tbuckley/cabot-search huggingface dataset:
Differentiated Cells in Prolonged Hypoxia Produce Highly Infectious Native‐Like Hepatitis C Virus Particles
Authors: Jade Cochard, Anne Bull‐Maurer, Clovis Tauber, Julien Burlaud‐Gaillard, Frédéric Mazurier, Jean‐Christophe Meunier, Philippe Roingeard, Philippe Chouteau
Journal: Hepatology (2021)

Standard hepatitis C virus (HCV) cell-culture models present an altered lipid metabolism and thus produce lipid-poor lipoviral particles (LVPs). These models are thereby weakly adapted to explore the complete natural viral life cycle.To overcome these limitations, we used an HCV cell-culture model based on both cellular differentiation and sustained hypoxia to better mimic the host-cell environment. The long-term exposure of Huh7.5 cells to DMSO and hypoxia (1% O2 ) significantly enhanced the expression of major differentiation markers and the cellular hypoxia adaptive response by contrast with undifferentiated and normoxic (21% O2 ) standard conditions. Because hepatocyte-like differentiation and hypoxia are key regulators of intracellular lipid metabolism, we characterized the distribution of lipid droplets (LDs) and demonstrated that experimental cells significantly accumulate larger and more numerous LDs relative to standard cell-culture conditions. An immunocapture (IC) and transmission electron microscopy (TEM) method showed that differentiated and hypoxic Huh7.5 cells produced lipoproteins significantly larger than those produced by standard Huh7.5 cell cultures. The experimental cell culture model is permissive to HCV-Japanese fulminant hepatitis (JFH1) infection and produces very-low-buoyant-density LVPs that are 6-fold more infectious than LVPs formed by standard JFH1-infected Huh7.5 cells. Finally, the IC-TEM approach and antibody-neutralization experiments revealed that LVPs were highly lipidated, had a global ultrastructure and a conformation of the envelope glycoprotein complex E1E2 close to that of the ones circulating in infected individuals.This relevant HCV cell culture model thus mimics the complete native intracellular HCV life cycle and, by extension, can be proposed as a model of choice for studies of other hepatotropic viruses.
18F-fluciclovine positron emission tomography (PET) in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate.
Authors: Pedro C. Barata, Charlotte Manogue, Ellen Jaeger, Malcolm Light, Patrick Cotogno, Elisa Marie Ledet, Janeiro Goffin, Jodi Lyn Layton, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2021)

TPS171 Background: Conventional imaging of prostate cancer has limitations in staging, restaging after biochemical relapse, and response assessment. Functional imaging with positron emission tomography (PET) can target various aspects of tumor biology and has shown to be superior in the detection of prostate cancer compared with conventional computed tomography (CT) and bone scans. 18F-Fluciclovine, a synthetic amino acid transported across mammalian cell membranes by amino acid transporters that is upregulated to a greater extent in prostate cancer cells than in surrounding tissue, is currently approved for PET imaging for patients with biochemical recurrence. The role of 18F-Fluciclovine PET scans in monitoring response to novel hormonal therapies such as abiraterone acetate is unclear. We hypothesize that 1) using 18F-Fluciclovine PET scanning will allow a more sensitive assessment of mCRPC patients at the initiation of systemic therapy with abiraterone acetate and 2) the changes observed in 18F-Fluciclovine PET will correlate better with the serologic changes in PSA, allowing superior disease monitoring, than conventional imaging modalities. Methods: This single-arm, pilot study (NCT04158245) will describe the changes in 18F-Fluciclovine PET scan and compare these results with PSA and conventional computerized tomography (CT) and bone scans, in mCRPC patients treated with abiraterone acetate plus prednisone. Patients must have a detectable baseline PSA of ≥ 2 ng/mL and metastatic disease detected on conventional CT and bone scans. The use of docetaxel in the hormone-sensitive setting is allowed. Twelve patients will be treated with abiraterone 1000 mg daily plus prednisone 5 mg (or dexamethasone 0.5 mg) daily for mCRPC and get 18F-Fluciclovine PET and conventional CT and bone scans at baseline and 12 weeks after starting abiraterone therapy or at disease progression. PSA progression will be defined as a repeated increase in PSA of at least 2 ng/dL and 25% from nadir values, at least 1 week apart, according to PCWG3 criteria and clinical or radiographic progression by RECIST version 1.1. The co-primary objectives of the study include the 18F-Fluciclovine PET changes at baseline and 12 weeks after abiraterone acetate for mCRPC and the comparison between 18F-Fluciclovine PET and conventional scans. Secondary and exploratory endpoints include PSA response, PSA progression and genomic alterations by next-generation sequencing. As of 12 September 2020, this trial is actively enrolling. Clinical trial information: NCT04158245.
Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment
Authors: Man-Fung Yuen, Danny Ka-Ho Wong, Thomas Schluep, Ching-Lung Lai, Carlo Ferrari, Stephen Locarnini, Regina Cheuk-Lam Lo, Robert G Gish, James Hamilton, Christine I Wooddell, Lung Yi Mak, Bruce D Given
Journal: Gut (2021)

