tbuckley/cabot-search huggingface dataset:
Dying at home during covid-19: a view from primary care
Authors: Sarah Mitchell, Helen Chapman, Iolanthe Fowler, Laura McTague
Journal: BMJ (2021)

<h3>Abstract</h3> The ratio between excitatory and inhibitory neurons (E/I ratio) is vital for cortical circuit dynamics, computation, and behavior. This ratio may be under the dynamic control of neuromodulatory systems, which are in turn implicated in several neuropsychiatric disorders. In particular, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems have highly specific effects on excitatory and inhibitory cortical neurons, which might translate into changes in the local net E/I ratio. Here, we assessed and compared their net effects on net E/I ratio in human cortex, through an integrated application of computational modeling, placebo-controlled pharmacological intervention, magnetoencephalographic recordings of cortical activity dynamics, and perceptual psychophysics. We found that catecholamines, but not acetylcholine, altered both the temporal structure of intrinsic activity fluctuations in visual and parietal cortex, and the volatility of perceptual inference based on ambiguous visual input. Both effects indicate that catecholamines increase the net E/I ratio in visual and parietal cortex.
A familial TSC1 exon 5 microdeletion associated with angiolipomas and renal-cell carcinoma: A mTORopathy Tunisian familial pedigree
Authors: N. Bouayed Abdelmoula, B. Abdelmoula, I. Masmoudi, I. Bouaziz, R. Dhouib, S. Sallemi, M. Keskes, M. Sehli, K. Chaabouni, S. Falleh, A. Medhioub, K. Khelfi, R. Rhaiem, E. Khouaja, I. Norddine, N. Boukthir, R. Louati, N. Abdellaoui, O. Kaabi, K. Chaker, S. Aloulou, W. Smaoui
Journal: European Urology (2021)
Abstract 11332: Brachial Arterial Stiffness Differs From Aortic Stiffness in Relation to Cardiovascular Risk Factors
Authors: Ueda Tomohiro, Hiroki Teragawa, Chikage Oshita, Shuichi Nomura, Yuichi Fujii
Journal: Circulation (2019)

Introduction: The stiffness parameter β (β-value) is used to examine regional arterial stiffness. Additionally, the cardio-ankle vascular index (CAVI) reflects the global β-value from the thoracic ...
Abstract LB234: The Neuropilin-2 targeting antibody ATYR2810 inhibits non-small cell lung cancer tumor growth in monotherapy and combination therapy
Authors: Alison G. Barber, Zhiwen Xu, Justin Rahman, Hira Lal Goel, Arthur M. Mercurio, Christoph Burkart, Leslie A. Nangle
Journal: Cancer Research (2021)

Abstract Lung cancer remains one of the leading cancer types and is the foremost cause of cancer-related deaths, yet treatment options for advanced lung cancer remain limited. Novel therapies targeting factors critical to the progression of lung cancer are essential. Neuropilin-2 (NRP2) acts as a co-receptor for VEGF and has been correlated with aggressive cancer growth and metastasis. The expression of NRP2 has been shown to be upregulated in several cancers, including non-small cell lung cancer (NSCLC), and the expression of NRP2 in NSCLC is associated with increased invasive tumor growth in vitro as well as a significant decrease in patient survival. As shown previously, aTyr has developed ATYR2810, a domain-specific anti-human monoclonal antibody to NRP2 which blocks its binding to VEGF. Importantly, ATYR2810 blocks VEGF binding in a highly specific manner and does not affect the binding of Semaphorin-3F or subsequent Semaphorin-3F-induced dimerization of NRP2 and PlexinA1. In this study, we have used ATYR2810 to examine the effects of blocking VEGF-mediated NRP2 signaling both as monotherapy and in combination therapy. Using in vitro 3D colony formation assays, we found that ATYR2810 used as monotherapy led to a significant reduction in colony formation in the A549 NSCLC cell line. The effects of ATYR2810 were also examined in NSCLC xenografts, where the use of ATYR2810 as a single agent was found to result in the inhibition of tumor growth. Interestingly, the tumor growth inhibition observed with ATYR2810 as monotherapy was comparable to that of cisplatin monotherapy, suggesting that ATYR2810 may be a potent inhibitor of tumor growth in the A549 xenograft model. The effects of ATYR2810 combination therapy in NSCLC xenografts was also examined, and we found that the use of ATYR2810 in combination with either 5-FU or cisplatin enhanced tumor growth inhibition as compared to the use of either chemotherapeutic agent alone. Taken together, these results suggest that NRP2 may be an important target in aggressive NSCLC and that the use of our novel ATYR2810 antibody to block VEGF-mediated NRP2 signaling may serve as a valuable therapeutic agent both as monotherapy as well as in combination therapy. Citation Format: Alison G. Barber, Zhiwen Xu, Justin Rahman, Hira Lal Goel, Arthur M. Mercurio, Christoph Burkart, Leslie A. Nangle. The Neuropilin-2 targeting antibody ATYR2810 inhibits non-small cell lung cancer tumor growth in monotherapy and combination therapy [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 LB234.
Abstract 2373: Expression of exosomal let-7g in biofluids and outcome in colon cancer patient treated with anti-EGFR therapy
Authors: Jens C. Hahne, Andrea Lampis, Michele Ghidini, Margherita Ratti, Chiara Senti, Rodolfo Passalacqua, Luciano Cascione, Chiara Braconi, Owen Sansom, Matteo Fassan, Nicola Valeri
Journal: Cancer Research (2021)

