tbuckley/cabot-search huggingface dataset:
Hepatitis B Virus Serum DNA andRNA Levels in Nucleos(t)ide Analog‐Treated or Untreated Patients During Chronic and Acute Infection
Authors: Emily K. Butler, Jeffrey Gersch, Anne McNamara, Ka‐Cheung Luk, Vera Holzmayer, Maria de Medina, Eugene Schiff, Mary Kuhns, Gavin A. Cloherty
Journal: Hepatology (2018)

Treatment of chronic hepatitis B (CHB) patients with nucleos(t)ide analogs (NAs) suppresses hepatitis B virus (HBV) DNA synthesis but does not affect synthesis of HBV pregenomic RNA (pgRNA). Hepatitis B virus pgRNA is detectable in the serum during NA treatment and has been proposed as a marker of HBV covalently closed circular DNA activity within the infected hepatocyte. We developed an automated assay for the quantification of serum HBV pgRNA using a dual‐target real‐time quantitative PCR approach on the Abbott m 2000 sp/rt system. We demonstrate accurate detection and quantification of serum HBV RNA. Hepatitis B virus DNA was quantified using the Abbott RealTi m e HBV viral load assay. We further compared serum nucleic acid levels and kinetics in HBV‐positive populations. Samples included on‐therapy CHB samples (n = 16), samples (n = 89) from 10 treatment naïve CHB subjects receiving 12 weeks of NA treatment with 8‐week follow‐up, hepatitis B surface antigen–positive blood donor samples (n = 102), and three seroconversion series from plasmapheresis donors (n = 79 samples). Conclusion : During NA treatment of CHB subjects, we observed low correlation of HBV DNA to pgRNA levels; pgRNA concentration was generally higher than HBV DNA concentrations. In contrast, when NA treatment was absent we observed serum pgRNA at concentrations that correlated to HBV DNA and were approximately 2 log lower than HBV DNA. Importantly, we observe this trend in untreated subject samples from both chronic infections and throughout seroconversion during acute infection. Results demonstrate that the presence of pgRNA in serum is part of the HBV lifecycle; constant relative detection of pgRNA and HBV DNA in the serum is suggestive of a linked mechanism for egress for HBV DNA or pgRNA containing virions.
A Gallium-67/68–Labeled Antibody Fragment for Immuno-SPECT/PET Shows Low Renal Radioactivity Without Loss of Tumor Uptake
Authors: Tomoya Uehara, Miki Yokoyama, Hiroyuki Suzuki, Hirofumi Hanaoka, Yasushi Arano
Journal: Clinical Cancer Research (2018)

Purpose: This study was undertaken to evaluate the renal radioactivity levels of a newly designed 67Ga-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule.Experimental Design:67Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) was conjugated with an antibody Fab fragment through a Met-Val-Lys linkage (67Ga-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and 67Ga-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight 67Ga-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of 67Ga-NOTA-MVK-Fab into mice was compared with 67Ga-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates 67Ga-NOTA-Met (67Ga-NOTA-MI-Fab) or a conventional thiourea linkage (67Ga-NOTA-Fab).Results: The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate 67Ga-NOTA-Met. When injected into mice, all three 67Ga-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where 67Ga-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (P < 0.05), followed by 67Ga-NOTA-MI-Fab, which was well reflected in the SPECT/CT images.Conclusions: These findings indicated that our proposal of liberating a radiolabeled compound to urinary excretion from antibody fragments at the renal BBM to reduce the renal radioactivity levels was applicable to 67/68Ga-labeled antibody fragments. Because antibody fragments and constructs share similar metabolic fates in the kidney, the present labeling procedure would also apply to a variety of antibody fragments and constructs of interest. Clin Cancer Res; 24(14); 3309-16. ©2018 AACR.
Low concentrations of valproic acid increase invasiveness in non-metastatic osteosarcoma cell line SaOS2
Authors: Hillary Gibbons, Mandy Hall, Jesus Trevino, Pingyu Zhang, Dennis Hughes
Journal: Cancer Research (2008)