Objective We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520. Design The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4–9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured. Results All patients had 28.9–30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of −1.7 and −3.5 log IU/mL &gt;30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction &gt;29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with &lt; 10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL. Conclusions MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable. Trial registration number NCT02065336 .
From the discovery of DNA to current tools for DNA editing
Authors: Pascal Maguin, Luciano A. Marraffini
Journal: The Journal of Experimental Medicine (2021)

In 1944, the Journal of Experimental Medicine published the groundbreaking discovery that DNA is the molecule holding genetic information (1944. J. Exp. Med.https://doi.org/10.1084/jem.79.2.137). This seminal finding was the genesis of molecular biology and the beginning of an incredible journey to understand, read, and manipulate the genetic code.
Letter to the Editor: Recognizing Significant Role of Neoadjuvant Radiotherapy for HCC With Vascular Invasion
Authors: Xiu‐Ping Zhang, Guo‐Dong Zhao, Qu Liu, Rong Liu
Journal: Hepatology (2021)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the article by Liou et al. in Hepatology,(1) which explored ablative intent yttrium‐90 radiation lobectomy with nivolumab as a neoadjuvant to resection for advanced HCC with macrovascular invasion, successfully resulting in complete pathologic response after treatments. The authors’ conclusions underline the significant role of neoadjuvant radiotherapy (RT) for advanced HCC. Based on this, we would like to raise the following comment. Firstly, controversy exists among experts from the West and the East on the treatment of patients with HCC and macrovascular invasion.(2) In our previous studies,(3) external RT showed a strong application prospect in HCC with portal vein tumor thrombus (PVTT). For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. In addition, by downstaging the extent of PVTT and HCC using neoadjuvant RT, the chance of tumor spread or residual disease could be lowered, thus resulting in better postoperative survival. Secondly, this study focused on internal RT using yttrium‐90 as a new treatment strategy for HCC with vascular invasion, which echoed a previous exploration on yttrium‐90 for HCC.(4) A potential mechanism of yttrium‐90 with nivolumab may be that yttrium‐90 led to the release of more tumor antigens, which activated tumor immunity. Moreover, advanced HCC with macrovascular invasion should not be considered a contraindication for surgery.(5) Neoadjuvant treatments could be the trend for advanced HCC treatment; thus, patients who cannot be operated can have the chance of en bloc resection with a longer survival prognosis. In summary, the study by Liou et al.(1) is a great work focusing on therapies for advanced HCC with macrovascular invasion applying neoadjuvant internal RT with yttrium‐90 combined with nivolumab. It is vital to explore biomarkers predicting the response to radiation and indications for yttrium‐90 in these patients.
Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate- and high-risk prostate cancer overall, and in those who also received salvage radiotherapy.
Authors: Bruce J. Trock, Saradha Rajamani, Igor Vidal, Stephanie Glavaris, Tracy Jones, Misop Han, Alan W. Partin, Todd Cohen, Steven Stone, Angelo M De Marzo
Journal: Journal of Clinical Oncology (2021)