Abstract Introduction: Monoclonal antibodies against the Epidermal Growth Factor Receptor (EGFR) such as cetuximab or panitumumab are used for the treatment of metastatic colorectal cancer (mCRC) patients. Unfortunately, most patients develop resistance against these therapies within months. Several studies have shown that aberrations in the RAS pathway are responsible for resistance. However, even in metastases that are refractory to anti-EGFR treatment a significant fraction of RAS wild-type (wt) cells remain. These findings suggest a cross-talk between RAS mutant and wt cells in mediating resistance in the wt compartment. Methods: Mouse and patient-derived organoids from mCRC as well as CRC cell lines were used to test the contribution of extracellular vesicles in mediating resistance in RAS wt cells. Using conditioned media, transfection experiments and liquid biopsies (plasma and urine) from patients differential expression of the let-7g microRNA was demonstrated in microvesicles from cetuximab sensitive and resistant cells. Changes in expression of let-7g were further analyzed by in-situ hybridization in tissues. Results: Conditioned media from RAS mutant organoids rendered RAS wt organoids resistant against cetuximab treatment. Basal let-7g expression from pre-treatment plasma and urine samples of RAS wt patients correlated with clinical outcome and changes in let-7g circulating levels mirrored clinical behavior. In-situ hybridization in tissues confirmed changes in expression of the let-7g microRNA observed in plasma and urine samples. Conclusions: Our data suggest that let-7g microRNA might function as a paracrine mediator of anti-EGFR resistance and might be exploited as a non-invasive biomarker of resistance to cetuximab treatment. Further work is ongoing to characterize the molecular mechanisms underpinning let-7g mediated effect on anti-EGFR sensitivity in RAS wt CRC cells. Citation Format: Jens C. Hahne, Andrea Lampis, Michele Ghidini, Margherita Ratti, Chiara Senti, Rodolfo Passalacqua, Luciano Cascione, Chiara Braconi, Owen Sansom, Matteo Fassan, Nicola Valeri. Expression of exosomal let-7g in biofluids and outcome in colon cancer patient treated with anti-EGFR therapy [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 2373.
Recurrence-free survival following resection of low-grade, Non-Muscle-Invasive Urothelial Cancer (NMIBC): A Southwest Oncology Group (SWOG) S0337 post-hoc analysis
Authors: N. Corsi, A. Sood, J. Keeley, D. Dalela, C. Bronkema, N. Rakic, M. Stricker, G. Novara, C. Rogers, F. Abdollah
Journal: European Urology (2021)
Abstract 791: Incidence rates of digestive cancers among US military servicemen: Comparison with the rates in the general US population
Authors: Julie A. Bytnar, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2021)