3760  Introduction:  Osteosarcoma is the most common bone cancer and the sixth most common cancer among children. Valproic acid is an anti-convulsant with HDAC inhibitory properties used in osteosarcoma treatment. A recent report indicates that valproic acid upregulates Notch signaling in carcinoid cells. Our recent studies indicate that Notch-mediated Hes1 expression induces invasion and metastasis in osteosarcoma. If valproic acid can induce Notch signaling in non-metastatic osteosarcoma, treatment of osteosarcoma patients with valproic acid might increase the invasiveness of their disease, countering the anti-tumor effects.  Methods:  This study was conducted using two osteosarcoma cell lines, SaOS2 and OS 187. SaOS2 is non-metastatic and has no endogenous Notch signaling. OS 187 is metastatic and has endogenous Notch signaling. Cells were treated with valproic acid at 0.3, 0.6, 1, 2, and 4 mM for 48 hours (Note: 0.3 mM = 50 µg/mL; therapeutic levels range from 50-100 µg/mL). Matrigel invasion was assayed in triplicate at 48 hours. RNA was isolated from cells treated with valproic acid for 48 hours. RT-PCR was used to assess expression of the Notch pathway genes DLL1, Notch1, Notch2 and Hes1.  Results:  After 48 hours of treatment, the cell morphology changed from round to spindle-shaped. At this time, OS 187 showed 79% cell loss at 1mM valproic acid (p value = 0.000025) and SaOS2 cell loss was 45% at 1 mM (p value = .088065). Significant cell loss in SaOS2 at 48 hours only occurred at 4mM valproic acid exposure (p value = .015512). In OS 187, PCR for Notch pathway expression showed no change of Notch 1, Notch 2, and Hes1 and a slight decrease in DLL1 with valproate exposure. In SaOS2, expression of Hes1 and DLL1 directly correlated with valproic acid concentration. Notch 1 induction was seen at 0.3 mM and remained expressed at a steady level. Notch 2 induction was not observed. Matrigel staining showed a 250-fold increase in invasion at 0.3 mM in SaOS2 (p value = .024938). After 0.3 mM, invasion decreased in a dose-dependent manner to non-invasiveness at 4 mM.  Discussion:  Valproic acid increases Notch-mediated invasion in non-metastatic osteosarcoma at therapeutic doses. The probable mechanism for this increased invasion is upregulation of the Notch pathway due to the HDAC inhibiting activity of valproic acid, seen by DLL1, Notch1, and Hes1 induction in SaOS2 with valproic acid. These data suggest caution should be used when treating non-metastatic osteosarcoma patients with valproic acid.
sNASP inhibits TLR signaling to regulate immune response in sepsis
Authors: Feng-Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui-Ming Chang, Edward T.H. Yeh
Journal: Journal of Clinical Investigation (2018)

Many Toll-like receptors (TLRs) signal through TNF receptor–associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. In sNasp S158A knockin (S158A-KI) mice, LPS-treated macrophages could not phosphorylate sNASP, which remained bound to TRAF6. S158A-KI mice were more susceptible to sepsis due to a marked reduction in IL-1β, TNF-α, and IFN-γ production accompanied by an inability to clear bacteria and recruit leukocytes. Furthermore, phosphorylation-regulated release of sNASP from TRAF6 is observed following activation of TLR-1, -2, -4, -5, and -6. Thus, sNASP is a negative regulator of TLR signaling to modulate the innate immune response.
P528Vardenafil prevents the diastolic dysfunction
Authors: B Bodi, A Csongradi, J Tamas, C S Matyas, A Toth, B Merkely, T Radovits, Z Papp
Journal: Cardiovascular Research (2018)

conditions and under adrenergic and hypoxic stress.Morphologically, confocal imaging revealed that the DCM hiPSC-CMs displayed more nucleoplasmic Lamin A compared to the control.The fluorescence intensities ratios of the lamina to nucleoplasm significantly more in Control compared to DCM.Electrophysiologically, the DCM model displayed bradycardia and increased arrhythmias at multi cellular level by MEA and at single cell level by calcium imaging both at baseline and under adrenaline.Calcium imaging revealed significantly altered calcium decay characteristics in the DCM model.Induction of stress on cardiac aggregates using hypoxic conditions displayed an exaggerated effect on the DCM.In conclusion, our model recapitulated major phenotype characteristics as observed in DCM patients and is a proof of concept that this model can be used to study the disease mechanisms further and can serve as a platform for drug screening.
P181Association between adrenomedullin polymorphism and high blood pressure in a population of Lithuanian children and adolescents
Authors: S Simonyte, R Kuciene, J Medzioniene, V Dulskiene, V Lesauskaite
Journal: Cardiovascular Research (2018)

