tbuckley/cabot-search huggingface dataset:
Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy
Authors: Xin Sun, Yuhan Shu, Guiqin Ye, Caixia Wu, Mengting Xu, Ruilan Gao, Dongsheng Huang, Jianbin Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.
Abstract 16338: Machine Learning Prediction of Human Interpretable Local Features on Echocardiogram
Authors: David Ouyang, Amirata Ghorbani, Jonathan H Chen, Robert A Harrington, Euan A Ashley, David Liang, James Zou
Journal: Circulation (2019)

Introduction: Echocardiography is the most common modality of cardiovascular imaging, essential for management of cardiomyopathy, valvular disease, and other cardiovascular diseases. Recent advance...
O11-3 Phase 2 trial of atezolizumab with bevacizumab for patients with PD-L1 high non-Sq NSCLC (WJOG10718L/At Be Study)
Authors: Atsushi Nakamura, Takashi Seto, Hidetoshi Hayashi, Haruyasu Murakami, Seiji Niho, Terufumi Kato, Hideo Saka, Hiroshige Yoshioka, Isamu Okamoto, Koichi Azuma, Haruko Daga, Satoru Miura, Kazumi Nishino, Rie Tohnai, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Journal: Annals of Oncology (2021)
Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab
Authors: Austin G. Kulasekararaj, Antonio M. Risitano, Jaroslaw P. Maciejewski, Rosario Notaro, Peter Browett, Jong Wook Lee, Mingjun Huang, Michael Geffner, Robert A. Brodsky
Journal: Blood (2021)
Macrophage-Derived Cholesterol Contributes to Therapeutic Resistance in Prostate Cancer
Authors: Asmaa El-Kenawi, William Dominguez-Viqueira, Min Liu, Shivanshu Awasthi, Julieta Abraham-Miranda, Aysenur Keske, KayLee K. Steiner, Leenil Noel, Amparo N. Serna, Jasreman Dhillon, Robert J. Gillies, Xiaoqing Yu, John M. Koomen, Kosj Yamoah, Robert A. Gatenby, Brian Ruffell
Journal: Cancer Research (2021)

Abstract Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC. Significance: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens. See related commentary by Al-Janabi and Lewis, p. 5399
Dual actions of osteoclastic-inhibition and osteogenic-stimulation through strontium-releasing bioactive nanoscale cement imply biomaterial-enabled osteoporosis therapy
Authors: Na-Hyun Lee, Min Sil Kang, Tae-Hyun Kim, Dong Suk Yoon, Nandin Mandakhbayar, Seung Bin Jo, Hye Sung Kim, Jonathan C. Knowles, Jung-Hwan Lee, Hae-Won Kim
Journal: Biomaterials (2021)
Abstract 14339: The Impact of Obesity on Mitral Valve Surgery Outcome for Patients With Mitral Valve Regurgitation
Authors: Mohamad Soud, Yasser Al-khadra, Homam Moussa Pacha, Fahed Darmoch, Zaher Fanari, Amir Kaki, Wael AlJaroudi, M Chadi Alraies
Journal: Circulation (2018)

Introduction: Several studies have shown an “obesity paradox” in which obese people have a favorable outcome following cardiac surgeries. However, the impact of obesity on mitral valve surgery is u...
We need to bring R0 &lt; 1 to treat cancer too
Authors: Devabhaktuni Srikrishna, Kris Sachsenmeier
Journal: Genome Medicine (2021)

If each cancer cell produces on average more than one cancer cell, we see a net growth of the tumors and metastases and vice versa. We review recent clinical results for microsatellite stable metastatic colorectal cancer (MSS-mCRC) suggesting immunotherapy combinations with personalized vaccines, checkpoint inhibitors, targeted therapies, multikinase inhibitors, chemotherapies, and radiation that simultaneously slow cancer cell growth rate and enhance T cell killing rate of cancer cells may in future synergize to control the disease.
Saliva molecular testing for SARS-CoV-2: simplifying the diagnosis without losing accuracy
Authors: Francesca Saluzzo, Paola Mantegani, Valeria Poletti de Chaurand, Federica Cugnata, Patrizia Rovere-Querini, Marta Cilla, Patrizia Paola Erba, Sara Racca, Cristina Tresoldi, Caterina Uberti-Foppa, Clelia Di Serio, Daniela Maria Cirillo
Journal: European Respiratory Journal (2021)

