tbuckley/cabot-search huggingface dataset:
Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma
Authors: Taro Yamashita, Naohiko Koshikawa, Tetsuro Shimakami, Takeshi Terashima, Masatoshi Nakagawa, Kouki Nio, Rika Horii, Noriho Iida, Kazunori Kawaguchi, Kuniaki Arai, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda, Azusa Kitao, Satoshi Kobayashi, Shizuko Takahara, Yasuhito Imai, Kenichi Yoshimura, Toshinori Murayama, Yasunari Nakamoto, Eisaku Yoshida, Toru Yoshimura, Motoharu Seiki, Shuichi Kaneko
Journal: Hepatology (2021)

Backgrounds and Aims Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). Approach and Results In HCC cell lines, LG2m was expressed in alpha‐fetoprotein (AFP)‐negative, CD90‐positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida’s S1/Boyault’s G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m‐high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan‐Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR ( P &lt; 0.0001). Conclusions LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.
Abstract 15167: Short-term Sequalae of Children With Paediatric Inflammatory Multisystem Syndrome Temporarily Associated With Sars-cov-2 Infection (pims-ts) Assessed by Cardiovascular Magnetic Resonance
Authors: Ivan Bermejo Altamar, Elisabeth Whittaker, jethro herberg, Alain Fraisse, Carles Bautista, Heechan Kang, Rowlinson Giselle, Rick Wage, Mary Lane, Enrico Piccinelli, Giovanni Di Salvo, Raad Mohiaddin, Dudley J Pennell, Sylvia J Krupickova
Journal: Circulation (2020)

Introduction: Children with paediatric inflammatory multisystem syndrome temporally associated with SARS CoV2 infection (PIMS-TS) present with evidence of multiorgan dysfunction. Cardiac features include partial or typical Kawasaki disease symptoms or ventricular impairment. The aim of this study was to assess short term sequelae of cardiac involvement in patients with PIMS-TS. Methods: 17 consecutive paediatric patients with PIMS-TS were referred for CMR at our institution. The referring criteria were: Echocardiographic finding of LV dysfunction at presentation (53%), dilated coronary arteries (27%) and high cardiac markers without LV dysfunction (20%). 16 patients completed the scan and were included into the analysis. Results: Age of the patients was 17 months-12 years (mean 6.4 years), 12 (80%) were male. Six (40%) patients required general anaesthesia. The time between the onset of the symptoms and the scan was 12-72 days. All patients had SARS CoV2 PCR negative at the time of scan, 2 patients were previously positive and 12 (80%) had positive IgG. CMR indexed volumes (ml/m2) were in normal range: LVEDV 65±11, LVESV 24±7, RVEDV 67±12, RVESV 27±7. LV mass index were normal 45±8 gr/m2. No overt areas of myocardial oedema or acute inflammation on STIR (short tau inversion recovery) images were found. Mildly reduced LV ejection fraction was found in 1 patient with subtle linear late gadolinium enhancement (LGE) in the midventricular midmyocardial interventricular septum with negative STIR images. Another patient was found to have LGE of the proximal parts of mitral valve papillary muscles, but no abnormalities in the LV ejection fraction or mitral valve function were found. Two patients had a small pericardial effusion. 3 patients had dilated neck and/or innominate veins, 2 of them with phlebectatic appearance. One patient had enlarged liver, another liver and spleen. Conclusion: in conclusion no significant myocardial sequelae have been found in most of the patients presenting with PIMS-TS short-term after onset of symptoms. This might indicate rapid recovery of the cardiac inflammation in most of the patients. More follow up is needed to clarify if there will be any potential sequelae from the acute episode as well as the outcome of phlebectasia.
scSorter: assigning cells to known cell types according to marker genes
Authors: Hongyu Guo, Jun Li
Journal: Genome biology (2021)