Abstract Background: Digestive cancers greatly contribute to the cancer burden in the United States. These cancers are more common among men and some are increasing among adults under age 50. Military population, which is dominantly male and young, and general populations differ in exposure to risk factors for these cancers. However, no studies have systematically investigated whether the incidence rates of these cancers differ between the two populations. This study aimed to compare incidence rates and trends of select digestive cancers between active-duty military and general populations. Methods: Data were from the Department of Defenses' Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results 9 (SEER-9) registries. Age-adjusted incidence rates of colorectal, stomach, liver, and pancreatic cancers among men aged 20-59 years during 1990-2013 were compared between the two populations. Stratified analyses were done for colorectal and stomach cancers. Results: The age-adjusted incidence rates of colorectal, stomach, liver, and pancreatic cancers were overall lower among active-duty than SEER (IRR=0.86, 95% CI=0.81-0.92; IRR=0.65, 95% CI=0.55-0.76; IRR=0.39, 95% CI=0.30-0.49; IRR=0.51, 95% CI=0.41-0.62, respectively). This was observed in the subgroups stratified by age for colorectal and stomach cancers except that among men aged 40-59 with colorectal cancer. The incidence rate of colorectal cancer was decreased the latest period (2010-2013) in ACTUR. Conclusion: The incidence rates for selected digestive cancers overall were lower in the active-duty military population than the U.S. general population. This study highlights the need for more research enhancing our understanding of variations in these cancers between the two populations. Citation Format: Julie A. Bytnar, Craig D. Shriver, Kangmin Zhu. Incidence rates of digestive cancers among US military servicemen: Comparison with the rates in the general US population [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 791.
Thulium Laser Enucleation (ThuLEP) versus Transurethral Bipolar Prostate Resection (TURP): Prospective randomized study: Early intra- and postoperative results
Authors: M.L. Zanoni, P. Vota, G. Toia, C. Mazzieri, M.N. Sangalli, A. Mandressi, F. Grizzi, N. Frego, N. Buffi, G. Lughezzani, M. Lazzeri, G. Guazzoni, G. Taverna
Journal: European Urology (2021)
Abstract 375: High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy
Authors: Seung Hyeun Lee, Ji-Youn Sung
Journal: Cancer Research (2021)

Abstract Purpose: Although high tumor mutation burden (TMB) has shown association with benefit from immune checkpoint blockade therapies, its implications in lung cancer patients with driving mutations are still unclear. The objective of this study is to determine the association between TMB and treatment outcome in epidermal growth factor receptor (EGFR)-mutated lung cancer treated with tyrosine kinase inhibitors (TKIs). Methods: We evaluated TMB in EGFR-mutant, lung adenocarcinoma patients who received first-line EGFR-TKIs. TMB was estimated by next-generation sequencing with a cancer gene panel (Oncomine™ Tumor Mutation Load Assay). We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutation according to the different TMB groups. Results: Among the 131 patients who were treated with EGFR-TKIs, a total of 63 patients were eligible for the analysis. TMB was stratified by tertiles; low (≤2.13 mutations/Mb), intermediate (2.14-4.25 mutations/Mb), and high (&amp;gt;4.25 mutations/Mb). The TMB levels were not associated with any clinical parameters. The RR was significantly lower in the high TMB group than in the other groups (43.5% vs. 72.1% vs. 78.5%, all p = 0.01). In multivariate analysis, high TMB was independently associated with a shorter PFS in the overall population (hazard ratio [HR] = 2.64, p = 0.004), and associated with shorter OS in patients with exon 19 deletion (HR = 2.55, p = 0.041) compared with low TMB. The frequencies of secondary T790M mutation after TKI failure were not different among the different TMB groups. Conclusion: High TMB was associated with unfavorable clinical outcome in patients with lung adenocarcinoma treated with EGFR-TKIs. Although further large-scaled studies are required, our data suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and may constitute a distinct subgroup warranting tailored therapeutic approach in this clinical setting. Citation Format: Seung Hyeun Lee, Ji-Youn Sung. High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy [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 375.
Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis
Authors: Maria Bartosova, Conghui Zhang, Betti Schaefer, Rebecca Herzog, David Ridinger, Ivan Damgov, Eszter Levai, Iva Marinovic, Christoph Eckert, Philipp Romero, Peter Sallay, Akos Ujszaszi, Markus Unterwurzacher, Anja Wagner, Georg Hildenbrand, Bradley A. Warady, Franz Schaefer, Sotirios G. Zarogiannis, Klaus Kratochwill, Claus Peter Schmitt
Journal: Circulation Research (2021)

[Figure: see text].
Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany
Authors: Bjoern Jensen, Nadine Luebke, Torsten Feldt, Verena Keitel, Timo Brandenburger, Detlef Kindgen-Milles, Matthias Lutterbeck, Noemi F Freise, David Schoeler, Rainer Haas, Alexander Dilthey, Ortwin Adams, Andreas Walker, Joerg Timm, Tom Luedde
Journal: The Lancet Regional Health - Europe (2021)

Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants.After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration.After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution - known to confer immune escape - was detected at the time of viral rebound but not before bamlanivimab treatment.Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies.All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
Abstract LB075: Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases
Authors: Byoung S. Kwon, Seunghyun Lee, Jin-Kyung Choi, Bora Hwang, Sun-Woo Im, Yun-Sook Lim, Bumseok Kim, Soon B. Hwang, HoonSung Jeh
Journal: Cancer Research (2021)

