tbuckley/cabot-search huggingface dataset:
Pharmacokinetics, tissue distribution, efficacy and toxicity studies of the antimelanoma immunocytokine scFvMEL/TNF
Authors: Yuying Liu, Weihe Zhang, Lawrence H. Cheung, Qingping Wu, Chun Li, Carolyn S. Van Pelt, Michael G. Rosenblum
Journal: Cancer Research (2006)

3726   The immunocytokine scFvMEL/TNF, a fusion protein composed of human cytokine tumor necrosis factor-alpha (TNF) and a single-chain Fv (scFvMEL), targets the melanoma gp240 antigen and exerts impressive cytotoxic effects in vitro. Pharmacokinetic studies with  125  I-scFvMEL/TNF showed triphasic clearance with calculated half-lives of 0.38, 3.9 and 17.6 hours for the alpha, beta and gamma phases respectively. The 45-kDa construct was found to self-aggregate into a 135-kDa trimer by virtue of the TNF component and this effect is likely to be responsible for the relatively long plasma half-life. Radiolabled scFvMEL/TNF was administered to nude mice bearing human melanoma xenografts, and mice were sacrificed at 24, 48 and 72 h after administration. We found that kidney and spleen contained the highest tissue: blood ratio of all normal organs. At 24 hr after administration, kidney, spleen and liver also contained the highest concentration of drug/gram tissue weight, although these concentrations declined over time. In contrast to normal organs, both the concentration of the label in tumor as well as the tissue: blood ratio of tumor tissue increased over time. Tumor was the highest site of accumulation by 72 hr after administration (% ID/g, 0.158; tumor-to-blood ratio, 7.6 ± 2.2), followed by kidney (% ID/g, 0.089; tissue-to-blood ratio, 5.1 ± 0.2), spleen (% ID/g, 0.049; tissue-to-blood ratio, 2.6 ± 0.8) and liver (% ID/g, 0.042; tissue-to-blood ratio, 1.6 ± 0.8). The maximal tolerated dose (MTD) of scFvMEL/TNF was 4 mg/kg with intravenous administration on a daily × 5 schedule. There were no changes in gross pathology, clinical chemistry or hematological parameters at doses up to 3 mg/kg. Therapeutic studies at a dose of 2.5 mg/kg with mice bearing established (∼ 50 mm 3 ) human melanoma A375 GFP xenograft tumors transfected with GFP demonstrated potent tumor suppression and complete tumor regression of all lesions (5/5 mice tumor-free on day 43). Mice bearing larger tumors (∼ 150 mm 3 ) also showed tumor regression (3/5 tumor free on day 44). There was no subsequent outgrowth of tumors from mice rendered tumor free. These data show that scFvMEL/TNF can target melanoma cells in vivo and can result in pronounced anti-melanoma effects after systemic administration. Toxicology studies indicate the relative safety of this agent at doses that are therapeutically effective and provide guidance to projected Phase I starting doses in patients at this schedule. Research conducted, in part, by the Clayton Foundation for Research.
Intradermal injection of allogeneic normal human broblasts promotes type VII collagen deposition at the dermal-epidermal junction in individuals with recessive dystrophic epidermolysis bullosa
Authors: T Wong, L Gammon, L Liu, L Ozoemena, P J C Dopping-Hepenstal, C Jones, I M Leigh, H Navsaria, John McGrath
Journal: British Journal of Dermatology (2007)
Multifunctional Nanotube–Mucoadhesive Poly(methyl vinyl ether‐<i>co</i>‐maleic acid)@Hydroxypropyl Methylcellulose Acetate Succinate Composite for Site‐Specific Oral Drug Delivery
Authors: Nattha Kerdsakundee, Wei Li, João Pedro Martins, Zehua Liu, Feng Zhang, Marianna Kemell, Alexandra Correia, Yaping Ding, Mikko Airavaara, Jouni Hirvonen, Ruedeekorn Wiwattanapatapee, Hélder A. Santos
Journal: Advanced Healthcare Materials (2017)