Abstract On single-cell RNA-sequencing data, we consider the problem of assigning cells to known cell types, assuming that the identities of cell-type-specific marker genes are given but their exact expression levels are unavailable, that is, without using a reference dataset. Based on an observation that the expected over-expression of marker genes is often absent in a nonnegligible proportion of cells, we develop a method called scSorter. scSorter allows marker genes to express at a low level and borrows information from the expression of non-marker genes. On both simulated and real data, scSorter shows much higher power compared to existing methods.
Endoscopic submucosal dissection for localized amyloidosis of the sigmoid colon
Authors: Kei Nakazawa, Yutaka Saito, Shigetaka Yoshinaga, Shigeki Sekine, Kazuhide Higuchi
Journal: Endoscopy (2021)

Amyloidosis is a rare disease caused by the extracellular deposition of amyloid, which results from the self-assembly of various precursor proteins with a highly ordered and abnormal cross-β sheet structure [1] [2].
Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs
Authors: E. Felip, A.T. Shaw, A. Bearz, D.R. Camidge, B.J. Solomon, J.R. Bauman, T.M. Bauer, S. Peters, F. Toffalorio, A. Abbattista, H. Thurm, G. Peltz, R. Wiltshire, B. Besse
Journal: Annals of Oncology (2021)

<h3>Background</h3> Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against <i>ALK</i>-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in <i>ALK</i>-positive NSCLC that progressed on second-generation ALK TKIs. <h3>Patients and methods</h3> In the ongoing phase II study (NCT01970865), patients with <i>ALK</i>-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. <h3>Results</h3> Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). <h3>Conclusions</h3> Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.
3-Year Outcomes of Transcatheter Mitral Valve Repair in Patients With Heart Failure
Authors: Michael J. Mack, JoAnn Lindenfeld, William T. Abraham, Saibal Kar, D. Scott Lim, Jacob M. Mishell, Brian K. Whisenant, Paul A. Grayburn, Michael J. Rinaldi, Samir R. Kapadia, Vivek Rajagopal, Ian J. Sarembock, Andreas Brieke, Jason H. Rogers, Steven O. Marx, David J. Cohen, Neil J. Weissman, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2021)
Nrf2-dependent antioxidant response is regulated by p300/CBP mediated reversible acetylation
Authors: Zheng Sun, Nicole Villeneuve, Donna Zhang
Journal: Cancer Research (2008)

1747  Nrf2 is a critical transcription factor that regulates endogenous antioxidants, phase II detoxification enzymes and other cellular defensive proteins through the antioxidant responsive element (ARE) in the promoter regions of these genes. Understanding the molecular mechanisms by which Nrf2 is regulated is important for pharmaceutical intervention of the antioxidant signaling pathway. We have previously shown that Keap1, functioning as a molecular switch, targets Nrf2 for ubiquitin-mediated proteasomal degradation under normal cellular redox conditions. Upon oxidative stress, the enzymatic activity of Keap1-dependent ligase is inhibited, leading to Nrf2 protein accumulation and enhanced Nrf2-dependent transactivation. In addition to keap1-dependent on-and-off regulatory mechanism in controlling Nrf2 activity, here we further show additional levels of regulation within the nucleus. Histone acetyltransferase p300/CBP (CREB binding protein) fine-tunes Nrf2 functions through both acetylation-dependent and independent mechanisms. We have characterized the physical and functional interactions between p300/CBP and Nrf2, and have identified specific lysine residues within Nrf2 that is acetylated by p300/CBP. These findings clearly demonstrate the complexity of Nrf2 regulation, which provides insights into how Nrf2 signaling is integrated with other signaling pathways through interacting with transcription co-activators within the nucleus.  (NIEHS 1RO1ES015010-01, ACS RSG-07-154-01)
Abstract PS19-15: N-RAS as a marker for DCIS progression
Authors: Eric C Chang, Zeyi Zheng, Hanan Elsarraj, Yan Hong, Yichao Shen Shen, Flora Lo, Long Feng, Xian H.-F. Zhang, Fariba Behbod
Journal: Cancer Research (2021)