247 Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score &gt;4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p&lt;0.00001. SRT (56%) or SRT+ADT (44%) were received by 172 men, of whom 78% had Gleason &gt;4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings. [Table: see text]
n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies
Authors: Frank Qian, Andres V. Ardisson Korat, Fumiaki Imamura, Matti Marklund, Nathan Tintle, Jyrki K. Virtanen, Xia Zhou, Julie K. Bassett, Heidi Lai, Yoichiro Hirakawa, Kuo-Liong Chien, Alexis C. Wood, Maria Lankinen, Rachel A. Murphy, Cecilia Samieri, Kamalita Pertiwi, Vanessa D. de Mello, Weihua Guan, Nita G. Forouhi, Nick Wareham, InterAct Consortium, Frank B. Hu, Ulf Riserus, Lars Lind, William S. Harris, Aladdin H. Shadyab, Jennifer G. Robinson, Lyn M. Steffen, Allison Hodge, Graham G. Giles, Toshiharu Ninomiya, Matti Uusitupa, Jaakko Tuomilehto, Jaana Lindström, Markku Laakso, David S. Siscovick, Catherine Helmer, Johanna M. Geleijnse, Jason H.Y. Wu, Amanda Fretts, Rozenn N. Lemaitre, Renata Micha, Dariush Mozaffarian, Qi Sun
Journal: Diabetes Care (2021)

Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.
Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial
Authors: Melanie Davies, Louise Færch, Ole K Jeppesen, Arash Pakseresht, Sue D Pedersen, Leigh Perreault, Julio Rosenstock, Iichiro Shimomura, Adie Viljoen, Thomas A Wadden, Ildiko Lingvay
Journal: The Lancet (2021)
mRNA-encoded, constitutively active STINGV155M is a potent genetic adjuvant of antigen-specific CD8+ T cell response
Authors: Sze-Wah Tse, Kristine McKinney, William Walker, Mychael Nguyen, Jared Iacovelli, Clayton Small, Kristen Hopson, Tal Zaks, Eric Huang
Journal: Molecular Therapy (2021)

mRNA vaccines induce potent immune responses in preclinical models and clinical studies. Adjuvants are used to stimulate specific components of the immune system to increase immunogenicity of vaccines. We utilized a constitutively active mutation (V155M) of the stimulator of interferon (IFN) genes (STING), which had been described in a patient with STING-associated vasculopathy with onset in infancy (SAVI), to act as a genetic adjuvant for use with our lipid nanoparticle (LNP)-encapsulated mRNA vaccines. mRNA-encoded constitutively active STINGV155M was most effective at maximizing CD8+ T cell responses at an antigen/adjuvant mass ratio of 5:1. STINGV155M appears to enhance development of antigen-specific T cells by activating type I IFN responses via the nuclear factor κB (NF-κB) and IFN-stimulated response element (ISRE) pathways. mRNA-encoded STINGV155M increased the efficacy of mRNA vaccines encoding the E6 and E7 oncoproteins of human papillomavirus (HPV), leading to reduced HPV+ TC-1 tumor growth and prolonged survival in vaccinated mice. This proof-of-concept study demonstrated the utility of an mRNA-encoded genetic adjuvant.
Therapeutic Neuromodulation for Bipolar Disorder—The Case for Biomarker-Driven Treatment Development
Authors: Joan A. Camprodon
Journal: JAMA Network Open (2021)

Alexander McGirr, MD, PhD; Fidel Vila-Rodriguez, MD, PhD; Jaeden Cole, BSc; Ivan J. Torres, PhD; Shyam Sundar Arumugham, MBBS; Kamyar Keramatian, MD, MSc; Gayatri Saraf, MD; Raymond W. Lam, MD; Trisha Chakrabarty, MD; Lakshmi N. Yatham, MBBS, MBA
Abstract 15849: Heart Failure and Chronic Kidney Disease in Patients Undergoing Non-Cardiac Surgery
Authors: Boyangzi Li, Tanya Wilcox, Nathaniel Smilowitz, Jonathan D Newman, Jeffrey S Berger
Journal: Circulation (2019)