<b>This study demonstrated that the use of point of care technologies on saliva represents a valid and highly specific solution to simplify, speed up and broadly distribute the diagnostic process for the control of the COVID-19 epidemic</b>https://bit.ly/3oh4bds
Populations of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae are different in human-polluted environment and food items: a multicentre European study
Authors: Daniel Martak, Julia Guther, Tess D. Verschuuren, Benoit Valot, Nadine Conzelmann, Stefanie Bunk, M. Eugenia Riccio, Elena Salamanca, Alexandre Meunier, Charles P. Henriot, Caroline Pressacco Brossier, Xavier Bertrand, Ben S. Cooper, Stephan Harbarth, Evelina Tacconelli, Ad C. Fluit, Jesús Rodriguez-Baño, Jan A.J.W. Kluytmans, Silke Peter, Didier Hocquet
Journal: Clinical Microbiology and Infection (2021)

To assess the extent to which food items are a source of extended-spectrum β-lactamase (ESBL) -producing Escherichia coli (ESBL-Ec) and ESBL-producing Klebsiella pneumoniae (ESBL-Kp) for humans in five European cities.We sampled 122 human polluted (hp)-environments (sewers and polluted rivers, as a proxy of human contamination) and 714 food items in Besançon (France), Geneva (Switzerland), Sevilla (Spain), Tübingen (Germany) and Utrecht (The Netherlands). A total of 254 ESBL-Ec and 39 ESBL-Kp isolates were cultured. All genomes were fully sequenced to compare their sequence types (ST) and core genomes, along with the distribution of blaESBL genes and their genetic supports (i.e. chromosome or plasmid).Sequence data revealed that ESBL-Ec and ESBL-Kp isolates from hp-environments were genetically different from those contaminating food items. ESBL-Ec ST131 was widespread in the hp-environment (21.5% of the isolates) but absent from the food items tested. ESBL-Ec ST10 was in similar proportions in hp-environments and food items (15 and 10 isolates, respectively) but mostly carried reservoir-specific blaESBL. blaCTX-M-1 and blaSHV-12 predominated in food-related E. coli isolates (32% and 34% of the isolates, respectively), whereas blaCTX-M-15 and blaCTX-M-27 predominated in isolates from hp-environments (52% and 15% of the isolates, respectively).We found a very limited connection between ESBL-Ec and ESBL-Kp populations retrieved in food items and from hp-environments and blaESBL. This suggests that human-to-human contamination, rather than the food chain, is possibly the most frequent route of ESBL-Ec and ESBL-Kp transmission in high-income countries.
Total tumor volume reduction and low PSMA expression in patients receiving Lu-PSMA therapy
Authors: Robert Seifert, Katharina Kessel, Katrin Schlack, Matthias Weckesser, David Kersting, Konstantin E. Seitzer, Manuel Weber, Martin Bögemann, Kambiz Rahbar
Journal: Theranostics (2021)

Background: [ 177 Lu]-PSMA-617 (Lu-PSMA) therapy is a promising therapeutic option for end-stage prostate cancer patients.Early treatment response at the first restaging after two therapy cycles might correlate with high treatment efficacy and long overall survival (OS).Therefore, the aim of this study was to evaluate whether early reduction in tumor volume is a positive prognosticator for OS.To this end, PSMA PET prior to therapy (baseline) and at first restaging after two therapy cycles (interim; i.e., 12 weeks) were compared.Methods: Patients with metastatic castration-resistant prostate cancer who received Lu-PSMA therapy were reviewed for this analysis.All patients with available baseline and interim [ 68 Ga]-PSMA-11 PET/CT were included in this analysis (n = 33).All PSMA avid metastases in baseline and interim PETs were semi-automatically segmented.The average PSMA expression (mean SUVmax of all metastases), total tumor volume (PSMA-TV) and TLQ (quotients of tumor volume and SUVmean summed over all metastases) were quantified at baseline and interim timepoints.Response in PSMA-TV was assumed when a decline > 30% was present.OS and biochemical response were available for all patients.Results: Baseline PSMA-TV was a statistically significant prognosticator of OS (HR = 1.618 95%CI: 1.117 -2.343, p = 0.011).Reduction in PSMA-TV was not a statistically significant positive prognosticator of OS in the total cohort (HR = 0.829 95%CI: 0.559 -1.230, p = 0.352).Likewise, there was no statistical difference in survival time comparing patients with PSMA-TV response to those without (13.2 vs. 15.6 months, p = 0.1).In the subgroup of patients with PSMA-TV response, mean SUVmax was a statistically significant prognosticator of OS (binarized by median; HR = 0.15; 95%CI: 0.03 -0.83; p < 0.05).If patients with low PSMA expression at baseline were excluded from the analysis, reduction in PSMA-TV became a positive prognosticator of OS in uni-and multivariable Cox regression (HR = 0.290; 95%CI: 0.108 -0.782; p = 0.015).Conclusion: PSMA-TV reduction was a positive prognosticator of OS only if patients with low PSMA expression were excluded.This might indicate that the PSMA-PETs of patients with low PSMA expression may not be suited for assessing PSMA-TV reduction.Future studies investigating the interplay of PSMA-TV and low PSMA expression response are warranted.
Tips and tricks in the endoscopic management of a complex biliary stone in Billroth II gastrectomy
Authors: Guilherme Henrique Peixoto de Oliveira, Diogo Turiani Hourneaux de Moura, Thomas R. McCarty, Pedro Victor Aniz Gomes de Oliveira, Mateus Pereira Funari, Spencer Cheng, Eduardo Guimarães Hourneaux de Moura
Journal: Endoscopy (2021)