Abstract Background: Ductal carcinoma in situ (DCIS) is a key premalignant stage. Approximately 50% of the DCIS cases will advance to invasive ductal carcinoma (IDC); however, they are usually universally treated leading to overtreatment. While earlier premalignant breast lesions, such as atypical ductal hyperplasia, are nearly all luminal and positive for estrogen receptor α (ER+), up to 8% DCIS are basal-like, which is more aggressive. We have previously shown that N-Ras, which is highly expressed selectively in the basal-like subtype, can promote the growth and transforming activity of basal-like breast cancer (PMID 26166574). In this study we investigate whether NRAS expression at DCIS can promote basal-like properties and the progression to invasiveness. Methods: NRAS mRNA levels in normal, DCIS, and IDC patient-derived microarray databases and tissue microarrays (TMAs) were compared using student t-test. Correlation between NRAS mRNA levels and basal-like properties was assessed by Pearson Correlation. ER protein levels were assessed by IHC. NRAS was expressed in a luminal DCIS cell line model SUM225PE cells and the resulting cells were injected intraductally into mice to assess expression of basal-like markers and invasiveness in vivo. Conversely, NRAS expression was silenced in a DCIS-like basal-like cell line SUM102 and increased expression of luminal markers was assessed by RNA-seq and western blot. Results: In microarray databases, DCIS samples with higher NRAS mRNA levels are enriched with basal-like gene expression signature; furthermore, NRAS mRNA levels appear to increase progressively from normal to DICS and from DCIS to IDC. A similar correlation between high NRAS levels and invasiveness and high Ki67 levels in TMAs was observed by RNA FISH. High levels of NRAS mRNAs also correlated with low ER levels. Conclusions: How to identify the subset of DCIS cases that will become invasive is critical for addressing the current problem of overtreatment. Our data support the hypothesis that high N-RAS levels in DCIS mark invasiveness, by presumably inducing basal-like more aggressive tumor activities. On-going studies will further delineate whether N-Ras is also responsible for driving DCIS to the invasive state. Citation Format: Eric C Chang, Zeyi Zheng, Hanan Elsarraj, Yan Hong, Yichao Shen Shen, Flora Lo, Long Feng, Xian H.-F. Zhang, Fariba Behbod. N-RAS as a marker for DCIS progression [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-15.
Reply to Christian Daniel Fankhauser, Arie Parnham, Vijay Sangar’s Letter to the Editor re: Paolo Dell’Oglio, Hielke M. de Vries, Elio Mazzone, et al. Hybrid Indocyanine Green–99mTc-nanocolloid for Single-photon Emission Computed Tomography and Combined Radio- and Fluorescence-guided Sentinel Node Biopsy in Penile Cancer: Results of 740 Inguinal Basins Assessed at a Single Institution. Eur Urol 2020;78:865–72
Authors: Paolo Dell’Oglio, Hielke M. de Vries, Elio Mazzone, Gijs H. KleinJan, Maarten L. Donswijk, Henk G. van der Poel, Simon Horenblas, Fijs W.B. van Leeuwen, Oscar R. Brouwer
Journal: European Urology (2021)
Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure
Authors: Huanan Shi, Bojun Zhang, Taylor Abo-Hamzy, James W. Nelson, Chandra Shekar R. Ambati, Joseph F. Petrosino, Robert M. Bryan, David J. Durgan
Journal: Circulation Research (2021)