Abstract An advanced oral drug delivery system that can effectively deliver drugs with poor oral bioavailability is strongly desirable. Herein, a multifunctional nano‐in‐micro structured composite is developed by encapsulation of the mucoadhesive poly(methyl vinyl ether‐ co ‐maleic acid) modified halloysite nanotubes (HNTs) with the pH‐responsive hydroxypropyl methylcellulose acetate succinate by the microfluidics to control the drug release, increase cell–particle interaction, and improve drug absorption. The microparticles show spherical shape, homogeneous particle size distribution (58 ± 1 µm), and pH‐responsive dissolution behavior at pH &gt; 6, and they prevent the premature release of curcumin in simulated pH conditions of the stomach and immediately release the curcumin in simulated pH conditions of the small intestine. The surface modification of HNT with mucoadhesive poly(methyl vinyl ether‐ co ‐maleic acid) significantly enhances its interactions with the intestinal Caco‐2/HT29‐MTX cells and the mouse small intestines, and increases the permeability of curcumin across the co‐cultured Caco‐2/HT29‐MTX cell monolayers by about 13 times compared to the free curcumin. Therefore, the developed multifunctional nanotube–mucoadhesive poly(methyl vinyl ether‐ co ‐maleic acid)@hydroxypropyl methylcellulose acetate succinate composite is a promising oral drug delivery system for drugs with poor oral bioavailability.
Surveillance perspective on Lyme borreliosis across the European Union and European Economic Area
Authors: Cees C van den Wijngaard, Agnetha Hofhuis, Mariana Simões, Ente Rood, Wilfrid van Pelt, Herve Zeller, Wim Van Bortel
Journal: Eurosurveillance (2017)

Lyme borreliosis (LB) is the most prevalent tick-borne disease in Europe. Erythema migrans (EM), an early, localised skin rash, is its most common presentation. Dissemination of the bacteria can lead to more severe manifestations including skin, neurological, cardiac, musculoskeletal and ocular manifestations. Comparison of LB incidence rates in the European Union (EU)/European Economic Area (EEA) and Balkan countries are difficult in the absence of standardised surveillance and reporting procedures. We explored six surveillance scenarios for LB surveillance in the EU/EEA, based on the following key indicators: (i) erythema migrans, (ii) neuroborreliosis, (iii) all human LB manifestations, (iv) seroprevalence, (v) tick bites, and (vi) infected ticks and reservoir hosts. In our opinion, neuroborreliosis seems most feasible and useful as the standard key indicator, being one of the most frequent severe LB manifestations, with the possibility of a specific case definition. Additional surveillance with erythema migrans as key indicator would add value to the surveillance of neuroborreliosis and lead to a more complete picture of LB epidemiology in the EU/EEA. The other scenarios have less value as a basis for EU-level surveillance, but can be considered periodically and locally, as they could supply complementary insights.
HSPC070, a novel ring finger protein gene, is preferentially expressed in myelocytic lineage and involved in g-protein mediated signal transduction
Authors: M. Ye, Q. H. Zhang, X. Y. Wu, C. J. Zhao, H. Y. Fan, S. J. Chen, X. Zhang, Q. H. Huang, Z. Chen, Y. X. Wang
Journal: Blood (2000)
Abstract P136: E2F2/4 Regulated by Serine 21 Phosphorylation of GSK-3α Play Compensatory Roles During Pressure Overload
Authors: Takanobu Yamamoto, Yasuhiro Maejima, Peiyong Zhai, Takahisa Matsuda, Junichi Sadoshima
Journal: Circulation Research (2011)

