuckley/cabot-search huggingface dataset:
Clinical phenotypes and outcomes of SARS-CoV-2, influenza, RSV and seven other respiratory viruses: a retrospective study using complete hospital data
Authors: Pontus Hedberg, John Karlsson Valik, Suzanne van der Werff, Hideyuki Tanushi, Ana Requena Mendez, Fredrik Granath, Max Bell, Johan Mårtensson, Robert Dyrdak, Olof Hertting, Anna Färnert, Anders Ternhag, Pontus Naucler
Journal: Thorax (2021)

An understanding of differences in clinical phenotypes and outcomes COVID-19 compared with other respiratory viral infections is important to optimise the management of patients and plan healthcare. Herein we sought to investigate such differences in patients positive for SARS-CoV-2 compared with influenza, respiratory syncytial virus (RSV) and other respiratory viruses. We performed a retrospective cohort study of hospitalised adults and children (≤15 years) who tested positive for SARS-CoV-2, influenza virus A/B, RSV, rhinovirus, enterovirus, parainfluenza viruses, metapneumovirus, seasonal coronaviruses, adenovirus or bocavirus in a respiratory sample at admission between 2011 and 2020. A total of 6321 adult (1721 SARS-CoV-2) and 6379 paediatric (101 SARS-CoV-2) healthcare episodes were included in the study. In adults, SARS-CoV-2 positivity was independently associated with younger age, male sex, overweight/obesity, diabetes and hypertension, tachypnoea as well as better haemodynamic measurements, white cell count, platelet count and creatinine values. Furthermore, SARS-CoV-2 was associated with higher 30-day mortality as compared with influenza (adjusted HR (aHR) 4.43, 95% CI 3.51 to 5.59), RSV (aHR 3.81, 95% CI 2.72 to 5.34) and other respiratory viruses (aHR 3.46, 95% CI 2.61 to 4.60), as well as higher 90-day mortality, ICU admission, ICU mortality and pulmonary embolism in adults. In children, patients with SARS-CoV-2 were older and had lower prevalence of chronic cardiac and respiratory diseases compared with other viruses. SARS-CoV-2 is associated with more severe outcomes compared with other respiratory viruses, and although associated with specific patient and clinical characteristics at admission, a substantial overlap precludes discrimination based on these characteristics.
Niobium carbide (MXene) reduces UHMWPE particle-induced osteolysis
Authors: Kuo-Yang Sun, Yizhang Wu, Jia Xu, Wenfang Xiong, Wei Xu, Jiawei Li, Ziying Sun, Zhongyang Lv, X.S. Wu, Qing Jiang, Hong-Ling Cai, Dongquan Shi
Journal: Bioactive Materials (2021)

Joint replacement surgery is one of the orthopedic surgeries with high successful rates; however, wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant. The implant-derived particulate debris such as ultrahigh molecular weight polyethylene (UHMWPE) can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species (ROS). ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis. In this work, we develop the few-layered Nb2C (FNC) as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption. Moreover, local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model. In sum, our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis.
Podcasts in urology: A growing tendency?
Authors: M.P. Moreno Fontela, B.A. Sinues-Ojas, M. Ramírez-Sánchez, I. Senra-Bravo, A. Coloma-Del-Peso, P. Garrido-Abad, M. Jiménez-Gálvez, C. Suárez-Fonseca, I. Pinazo-Rubio, M. Fernández-Arjona
Journal: European Urology (2021)
Abstract 2714: Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes
Authors: Janai Carr-Ascher
Journal: Cancer Research (2021)