Background: Heart failure (HF) and chronic kidney disease (CKD) are established risk factors for perioperative cardiovascular outcomes. The effects of comorbid HF and CKD on perioperative complicat...
Outcomes in men with metastatic castrate-resistant prostate cancer treated with early platinum-based chemotherapy following an unsatisfactory response to androgen receptor (AR) inhibition as part of the phase II dynamic allocation modular sequential (DynAMo) trial.
Authors: Paul Vincent Viscuse, Miao Zhang, Jingjing Liu, Rebecca Tidwell, Sumit Kumar Subudhi, Amado J. Zurita, Paul G. Corn, Shi-Ming Tu, John C. Araujo, Jennifer Wang, Eleni Efstathiou, Jianbo Wang, Patrick Glen Pilie, Patricia Troncoso, Jianhua Zhang, Christopher Logothetis, Ana Aparicio
Journal: Journal of Clinical Oncology (2021)

83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.
Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation
Authors: F. Thomas, M. Maillard, M. Launay, C. Tron, M.-C. Etienne-Grimaldi, E. Gautier-Veyret, V. Haufroid, N. Pallet, B. Royer, C. Narjoz, A. Schmitt
Journal: Annals of Oncology (2021)
Abstract 17182: Patterns of Discontinuation for Non-vitamin K Oral Anticoagulants in Atrial Fibrillation: Results From the ORBIT-AF II Registry
Authors: Benjamin A Steinberg, DaJuanicia N Simon, Laine Thomas, Jack Ansell, Bernard J Gersh, Gregg C Fonarow, Elaine Hylek, Peter R Kowey, Kenneth W Mahaffey, Eric D Peterson, Jonathan P Piccini
Journal: Circulation (2015)

Background: Oral anticoagulation (OAC) is effective at preventing stroke in patients with atrial fibrillation (AF), yet warfarin is often poorly tolerated. Non-vitamin K oral anticoagulants (NOACs) are as or more effective as warfarin, yet their tolerance and persistence in clinical practice is not known. Methods: We assessed patterns of persistent OAC use among 2,345 AF patients starting on therapy in the ORBIT-AF II registry (71% starting on a NOAC, and 29% on warfarin). Results: By 6 months, 364 (22%) patients started on a NOAC had discontinued or changed initial therapy versus 143 (21%) started on warfarin initially (p=0.5). Among warfarin users, patients who switched or discontinued therapy were of similar age (median ages 72 and 74 vs. 74 for stable users, p=0.7) and CHA2DS2-VASc scores (mean 98 and 3.66 vs. 3.84, p=0.4). Among NOAC users, those who discontinued treatment were younger (median age 68 vs. 73 for those who switched and 72 for stable users; p=0.0004), and lower CHA2DS2-VASc scores (3.02 vs. 3.58 and 3.47, respectively; p=0.0008). The median time to change or discontinuation was more rapid in those started on a NOAC vs warfarin (97 days vs. 122 days, p=0.003). Among those on warfarin at baseline, 7.6% (n=52) were switched to a NOAC within 6 months, whereas transitions from NOAC to warfarin was 2.5% (n=42).Transitions among NOACs occurred in 9.8%, 3.2%, and 5.5% of patients on baseline dabigatran, rivaroxaban, and apixaban, respectively. Physician preference was the most common reason for both OAC and warfarin changes (Table). Drug cost was the primary reason for change of therapy in 15% of NOAC users (vs. 0 for warfarin). Conclusions: At 6-month follow-up, one in five newly started on OAC had discontinued or changed. These rates of change were similar among warfarin and NOAC treated patients. Cost concerns drove discontinuation in a modest number of patients, however, cost concerns were more prevalent in NOAC-treated patients.
From antibody specificity to T cell recognition
Authors: Hye-Jung Kim, Harvey Cantor
Journal: The Journal of Experimental Medicine (2021)

Landsteiner’s definition of human blood groups and the genetic rules that govern blood transfusion represents a milestone in human genetics and a historic event in public health. His research into the specificity of serological reactions, although less well known, has had a critical influence on the development of contemporary views on immune recognition, clonal selection, and immunological self-tolerance.