Rationale: In recent years, it has been demonstrated that a pathological change in the gut microbiota, termed gut dysbiosis, can be an underlying factor for the development of hypertension. Prevention of this dysbiosis can attenuate or abolish hypertension. Translational mechanisms to prevent gut dysbiosis as well as understanding of the mechanisms linking gut dysbiosis to hypertension are lacking. Objective: We first examined the efficacy of intermittent fasting (IF) in altering the gut microbiota and lowering blood pressure (BP). Next, we utilized a multi-omics approach to examine microbial influenced metabolites that may serve as the link between the gut microbiota and host BP regulation. Methods and Results: We demonstrate that IF significantly altered the makeup of the gut microbiota, cecal and plasma metabolome, and prevented the development of hypertension in the spontaneously hypertensive stroke-prone rat. The beneficial effects of IF were shown to be due to alterations of the gut microbiota through germ-free transplantation studies. Germ-free rats receiving microbiota from IF spontaneously hypertensive stroke-prone rat had significantly lower BP as compared with germ-free rats receiving microbiota from ad libitum fed spontaneously hypertensive stroke-prone rats. Through whole genome shotgun sequence analysis of the microbiota and untargeted metabolomics of cecal content and plasma, we identified bile acid metabolism as a potential mediator in BP regulation. Finally, we show supplementation with cholic acid, or activation of the G protein-coupled bile acid receptor (TGR5), significantly reduced BP of the spontaneously hypertensive stroke-prone rats. Conclusions: These studies demonstrate the BP-lowering effects of IF involves manipulation of the gut microbiota and metabolome and implicate disrupted bile acid signaling as novel mechanisms by which gut dysbiosis contributes to hypertension.
Author Correction: Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts
Authors: Xing Yi Woo, Jessica Giordano, Anuj Srivastava, Zi-Ming Zhao, Michael W. Lloyd, Roebi de Bruijn, Yun-Suhk Suh, Rajesh Patidar, Li Chen, Sandra Scherer, Matthew H. Bailey, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Yuanxin Xi, Jing Wang, Jayamanna Wickramasinghe, Andrew V. Kossenkov, Vito W. Rebecca, Hua Sun, R. Jay Mashl, Sherri R. Davies, Ryan Jeon, Christian Frech, Jelena Randjelovic, Jacqueline Rosains, Francesco Galimi, Andrea Bertotti, Adam Lafferty, Alice C. O’Farrell, Elodie Modave, Diether Lambrechts, Petra ter Brugge, Violeta Serra, Elisabetta Marangoni, Rania El Botty, Hyunsoo Kim, Jong-Il Kim, Han-Kwang Yang, Charles Lee, Dennis A. Dean, Brandi Davis-Dusenbery, Yvonne A. Evrard, James H. Doroshow, Alana L. Welm, Bryan E. Welm, Michael T. Lewis, Bingliang Fang, Jack A. Roth, Funda Meric-Bernstam, Meenhard Herlyn, Michael A. Davies, Li Ding, Shunqiang Li, Ramaswamy Govindan, Claudio Isella, Jeffrey A. Moscow, Livio Trusolino, Annette T. Byrne, Jos Jonkers, Carol J. Bult, Enzo Medico, Jeffrey H. Chuang
Journal: Nature Genetics (2021)

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00811-4.
Tumor Functional Heterogeneity Unraveled by scRNA-seq Technologies
Authors: Laura González-Silva, Laura Quevedo, Ignacio Varela
Journal: Trends in cancer (2021)

In this Opinion article, the authors forgot to disclose their funding sources. The authors would like to acknowledge that I.V. is supported bySAF2016-76758-Rgrant from theSpanish Ministerio de Economía y Competitividad(MINECO) and byERC2014-StG637904grant from theEuropean Research Council. The authors apologize for this omission. Tumor Functional Heterogeneity Unraveled by scRNA-seq TechnologiesGonzález-Silva et al.Trends in CancerJanuary 3, 2020In BriefEffective cancer treatment has been precluded by the presence of various forms of intratumoral complexity that drive treatment resistance and metastasis. Recent single-cell sequencing technologies are significantly facilitating the characterization of tumor internal architecture during disease progression. New applications and advances occurring at a fast pace predict an imminent broad application of these technologies in many research areas. As occurred with next-generation sequencing (NGS) technologies, once applied to clinical samples across tumor types, single-cell sequencing technologies could trigger an exponential increase in knowledge of the molecular pathways involved in cancer progression and contribute to the improvement of cancer treatment. Full-Text PDF Open Access
Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade
Authors: Xiaowei Liu, Yanlin Feng, Jie Xu, Ying Shi, Jiqiao Yang, Rongjie Zhang, Jinen Song, Xin Bai, Xi Wu, Yu Bao, Ya Luo, Huifang Li, Li Chai, Changyang Gong, Yan Wang, Bo Chen, Jianping Hu, Yan Fu, Yongzhang Luo, Haiyuan Zhang, Hubing Shi
Journal: Journal of Controlled Release (2021)