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with two isoforms, alpha and beta, which have distinct functions in cardiomyocytes (CMs). GSK-3alpha is phosphorylated at S21 during pressure overload (PO), and inhibition of S21 phosphorylation in GSK-3alpha S21A knock-in (alpha−KI) mice promotes hypertrophy and heart failure in response to PO, accompanied by decreases in the total number of CMs in the heart. Since GSK-3alpha downregulates cyclinD1 in the nucleus, GSK-3alpha may negatively regulate E2F-mediated transcription. Reporter gene assays showed that the transcriptional activity of E2F was increased by GSK-3alpha knockdown (1.75 fold, p&lt;0.05). To evaluate the role of E2F isoforms in regulating cardiac hypertrophy and function during PO, E2F1−/−, E2F2−/+, E2F4−/+, and wild type (WT) mice were subjected to transverse aortic constriction (TAC). Left ventricular (LV) weight/ tibial length (LVW/TL) was significantly greater and LV ejection fraction (LVEF) was significantly decreased in both E2F2−/+ and E2F4−/+ after 2 weeks of TAC (LVW/TL: E2F2−/+=7.1±0.3, E2F4−/+=7.0±0.4, WT=5.9±0.3, p&lt;0.05 vs. WT; LVEF: E2F2−/+=53±1%, E2F4−/+=61±2%, WT=75±1%, p&lt;0.05 vs. WT). Thus, downregulation of either E2F2 or E2F4 induced a phenotype similar to that of alpha−KI in response to TAC. To examine the causative role of E2F2/E2F4 downregulation in mediating the cardiac phenotype in alpha-KI mice, adenovirus (Ad) harboring either E2F2 or E2F4 was injected into alpha-KI hearts. Rescue with E2F2 or E2F4 attenuated cardiac hypertrophy (LVW/TL: alpha−KI+E2F2=7.1±0.4, alpha−KI+E2F4=7.3±0.3, alpha−KI+LacZ=8.7±0.4, p&lt;0.05 vs. alpha−KI+LacZ) and improved LV dysfunction (LVEF: alpha−KI+E2F2=66±3%, alpha−KI+E2F4=60±2%, alpha−KI+LacZ=39±2%, p&lt;0.05 vs. alpha−KI+LacZ) in alpha−KI mice under PO conditions. Injection of either Ad-E2F2 or Ad-E2F4, but not of Ad-LacZ, significantly increased the number of Ki67-positive myocytes in the alpha-KI mice (alpha-KI+LacZ =0.7±0.3%, alpha-KI+E2F2=10.4±2.3%, alpha-KI+E2F4=9.2±1.5%, p&lt;0.05 vs. alpha-KI+LacZ). These results suggest that maintaining the activity of E2F2 and E2F4 through S21 phosphorylation of GSK-3alpha plays an essential role in preserving cardiac function during PO.
Young people with diabetes show no drop in admission rates, audit finds
Authors: Jacqui Wise
Journal: BMJ (2017)

Hospital admission rates among children and young people with diabetes in England and Wales have not fallen over three successive years despite overall improvements in care, the National Paediatric Diabetes Audit has found.1

The audit of hospital admissions, published by the Royal College of Paediatrics and Child Health, also found that about 23% of new cases of type 1 diabetes had diabetic ketoacidosis at diagnosis, a figure that has remained stable from 2012 to 2015.

Diabetic ketoacidosis can cause mental confusion, rapid heartbeat and …
Gut Microbiota-Mediated Personalized Treatment of Hyperlipidemia Using Berberine
Authors: Yan Wang, Qian Tong, Jia-Wen Shou, Zhen-Xiong Zhao, Xiao-Yang Li, Xian-Feng Zhang, Shu-Rong Ma, Chi-Yu He, Yuan Lin, Bao-Ying Wen, Fang Guo, Jie Fu, Jian-Dong Jiang
Journal: Theranostics (2017)