Abstract Approximately 13,000 people this year in the United States alone will be diagnosed with sarcoma and nearly 5,000 will lose their lives to this devastating disease. Soft tissue sarcomas are a clinically and biologically heterogeneous group of tumors made up of approximately fifty subtypes that are classified by their presumed mesenchymal origin. The development of novel therapies for sarcoma has been hampered by the considerable heterogeneity of the disease and the limited understanding of the molecular mechanisms driving sarcoma formation and evolution. Due to this, clinically, the majority of patients with aggressive soft tissue sarcoma subtypes are treated similarly despite evidence these subtypes are unique. Our lab has focused on the development of a new model for the study of sarcoma subtypes using a primary human transformation system. Based on TCGA data, one characteristic that is shared between sarcoma subtypes is the loss or silencing of p53 and Rb1. We have started with immortalized mesenchymal stem cells (MSC), the presumed cell of origin for sarcoma and introduced lentiviral constructs targeting p53 and Rb1 by CRISPR technology to delete these genes. Following this, we have added a barcoded oncogene library with genes implicated in sarcoma specific biology or across cancer subtypes. Using this system, we have successfully transformed these MSCs into high grade soft tissue sarcomas. The current goal is to continue to manipulate this system to develop multiple soft tissue sarcoma subtypes. By starting with the same cell of origin and arriving at different sarcoma subtypes, we can begin to understand the relationship between these subtypes which will inform clinical trial design. Using this system, we can investigate the development of sarcoma, understand subtype heterogeneity, and utilize this tool to develop novel therapies for our patients. Citation Format: Janai Carr-Ascher. Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes [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 2714.
Abstract 2640: Characterization and targeted therapy using patient tumor-derived 3-D spheroids in a metastatic castrate resistant prostate cancer model
Authors: Adam M. Kase, Winston Tan, John A. Copland
Journal: Cancer Research (2021)

Abstract Targeted therapy in prostate cancer is in its early stages and has a promising future since many genomic alterations in metastatic castrate resistant prostate cancer (mCRPC) do not have FDA approved agents for this indication. Three-dimensional culture has been shown to recapitulate patient response to therapy. We characterized a unique patient tumor-derived, GUR017M, 3D culture spheroid model and tested novel therapies based on its genomic profile. This tumor was obtained from a patient with mCRPC who progressed on enzalutamide, abiraterone, cabazitaxel, and had exposure to docetaxel, however discontinued due to toxicity. In order to characterize and test novel therapies for mCRPC, a 3-D spheroid drug assay was utilized and was able to recapitulate the GUR017M response to previous therapies (resistance to docetaxel and enzalutamide). Using a 3-D spheroid drug assay, single agents were investigated based on the GUR017M genomic profile which included cyclin D1, LYN, and FGF3/4/19 amplifications along with HRAS Q61R mutation, and TP53 splice site 672+2T&amp;gt;G. Single agents (abemaciclib, bafetinib, erdafitinib, tipifarnib, MK2206, APR-246) all caused dose dependent inhibition up to 100% inhibition. This rare prostate cancer model, GUR017M allows us to test novel single agents and combination strategies in 3-D culture. This patient tumor has also proven to be a successful PDTX model which allows for confirmatory testing in animal models in order to move forward with clinical trial proposals. Citation Format: Adam M. Kase, Winston Tan, John A. Copland. Characterization and targeted therapy using patient tumor-derived 3-D spheroids in a metastatic castrate resistant prostate cancer model [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 2640.
Abstract 2556: The somatic variant of HLRCC, an unrecognized type of RCC
Authors: Maria J. Merino, Esra Dikoglu, Sandeep Gurram, Marston Linehan, Ramaprasad Srinivasan
Journal: Cancer Research (2021)

Abstract Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome where affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Diagnosis of these tumors is done on clinical, morphologic and immunohistochemical (IHC) determination of negative staining for FH and genetic testing considered the gold standard. Somatic mutations in HLRCC RCC are not well recognized, and the morphologic features of tumors associated with the somatically mutated tumors has not been described. We report the clinical, morphologically and genetic findings of 7 patients with HLRCC and somatic mutations. Design: Clinicopathologic correlation was done in all cases. All patients (4 males and 3 females) denied family history of kidney cancer or skin lesions. Age range was from 27 to 77. All patients had metastatic disease when accepted for protocol. Genetic testing was performed in all cases and IHC for FH when material was available. Results: The genetic testing was negative for a germline mutation in all cases; however a pathogenic somatic mutation was found in all of them. Some of the somatic mutations included two copy deletion of 1q43, multiple break points on chromosome 1, and loss of heterozygosity. Morphologically the predominant pattern was extensive dense tubular formation with small tubules lined by clear or eosinophilic cells in which some nuclear features suggestive of HLRCC were identified (4 cases) the other cases showed cystic and papillary features. The diagnosis of HLRCC was suggested and FH performed with negative results. Conclusion: Pathologists need to be aware that HLRCC with somatic and no germline mutations may occur more frequently than suspected and that a negative family history is frequently obtained. Morphology is helpful. However, staining for FH with negative results should be suspicious of HLRCC and genetic testing repeated considering the possibility of a somatic mutation, so proper diagnosis is made, and patients receive proper therapies. Citation Format: Maria J. Merino, Esra Dikoglu, Sandeep Gurram, Marston Linehan, Ramaprasad Srinivasan. The somatic variant of HLRCC, an unrecognized type of RCC [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 2556.
Abstract 1723: WTX-124 is an IL-2 pro-drug conditionally activated in tumors and able to induce complete regressions in mouse tumor models
Authors: Andres Salmeron, Heather Brodkin, Daniel Hicklin, Nesreen Ismail, Kristin Morris, Christopher Nirschl, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, Jenna Sullivan, William Winston
Journal: Cancer Research (2021)