Post-surgical anatomy may make traditional endoscopic retrograde cholangiopancreatography challenging for the endoscopist. In patients with Billroth II gastrectomy, challenges include selective entrance to the afferent loop and cannulation of the common bile duct (CBD) due to the inverted position [1]. Endoscopic management of CBD stones may be especially difficult in these patients, especially those with complex biliary stones [2].
P49-9 Atezolizumab in combination with carboplatin and etoposide (CE) for small-cell lung cancer after failure to CE
Authors: Takayuki Takeda, Nobutaka Kataoka, Yusuke Kunimatsu, Yusuke Tachibana, Takumi Sugimoto, Izumi Sato, Nozomi Tani, Yuri Ogura, Kazuki Hirose
Journal: Annals of Oncology (2021)
The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains
Authors: Zhenyu Dai, Wei Mu, Ya Zhao, Xiangyin Jia, Jianwei Liu, Qiaoe Wei, Taochao Tan, Jianfeng Zhou
Journal: Molecular Therapy (2021)

T cell malignancies are a group of hematologic cancers with high recurrence and mortality rates. CD5 is highly expressed in ∼85% of T cell malignancies, although normal expression of CD5 is restricted to thymocytes, T cells, and B1 cells. However, CD5 expression on chimeric antigen receptor (CAR)-T cells leads to CAR-T cell fratricide. Once this limitation is overcome, CD5-targeting CAR-T therapy could be an attractive strategy to treat T cell malignancies. Here, we report the selection of novel CD5-targeting fully human heavy-chain variable (FHVH) domains for the development of a biepitopic CAR, termed FHVH3/VH1, containing FHVH1 and FHVH3, which were validated to bind different epitopes of the CD5 antigen. To prevent fratricide in CD5 CAR-T cells, we optimized the manufacturing procedures of a CRISPR-Cas9-based CD5 knockout (CD5KO) and lentiviral transduction of anti-CD5 CAR. In vitro and in vivo functional comparisons demonstrated that biepitopic CD5KO FHVH3/VH1 CAR-T cells exhibited enhanced and longer lasting efficacy; produced moderate levels of cytokine secretion; showed similar specificity profiles as either FHVH1, FHVH3, or the clinically tested H65; and is therefore suitable for further development.
An erythroid-to-myeloid cell fate conversion is elicited by LSD1 inactivation
Authors: Lei Yu, Greggory Myers, Chia-Jui Ku, Emily Schneider, Yu Wang, Sharon A. Singh, Natee Jearawiriyapaisarn, Andrew White, Takashi Moriguchi, Rami Khoriaty, Masayuki Yamamoto, Michael G. Rosenfeld, Julien Pedron, John H. Bushweller, Kim-Chew Lim, James Douglas Engel
Journal: Blood (2021)
Corrigendum to Flemming J, Marczenke M, Rudolph I-M, et al. Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome. Kidney Int. 2020;98:159–167
Authors: Julia Flemming, Maike Marczenke, Ina-Maria Rudolph, Rikke Nielsen, Tina Storm, Erik Ilsoe Christensen, Sebastian Diecke, Francesco Emma, Thomas E. Willnow
Journal: Kidney International (2021)

In the above-stated article, the given name and surname one of the authors, Erik Ilsoe Christensen, was presented inaccurately. The given name is Erik and the surname is Ilsoe Christensen. In addition, an additional affiliation of Maike Marczenke was omitted. The additional affiliation is the Department of Biology, Chemistry and Pharmacy, Freie Universitaet Berlin, Berlin, Germany. The authors would like to apologize for any inconvenience caused. Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndromeKidney InternationalVol. 98Issue 1PreviewDonnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Full-Text PDF Open Access
Unstable regulatory T cells, enriched for naïve and Nrp1<sup>neg</sup>cells, are purged after fate challenge
Authors: Steffie Junius, Adamantios V. Mavrogiannis, Pierre Lemaitre, Margaux Gerbaux, Frederik Staels, Vanshika Malviya, Oliver Burton, Václav Gergelits, Kailash Singh, Raul Yhossef Tito Tadeo, Jeroen Raes, Stephanie Humblet-Baron, Adrian Liston, Susan M. Schlenner
Journal: Science Immunology (2021)