Abstract Since the Spike protein on the surface of SARS coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor in human cells, the development of neutralizing proteins or antibodies targeting the receptor binding domain (RBD) of the spike protein is an important strategy for SARS-COV-2 therapy. We chose to develop molecularly-evolved soluble ACE2 protein on three grounds; 1) it can trap and neutralize the SARS-CoV-2 as neutralizing antibodies do, 2) it can supplement angiotensin II-converting enzyme activities that protect lung, heart, and kidneys of severe cases of infections and patients with underlying diseases, and 3) it may trap effectively SARS-CoV-2 mutants even though the mutations compromise the protection by neutralizing antibodies or vaccine. For the enhancement of ACE2 binding affinity to RBD, we used the 3D complex structure between ACE2 and RBD to select the major contributing ACE2 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The engineered ACE2, EU129, was fused with the human IgG1 Fc for long half-life and viral clearance. The binding affinity of EU129 to RBD was increased by about 500-folds compared to ACE2 wild-type in SPR analysis, and the neutralizing activity was also increased by about 130-folds compared to ACE2 wild-type in surrogate virus neutralization test (sVNT). In addition, it was confirmed that the enzymatic activity of ACE2, which prevents organ damage due to SARS-CoV-2 infection in the human, is maintained at a level similar to that of ACE2 wild-type. In vitro assays using live SARS-CoV-2 virus and Vero E6 cells, EU129 was shown to be more effective in inhibiting viral infection and amplification than ACE2 wild-type, which was confirmed through protein and RNA level and cell morphology change of the live virus. In vivo stability assays using BALB/c mice, EU129 showed enhanced binding to the RBD and maintained enzymatic activity similar to ACE2 wild-type. We generated EU129 with the improved binding affinity and neutralizing activity through ACE2 receptor engineering. It has angiotensin II-converting enzymatic activity for organ protection, thus EU129 is a better therapeutic candidate for severe cases of SARS-CoV-2 infection and patients with underlying diseases such as cancers. Citation Format: Byoung S. Kwon, Seunghyun Lee, Jin-Kyung Choi, Bora Hwang, Sun-Woo Im, Yun-Sook Lim, Bumseok Kim, Soon B. Hwang, HoonSung Jeh. Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases [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 LB075.
Has the COVID-19 outbreak changed the way we are treating prostate cancer? An EAU – YAU prostate cancer working group multi-institutional study
Authors: F. Zattoni, G. Marra, A. Kretschmer, F. Preisser, C. Kesch, J.P. Radtke, N. Hoffmann, A. Morlacco, F. Dal Moro, T.F. Soeterik, R.C. Van Den Bergh, F. Barletta, A. Briganti, F. Montorisi, G. Gandaglia
Journal: European Urology (2021)
Testicular tumors in prepubertal boys: A new chapter in 2021 EAU/ESPU Paediatric Urology guidelines
Authors: J.S.L.T. Quaedackers, R. Stein, N.R. Bhatt, H.S. Dogan, L.A. ’T Hoen, J.M. Nijman, C. Radmayr, M.S. Silay, S. Tekgul, Y.F. Rawashdeh, G. Bogaert
Journal: European Urology (2021)
Abstract 2325: Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells
Authors: Violet A. Kiesel, Stephen D. Hursting, Dorothy Teegarden
Journal: Cancer Research (2021)

Abstract Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current studies was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in non-metastatic M-Wnt compared to metastatic metM-Wntlung murine mammary cancer cell lines. We show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to non-metastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Further, hypoxia induces a greater suppression of glutamine to glutamate conversion in metastatic cells (15% in metastatic cells compared to 9% in non-metastatic cells). Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wntlung cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4), which mediated survival of hypoxic metastatic cells in detached conditions, as shown by genetic ATF4 depletion. These data indicate that more aggressive, metastatic cancer cells rely on metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, in hypoxia for survival in detached conditions. Citation Format: Violet A. Kiesel, Stephen D. Hursting, Dorothy Teegarden. Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells [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 2325.
Patient-reported outcomes after genital gender-affirming surgery with versus without urethral lengthening in transgender men
Authors: F.P.W. de Rooij, T.C. Van De Grift, H. Veerman, M. Al-Tamimi, W.B. Van Der Sluis, B.L. Ronkes, M. Özer, M.G. Mullender, M-B. Bouman, G.L.S. Pigot
Journal: European Urology (2021)
Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease
Authors: Ioanna Sakellari, Ioannis Batsis, Eleni Gavriilaki, Alkistis Panteliadou, Andriana Lazaridou, Despina Mallouri, Varnavas Constantinou, Giorgos Karavalakis, Apostolia Papalexandri, Panayotis Kaloyannidis, Anna Vardi, Christos Smias, Achilles Anagnostopoulos
Journal: Blood (2017)