Abstract Cancer Immunotherapy has established itself as the fourth pillar of cancer treatment thanks to the clinical success of checkpoint inhibitors. Despite the durable responses achieved by some patients using these new therapies, the proportion of responders remains low and restricted to some cancer types. Preclinical and clinical studies have demonstrated the promise of cytokine therapy to increase antitumor immunity, however systemic toxicity and poor pharmacokinetic profiles have limited their clinical application. One of these key cytokines, interleukin-2 (IL-2), is approved for clinical use in metastatic melanoma and renal cell carcinoma. Unfortunately, this treatment is linked to serious toxicities which limits its utility. To address these limitations, our approach takes advantage of the dysregulated protease tumor microenvironment (TME) to activate an IL-2 pro-drug (IL-2 INDUKINETM) only at the desired site of activity. Peripheral inactivation is achieved by linking the cytokine to an inactivation domain using a tumor protease-sensitive linker. The INDUKINE is also engineered with a half-life extension element to improve tumor exposure. Once the IL-2 INDUKINETM reaches the tumor, tumor-associated proteases cleave the linker and release the active cytokine. This work presents data summarizing the discovery, biochemical, cellular, and in vivo activity of our lead IL-2 INDUKINETM WTX-124 and reviews the mechanism of action of these molecules. Treatment with WTX-124 results in complete regression of tumors driven by the expansion and activation of CD8+ T cells and NK cells which increases the production of effector cytokines in the tumor. Activity is dependent on the proteolytic processing of the INDUKINE as a non-cleavable control INDUKINE lacks efficacy. PK analysis in mouse models demonstrates a favorable accumulation of free IL-2 in tumors compared to plasma. The animals that rejected the tumors upon IL-2 INDUKINETM treatment were protected against follow up re-challenge with the same tumor cell line. In vitro proteolytic activation by human tumor samples will also be presented. The tumor-selective activation of WTX-124 with reduced peripheral toxicities supports its further clinical development. Citation Format: Andres Salmeron, Heather Brodkin, Daniel Hicklin, Nesreen Ismail, Kristin Morris, Christopher Nirschl, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, Jenna Sullivan, William Winston. WTX-124 is an IL-2 pro-drug conditionally activated in tumors and able to induce complete regressions in mouse tumor models [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 1723.
Effectiveness and safety of a new helmet CPAP configuration allowing tidal volume monitoring in patients with COVID-19
Authors: C. Chiappero, G. Misseri, A. Mattei, M. Ippolito, C. Albera, E. Pivetta, A. Cortegiani, C. Gregoretti
Journal: Pulmonology (2021)