The combination of MAPK-targeted therapy and immune checkpoint blockade is one of the most promising regimens for patients with advanced melanoma. However, the synergistic efficacy of the combo regimen is still controversial in clinical trials. Here, we report that MAPK inhibition induced T-cell suppression within tumor microenvironment is mediated by attenuation of HSP27/HSP70 and deficiency of neoantigen presentation. To address this problem, we designed a photothermal-responsive on-demand controlled drug release gold nano-system to carry BRAF inhibitor. The nano-system can be specifically delivered into tumor cells rather than T-cells, and effectively transformed the optical energy into heat energy upon laser irradiation. Combination of photothermal and targeted therapy significantly promoted immunogenic cell death and T-cell infiltration. On top of this regimen, systematically administration of PD-1 antibody not only suppressed local-treated tumor but also inhibited abscopal tumor by enhancing generalized immune-related antitumor response. More importantly, the triple-combo regimen could efficiently convert immune "cold" tumors into "hot" ones. In conclusion, our research proves the advantage of photothermal-targeted-immune triple combinatorial regimen in treating tumors which are clinical unresectable multifocal and lack of T-cell infiltration.
Covid-19: Outcomes worsened in second wave for Pakistanis and Bangladeshis in England
Authors: Gareth Iacobucci
Journal: BMJ (2021)

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Abstract 11983: Oral Therapies for Type 2 Diabetes in Combination With Long-acting Insulin and the Risks of Myocardial Infarction and Stroke
Authors: James S Floyd, Kerri L Wiggins, Sascha Dublin, William T Longstreth, Nicholas L Smith, Barbara McKnight, Susan R Heckbert, Noel S Weiss, Bruce M Psaty
Journal: Circulation (2015)

Introduction/Hypothesis: The use of oral therapies in combination with insulin for the treatment of type 2 diabetes is common, but the cardiovascular risks or benefits are largely unknown. Among users of long-acting insulin, we conducted a population-based case-control study to evaluate the incident myocardial infarction (MI) and incident stroke risks associated with sulfonylurea and metformin use. We hypothesized that sulfonylurea use would be associated with elevated risk and metformin use with decreased risk. Methods: Cases were enrollees of Group Health Cooperative (GHC) with type 2 diabetes who used long-acting insulin at the time of diagnosis with a first MI (n=413) or first stroke (n=247) from 1995-2010. Controls (n=443) were randomly sampled GHC enrollees with type 2 diabetes who used long-acting insulin, matched to cases on age, sex, and calendar year. Sulfonylureas and metformin use was classified as current, past, or never using electronic pharmacy records. MI and stroke diagnoses and potential confounding variables were validated by medical record review. Analyses were adjusted for matching variables and cardiovascular risk factors, including smoking, duration of diabetes, blood pressure, and cholesterol. Results: Current use of sulfonylureas compared with never use was associated with a higher risk of MI (OR 1.67; 95% CI, 1.10-2.55) but not stroke (OR 1.22; 95% CI, 0.74-2.00). Current use of metformin compared with never use was associated with a lower risk of stroke (OR 0.54; 95% CI, 0.31-0.95) but not MI (OR 0.77; 95% CI 0.44-1.33). Past use of sulfonylureas and past use of metformin were not associated with either outcome. Findings were robust to sensitivity analyses that tested assumptions about eligibility criteria and medication adherence. An unmeasured confounder associated with a 2-fold increased MI risk would have to be present in 70% more current users than never users of sulfonylureas to render the sulfonylurea-MI odds ratio null. Conclusions: The use of sulfonylureas in combination with long-acting insulin may increase the risk of MI compared with insulin alone. Our study adds to a growing body of evidence that metformin may be an effective cardiovascular disease prevention therapy, even when used with insulin.