coronary artery following acute myocardial infarction.Pulmonary vascular remodeling including changes in the intima, media and adventitia, is the key structural alteration in PH.However, the role of CD271þMSCs in the pathogenesis of pulmonary hypertension (PH) are not well understood.Our objectives were to identify the role of CD271þMSCs in PB on the Patients diagnosed with PH.Methods: We selected patients diagnosed with PH, and examined their hemodynamic parameters including pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) and cardiac index (CI) by right heart catheterization.We also mesured six minutes walking (6MWT), and enforced echocardiography and blood gas analysis.Secondly, we collected blood samples and separated PB mono-nuclear cells (PBMNCs) by density gradient centrifugation.Then, we performed cell surface antigen analysis, such as CD271þCD45dimþ, CD271þCD34þ, CD271þCD90þ, and CD271þVEGFR2þ cells in PBMNCs by flow cytometry.We compared clinical data and the frequency of CD271þMSCs in PBMNCs of patients with pulmonary hypertension.Moreover, nine patients could be followed along clinical course with drug addition in 24 months.We tried to analyze transition of the CD271þMSCs in PBMNCs and compared those change with clinical data.Results: We selected 22 patients who matched PH criteria (group 1; n¼8, group 4; n¼8).The mean of WHO functional class was 2.14, and mPAP was 38.9610.1mmHg.The average frequency of CD271þCD45dimþ in PBMNCs (0.045960.0376%), was higher in the patients with PH than those in patients with atrial fibrillation (n¼4), angina pectoris (n¼15), and healthy control (n¼5) (P<0.05).We also found that the frequency of CD271þMSCs in PBMNCs was correlated with PVR, CI, and SPO2 (P<0.05).On the other hands, that wasn't correlated with 6MWT and mPAP.Interestingly, the frequency of CD271þMSCs in PBMNCs was significantly reduced along with improving PH after medical intervention in 2-24 months follow up (P<0.05).Conclusion: These results suggest that CD271þMSCs in PBMNCs, derived from bone marrow to circulation, associated with the disease worsens in the case of PH.The frequency of CD271þMSCs in PBMNCs might be useful for estimation of disease severity and prognosis in PH patients.
Case 12-2018: A 30-Year-Old Woman with Cardiac Arrest
Authors: Joshua N. Goldstein, David M. Dudzinski, Timothy B. Erickson, Grace Linder
Journal: New England Journal of Medicine (2018)

A 30-year-old woman was brought to the ED because of cardiac arrest. She was hypotensive, and pupillary, corneal, oculocephalic, cough, and gag reflexes were absent. Electrocardiography showed a wide-complex rhythm. A diagnosis and management decisions were made.
Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials
Authors: Jeremy M. O’Connor, Kristen L. Fessele, Jean Steiner, Kathi Seidl-Rathkopf, Kenneth R. Carson, Nathan C. Nussbaum, Emily S. Yin, Kerin B. Adelson, Carolyn J. Presley, Anne C. Chiang, Joseph S. Ross, Amy P. Abernethy, Cary P. Gross
Journal: JAMA Oncology (2018)

The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti-PD-1 agents). However, little is known about how quickly anti-PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials).
Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion–Positive Advanced NSCLC
Authors: Bianca van Veggel, Adrianus J. de Langen, Sayed M.S. Hashemi, Kim Monkhorst, Daniëlle A.M. Heideman, Erik Thunnissen, Egbert F. Smit
Journal: Journal of Thoracic Oncology (2018)
The Role of Palladin in Podocytes
Authors: Nadine Artelt, Tim A. Ludwig, Henrik Rogge, Panagiotis Kavvadas, Florian Siegerist, Antje Blumenthal, Jens van den Brandt, Carol A. Otey, Marie-Louise Bang, Kerstin Amann, Christos E. Chadjichristos, Christos Chatziantoniou, Karlhans Endlich, Nicole Endlich
Journal: Journal of the American Society of Nephrology (2018)