Nitroreductases (NRs) are bacterial enzymes that reduce nitro-containing compounds.We have previously reported that NR of intestinal bacteria is a key factor promoting berberine (BBR) intestinal absorption.We show here that feeding hamsters with high fat diet (HFD) caused an increase in blood lipids and NR activity in the intestine.The elevation of fecal NR by HFD was due to the increase in either the fraction of NR-producing bacteria or their activity in the intestine.When given orally, BBR bioavailability in the HFD-fed hamsters was higher than that in those fed with normal chow (by +72%, *P<0.05).BBR (100 mg/kg/day, orally) decreased blood lipids in the HFD-fed hamsters (**P<0.01)but not in those fed with normal diet.Clinical studies indicated that patients with hyperlipidemia had higher fecal NR activity than that in the healthy individuals (**P<0.01).Similarly, after oral administration, the blood level of BBR in hyperlipidemic patients was higher than that in healthy individuals (*P<0.05).Correlation analysis revealed a positive relationship between blood BBR and fecal NR activity (r=0.703).Thus, the fecal NR activity might serve as a biomarker in the personalized treatment of hyperlipidemia using BBR.
Abstract 302: Autophagy in the Aging Heart
Authors: Michael A Gurney, Roberta A Gottlieb, Phyllis-Jean Linton
Journal: Circulation Research (2012)

Autophagy maintains cellular homeostasis by lysosomal degradation and recycling of damaged/dysfunctional organelles, removal of aggregated proteins, and the provision of energy to cells in times of stress. Recently, autophagy has been shown to decline with age in the liver and thymus, prompting us to ask if there was a corresponding age-related decrease in autophagy in the heart. The comparison of membrane-associated LC3-II to cytosolic LC3-I is indicative of autophagosome formation, and is one of several parameters used to assess autophagic activity. Basal autophagy in C57BL/6 mice across five age groups from 2.5 to 24 months, assessed by Western Blot, demonstrated little variance in LC3-I but a significant decrease in LC3-II (ANOVA; n=3/age group; p&gt;0.05 and p&lt;0.0002, respectively). Also, a Triton-X insoluble fraction containing p62/SQSTM-1 and ubiquitinated proteins were shown to correlate with changes in aggrephagy. We found a significant increase in p62 and ubiquitinated proteins with increasing age (p&lt;0.01). Both findings suggest a decline in basal autophagy with age. When subjected to an acute stress, such as fasting, the levels of LC3-II but not LC3-I increased in young and old mice (n=4/age group; p&lt;0.05 and p&gt;0.05, respectively). To determine if flux was impaired in the aged, we treated fasted mice with chloroquine, which prevents autophagosome/lysosome fusion resulting in LC3-II accumulation. We found LC3-II accumulated only in the young (n=4; p&lt;0.01). Thus, the aged can mount an acute response but flux declines. Moreover, RT-qPCR analysis of cardiac tissue showed a significant decrease in atg5 and atg7 and a significant increase in atg8A , atg8B , lamp2A , atg4A , and atg4B expression with advancing age (&gt; 2.5 fold change). The dysregulated mRNA levels are suggestive of overcompensation of clearance, and the data support an overall decline in function with age. Although not manifest in the same manner, autophagy dysregulation also occurs with age in BALB/c mice, a shorter-lived strain. Our findings may be relevant to cardiac injury, such as in ischemia/reperfusion, given the emerging importance of autophagy in cardioprotection.
The evolution of chemotherapy for the treatment of prostate cancer
Authors: D.I. Quinn, H.M. Sandler, L.G. Horvath, A. Goldkorn, J.A. Eastham
Journal: Annals of Oncology (2017)

Chemotherapy has been explored as a treatment option for metastatic prostate cancer since the early 1980s. Docetaxel, a taxane chemotherapeutic, was approved for the treatment of men with metastatic castration-resistant prostate cancer in 2004, and is now standard of care for late stage disease. Recent clinical studies demonstrated that patients with metastatic castration-sensitive disease, and possibly those with high-risk localized prostate cancer also benefit from docetaxel administration, expanding the role of chemotherapy in the prostate cancer treatment landscape. Another taxane, cabazitaxel, is approved for post-docetaxel metastatic castration-resistant prostate cancer. Taxanes and other chemotherapeutics, such as carboplatin, are now being tested in combination regimens. This review presents an outline of recent and ongoing clinical studies assessing docetaxel and its derivative cabazitaxel at different stages of the disease, and in various combinations with other agents. We summarize current knowledge on biomarkers predictive of response to chemotherapy, which may in future be used to guide individualized treatment decisions.
Characteristics of Patients Presenting to the Emergency Department and Urgent Care for Treatment of Sunburn
Authors: Fan Di Xia, Mary Fuhlbrigge, Michael Waul, Cara Joyce, Arash Mostaghimi
Journal: JAMA Dermatology (2017)