High generated tidal volumes (Vt) have been correlated with higher risk of self-induced lung injury and worse clinical outcome. This study aimed to evaluate the effectiveness and safety of a new helmet continuous positive airway pressure delivered (h-CPAP) configuration allowing Vt monitoring in patients affected by COVID-19. This prospective observational study was performed in the respiratory intermediate care unit of University Hospital in Turin, Italy, between March 24th, and June 15th, 2020. Included patients were treated with CPAP via a single-limb intentional leak configuration by a turbine-driven ventilator, provided with a dedicated patch. Effectiveness and safety of the configuration and healthcare workers safety were the outcomes of the study. Thirty-five patients were included in this study. Median age was 67 years (IQR 57–76 years), and 30 patients (85.7%) were men. Median value of overall leaks (intentional plus unintentional) was 68 L/min (IQR 63–75). Reliability of Vt measurements was 100%. An out of scale of Vt (above 50% compared to the previous values) was never recorded. Six patients (17.1%) needed more than two helmet replacements, due to leak test >10 l/min. Arm oedema and skin breakdowns were reported in sixteen (45.7%) and seven (20%) patients respectively. Among the 63 healthcare workers involved in the care of COVID-19 patients during the study only one was positive at RT-PCR nasopharyngeal swab testing. The use of h-CPAP for treating COVID-19 in this configuration allowed for reliable Vt monitoring. Further studies evaluating this configuration in larger patients' cohorts are needed.
Refocusing the timeline of tuberculosis through the lens of BCG
Authors: David Dowdy
Journal: Thorax (2021)

An estimated 1.7 billion people—23% of the world’s population—have been infected by Mycobacterium tuberculosis .1 It has been known for over five decades that, once someone has been infected with M. tuberculosis for more than 2–5 years, the risk of developing tuberculosis (TB) disease—barring a second infection or immunosuppressive condition—is small.2 Nevertheless, numerous publications and textbooks continue to cite a ‘rule of thumb’ that 5% of people with latent TB infection will develop reactivation TB disease after this initial high-risk period. Multiple recent analyses have reaffirmed that this 5% figure is a substantial overestimate.3 4 

In this issue of Thorax , Trauer et al reanalyse data from 21 clinical trials of Bacille Calmette-Guerin (BCG) vaccination.5 Their comprehensive analysis provides yet another piece of evidence that the traditional conceptualisation of latent TB infection—as a static state in which people experience a constant, reasonably high risk of reactivation for many years, if not decades—should be abandoned.

Prior analyses have estimated that BCG-derived protection against TB disease may wane after about 10 years,6 though long-term follow-up data are scant. Trauer et al updated a prior meta-analysis of BCG vaccine trials7 to explore whether this waning of protection more likely reflects …
Abstract 1368: Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors
Authors: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska
Journal: Cancer Research (2021)

Abstract BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker. RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose. CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies. ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract. Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors [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 1368.
Interest of FGSI and LRINEC prognostic scores in the management of Fournier gangrene
Authors: B. Saidani, M. Chakroun, A. Saadi, S. Zaghbib, A. Bouzouita, A. Derouiche, M.R. Ben Slama, H. Ayed, M. Chebil
Journal: European Urology (2021)
Foxo1 deletion promotes the growth of new lymphatic valves
Authors: Joshua P. Scallan, Luz A. Knauer, Huayan Hou, Jorge A. Castorena-Gonzalez, Michael J. Davis, Ying Yang
Journal: Journal of Clinical Investigation (2021)

Patients with congenital lymphedema suffer from tissue swelling in part due to mutations in genes regulating lymphatic valve development. Lymphatic valve leaflets grow and are maintained throughout life in response to oscillatory shear stress (OSS), which regulates gene transcription in lymphatic endothelial cells (LECs). Here, we identified the first transcription factor, Foxo1, that repressed lymphatic valve formation by inhibiting the expression of valve-forming genes. We showed that both embryonic and postnatal ablation of Foxo1 in LECs induced additional valve formation in postnatal and adult mice in multiple tissues. Our quantitative analyses revealed that after deletion, the total number of valves in the mesentery was significantly (P < 0.01) increased in the Foxo1LEC-KO mice compared with Foxo1fl/fl controls. In addition, our quantitative real-time PCR (RT-PCR) data from cultured LECs showed that many valve-forming genes were significantly (P < 0.01) upregulated upon knockdown of FOXO1. To confirm our findings in vivo, rescue experiments showed that Foxc2+/- mice, a model of lymphedema-distichiasis, had 50% fewer lymphatic valves and that the remaining valves exhibited backleak. Both valve number and function were completely restored to control levels upon Foxo1 deletion. These findings established FOXO1 as a clinically relevant target to stimulate de novo lymphatic valve formation and rescue defective valves in congenital lymphedema.