Background Podocyte loss and effacement of interdigitating podocyte foot processes are the major cause of a leaky filtration barrier and ESRD. Because the complex three-dimensional morphology of podocytes depends on the actin cytoskeleton, we studied the role in podocytes of the actin bundling protein palladin, which is highly expressed therein. Methods We knocked down palladin in cultured podocytes by siRNA transfection or in zebrafish embryos by morpholino injection and studied the effects by immunofluorescence and live imaging. We also investigated kidneys of mice with podocyte-specific knockout of palladin (PodoPalld−/− mice) by immunofluorescence and ultrastructural analysis and kidney biopsy specimens from patients by immunostaining for palladin. Results Compared with control-treated podocytes, palladin-knockdown podocytes had reduced actin filament staining, smaller focal adhesions, and downregulation of the podocyte-specific proteins synaptopodin and α -actinin-4. Furthermore, palladin-knockdown podocytes were more susceptible to disruption of the actin cytoskeleton with cytochalasin D, latrunculin A, or jasplakinolide and showed altered migration dynamics. In zebrafish embryos, palladin knockdown compromised the morphology and dynamics of epithelial cells at an early developmental stage. Compared with PodoPalld+/+ controls, PodoPalld−/− mice developed glomeruli with a disturbed morphology, an enlarged subpodocyte space, mild effacement, and significantly reduced expression of nephrin and vinculin. Furthermore, nephrotoxic serum injection led to significantly higher levels of proteinuria in PodoPalld−/− mice than in controls. Kidney biopsy specimens from patients with diabetic nephropathy and FSGS showed downregulation of palladin in podocytes as well. Conclusions Palladin has an important role in podocyte function in vitro and in vivo .
Alarmingly poor oral health in international athletes competing in the Middle East
Authors: Ashley Knight, Mohammed Alsaey, Abdulaziz Farooq, Mathew G Wilson
Journal: British Journal of Sports Medicine (2018)

Clinical oral health examination of 187 UK professional footballers revealed that oral health was poor (37% players had active dental caries, 53% dental erosion  and 5% moderate–severe irreversible periodontal disease). Importantly, 20% reported that it impacted on their quality of life and 7% on their training and/or performance.1 Consequently, a call of action for oral health screening was recently issued in this journal to help improve the oral health of athletes.2 Aspetar Orthopaedic Sports Medicine Hospital (Doha, Qatar) accepted this call by investing in a sports dentistry department. Following the ethical approval, 1245 individuals (91.7% male) presented at our facility for dental screening, of whom 56.5% were Arab, 29.6% Black, 7.9% White and 6.8% Asian. All individuals were registered with the Qatar Olympic Committee (QOC) and were invited for dental screening via Qatar’s National Sports Medicine Programme. Informed consent was provided by all individuals, with parents/guardians providing for those individuals aged under 18 years. Athletes (n=1079; age 21.7±6.8 years) were defined as a QOC registered individual who undertook regular exercise or training (≥6 hours/week) for …
Cascade-amplifying synergistic effects of chemo-photodynamic therapy using ROS-responsive polymeric nanocarriers
Authors: Chun-Yang Sun, Ziyang Cao, Xue-Jun Zhang, Rong Sun, Chun-Shui Yu, Xianzhu Yang
Journal: Theranostics (2018)

The simple integration of chemotherapeutic drugs and photosensitizers (PSs) into the same nanocarriers only achieves a combination of chemo-photodynamic therapy but may not confer synergistic effects.The boosted intracellular release of chemotherapeutic drugs during the photodynamic therapy (PDT) process is necessary to achieve a cascade of amplified synergistic therapeutic effects of chemo-photodynamic therapy.Methods: In this study, we explored an innovative hyperbranched polyphosphate (RHPPE) containing a singlet oxygen (SO)-labile crosslinker to boost drug release during the PDT process.The photosensitizer chlorin e6 (Ce6) and doxorubicin (DOX) were simultaneously loaded into RHPPE nanoparticles (denoted as SO HNPCe6/DOX).The therapeutic efficacy of SO HNPCe6/DOX against drug-resistant cancer was evaluated in vitro and in vivo.Results: Under 660-nm light irradiation, SO HNPCe6/DOX can produce SO, which not only induces PDT against cancer but also cleaves the thioketal linkers to destroy the nanoparticles.Subsequently, boosted DOX release can be achieved, activating a chemotherapy cascade to synergistically destroy the remaining tumor cells after the initial round of PDT.Furthermore, SO HNPCe6/DOX also efficiently detected the tumor area by photoacoustic/magnetic resonance bimodal imaging.Under the guidance of bimodal imaging, the laser beam was precisely focused on the tumor areas, and subsequently, SO HNPCe6/DOX realized a cascade of amplified synergistic chemo-photodynamic therapeutic effects.High antitumor efficacy was achieved even in a drug-resistant tumor model. Conclusion:The designed SO HNPCe6/DOX with great biocompatibility is promising for use as a co-delivery carrier for combined chemo-photodynamic therapy, providing an alternative avenue to achieve a cascade of amplified synergistic effects of chemo-photodynamic therapy for cancer treatment.
P363Nucleostemin is prerequisite for Notch signaling and pro-inflammatory phenotype conversion of the endothelial cell in atherosclerosis
Authors: K Iwai, K Watanabe, Y Igarashi, T Himeno, T Morita, H Yano, M Okuro, S Morimoto
Journal: Cardiovascular Research (2018)