Lymphophenic fate challenge purges incompletely committed regulatory T cells, a subset enriched for naïve neuropilin-1–negative T reg .
Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non–Small Cell Lung Cancer
Authors: Heath Skinner, Chen Hu, Theodoros Tsakiridis, Rafael Santana-Davila, Bo Lu, Jeremy J. Erasmus, Anthony J. Doemer, Gregory M. M. Videtic, James Coster, Alex Xuezhong Yang, Richard Y. Lee, Maria Werner-Wasik, Philip E. Schaner, Steven E. McCormack, Benjamin T. Esparaz, Ronald C. McGarry, Jose Bazan, Timothy Struve, Rebecca Paulus, Jeffrey D. Bradley
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Non–small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. <h3>Objective</h3> To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. <h3>Design, Setting, and Participants</h3> The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. <h3>Interventions</h3> Chemoradiation and consolidation chemotherapy with or without metformin. <h3>Main Outcomes and Measures</h3> The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. <h3>Results</h3> A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73;<i>P</i> = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69;<i>P</i> = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. <h3>Conclusions and Relevance</h3> In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02186847
Comparison of self-collected mouth gargle with deep-throat saliva samples for the diagnosis of COVID-19
Authors: Christopher KC Lai, Grace CY Lui, Zigui Chen, Yuk-Yam Cheung, Kwok Chu Cheng, Agnes SY Leung, Rita WY Ng, Jo LK Cheung, Apple CM Yeung, Wendy CS Ho, Kate C Chan, David SC Hui, Dominic NC Tsang, Paul KS Chan
Journal: Journal of Infection (2021)
P13-8 A retrospective analysis on the prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders
Authors: Takenori Takahata, Kengo Hasui, Yu Chen, Kensuke Saito, Kota Sasaki, Rina Watanabe, Keisuke Hasui, Hiroto Hiraga, Hirotake Sakuraba, Shinsaku Fukuda, Atsushi Sato
Journal: Annals of Oncology (2021)
Vestibular Schwannomas
Authors: Constantin Tuleasca, Roy T Daniel, Marc Levivier
Journal: New England Journal of Medicine (2021)

Vestibular SchwannomasTo the Editor: In their article (April 8 issue), 1 Carlson and Link state that because of surgical risks -in particular, risks to the facial nerve -the practice of intentionally leaving a tumor remnant has gained popularity.Such an approach is usually considered in the case of large vestibular schwannomas but not for small or medium-sized tumors, for which radiosurgery is the treatment of choice (supported by level II evidence), 2 since it offers a high degree of facial and cochlear functional preservation. 3 For large vestibular schwannomas, a "nerve-centered approach" with planned intracapsular resection offers equivalent functional outcomes 4 but may expose patients to further remnant growth.For this reason, we suggest a combined approach, including postoperative radiosurgery aimed at attaining better oncologic control. 5However, tumor remnants render planning for radiosurgery difficult, as a result of complex shapes, variability in residual volume, and difficulties in delineating the target volume.To date, we have had high rates of tumor control with our approach, albeit slightly lower than those obtained with upfront radiosurgery for small and medium-sized vestibular schwannomas.The major advantage of this middle ground we advocate is preservation of facial and cochlear function for patients with large vestibular schwannomas that is equivalent to that achieved with up-front radiosurgery in patients with small or medium-sized schwannomas.
P1-3 Clinical profile and treatment outcomes of esophageal cancer patients treated with nivolumab: A real world data
Authors: Ryuichi Morita, Takeshi Ishikawa, Tomoki Sakakida, Kohei Asaeda, Reo Kobayashi, Hajime Miyazaki, Toshifumi Doi, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiko Uchiyama, Tomohisa Takagi, Hirotaka Konishi, Atsushi Shiozaki, Hitoshi Fujiwara, Hideyuki Konishi, Yuji Naito, Yoshito Itoh
Journal: Annals of Oncology (2021)
Minimal Residual Disease Monitoring by RQ-PCR in Core Binding Factor Positive AML Allows Risk-Stratification and Predicts Relapse: Results of the UK MRC AML-15 Trial.
Authors: John Ahman Liu-Yin, Sarah B. Daly, Michelle A. Sale, Stuart Green, Khalid Tobal, Robert Hills, Alan Burnett
Journal: Blood (2007)
Epidemiological and genetic characterization of measles virus circulating strains at Marseille, France during 2017–2019 measles outbreak
Authors: Rita Jaafar, Christine Zandotti, Clio Grimaldier, Maëlia Etoundi, Ines Kadri, Celine Boschi, Priscilla Jardot, Philippe Colson, Didier Raoult, Bernard La Scola, Sarah Aherfi
Journal: Journal of Infection (2021)