stenting.Morphological studies included 287 segments of CA, which were distributed based on the period passed after the stenting: 0-30 days, 30-180 days, and > 180 days.In the tissue of CA the presence or absence of restenosis were morphologically verified.Blood samples of 40 patients with coronary stents after acute myocardial infarction (AMI) were used to study the levels of IL-1b and PAI-1 in blood serum.Blood samples were taken depending on the period passed after the stenting: 0-30 days, 30-180 days, and > 180 days.All patients underwent coronary angiography confirming the presence or absence of restenosis.Results: Restenosis was morphologically verified in the CA samples of the dead in the period between 0 to 30 days after stenting and was angiographically confirmed in patients in the period of 180 days.With the development of restenosis, there is a decrease of IL-1b and an increase of PAI-1 in the tissues and blood (p< 0.05).The maximum value of IL-1b level was detected in a period of 0 to 30 days in the tissue samples (29.5 [26.6; 33.2]) and blood samples (1.72 [1.24; 2.06]) after stenting.The maximum value of PAI-1 level was detected in the period of 30 to 180 days in the tissue samples (17.98 [13.95; 21.33]) and blood samples (5968 ([4781; 6600]) after stenting.There is a positive correlation between the level of IL-1b in the stented CA tissue and in the blood serum (r ¼ 0.22, p <0.05) and between the level of PAI-1 in the stented CA tissue and in the blood serum (r ¼ 0.62; h< 0.05) of patients with AMI after stenting.Conclusion: Restenosis is verified morphologically in 30 days after stenting and accompanied by an increase of PAI-1 expression and a decrease of IL-1b expression in CA tissues.Thrombosis of CA which not associated with restenosis, is usually observed, in the early stenting period (0-30 days) and characterized by maximum values of IL-1b in the CA tissue of the dead and serum of patients (p <0.05).Angiographic restenosis is confirmed among patients after 180 days after stenting, while the maximum concentration of PAI-1 is observed (p <0.05) in the blood serum of patients with restenosis.Restenosis is confirmed angiographically among patients after 180 days stenting, while the maximum concentration of PAI-1 is observed (p <0.05) in the blood serum of patients with restenosis.
High Positive End-Expiratory Pressure Allows Extubation of an Obese Patient
Authors: Maddalena Teggia Droghi, Roberta R. De Santis Santiago, Riccardo Pinciroli, Francesco Marrazzo, Edward A. Bittner, Marcelo B. P. Amato, Robert M. Kacmarek, Lorenzo Berra
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Persistent improvement of liver function tests and health-related quality of life from an individualized exercise program in patients with histological confirmed NAFLD – the HELP study
Authors: Y. Huber, D. Pfirrmann, I. Gebhardt, C. Labenz, B. Straub, J. Kittner, M.-A. Wörns, P. Galle, P. Simon, Jörn Schattenberg
Journal: Journal of Hepatology (2018)
Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial
Authors: Rebekka Schäfer, Vratislav Strnad, Csaba Polgár, Wolfgang Uter, Guido Hildebrandt, Oliver J Ott, Daniela Kauer-Dorner, Hellen Knauerhase, Tibor Major, Jaroslaw Lyczek, Jose Luis Guinot, Jürgen Dunst, Cristina Gutierrez Miguelez, Pavel Slampa, Michael Allgäuer, Kristina Lössl, György Kovács, Arnt-René Fischedick, Rainer Fietkau, Alexandra Resch, Anna Kulik, Leo Arribas, Peter Niehoff, Ferran Guedea, Annika Schlamann, Christine Gall, Bülent Polat, Thomas G Wendt, Marion Hindemith, Richard Pötter, Martina Malzer
Journal: The Lancet Oncology (2018)
Effects of liver transplantation (LTx) on health-related quality of life (HRQoL) in patients with PBC
Authors: M. Krawczyk, Małgorzata Koźma, A. Szymańska, K. Leszko, M. Przedniczek, K. Mucha, B. Foroncewicz, L. Paczek, B. Moszczuk, P. Milkiewicz, R.-W. Joanna
Journal: Journal of Hepatology (2018)