IMPORTANCEThe effect of vaccination on emergency department (ED) utilization for herpes zoster (HZ) has not been examined to date.OBJECTIVE To determine trends in US ED utilization and costs associated with HZ. DESIGN, SETTING, AND PARTICIPANTSThe Nationwide Emergency Department Sample data set was examined for temporal trends in the number of visits and costs for treatment of HZ in EDs in the United States from January 1, 2006, through December 31, 2013.Cases of HZ were identified using validated International Classification of Diseases, Ninth Revision-Clinical Modification diagnosis codes.Patients were stratified by age: less than 20 years (varicella vaccine recommended), 20 to 59 years (no vaccine recommended), and 60 years or older (HZ vaccine recommended).Population-based rates were estimated using sampling weights. MAIN OUTCOMES AND MEASURESPopulation-based incidence rates of HZ-related ED visits, charge for ED services, and total charges.RESULTS A total of 1 350 957 ED visits for HZ were identified between 2006 and 2013, representing 0.13% of all US ED visits.Of these patients, 563 200 (51.7%)were male; mean (SE) age was 54.0 (0.1) years.Between 2006 and 2013, the percentage of HZ-related ED visits increased from 0.13% to 0.14% (8.3%).This growth was driven by patients aged 20 to 59 years (increase of 22.8% [from 0.12% to 0.14% of ED visits]) while the proportion of ED HZ visits decreased for patients aged less than 20 years and 60 years or older, from 0.03% to 0.02% (-39.6%) and from 0.28% to 0.25% (-10.9%),respectively.For all age groups, there was an increase from 2006 to 2013 in overall adjusted total (from $92.83 to $202.47 million) and mean charges (from $763 to $1262) for HZ-related ED visits. CONCLUSIONS AND RELEVANCEThe number of ED visits and total cost associated with HZ increased between 2006 and 2013.Greater use was driven by an increased number of visits by patients aged 20 to 59 years, but populations recommended for vaccination (<20 and Ն60 years) demonstrated decreased ED utilization.Per-visit and total costs increased across all age groups.Vaccination may be associated with a reduction of ED utilization.Further research is required to confirm these results and examine the drivers of increased ED costs.
Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): Validation of the 16-gene Recurrence Score in stage III patients.
Authors: Bernard J. Escudier, Brian I. Rini, Jean-Francois Martini, Wayne Yen-Hwa Chang, Jan Breza, Ahmed Magheli, Christer Svedman, Margarita Lopatin, Dejan Knezevic, Audrey D. Goddard, Patricia A English, Rachel Li, Xun Lin, Olga Valota, Giacomo Cartenì, Michael D. Staehler, Robert J. Motzer, Alain Ravaud
Journal: Journal of Clinical Oncology (2017)

4508 Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in 615 patients (pts) with high-risk RCC (hazard ratio [HR] 0.76; P= 0.03) in the S-TRAC trial. The 16-gene Recurrence Score (RS) was developed and validated to predict risk of recurrence of RCC after nephrectomy in 2 cohorts of stage I–III pts (Rini et al., Lancet Oncol 2015;16:676-85). We present further validation of RS results in high-risk stage III pts from S-TRAC. Methods: The study was prospectively designed with prespecified genes, algorithm, endpoints, analytical methods, and analysis plan using primary RCC tissues from 212 evaluable pts with informed consent. Gene expression was quantitated by RT-PCR; primary analysis focused on stage III (n = 193 pts). Time to recurrence (TTR) and DFS were analyzed using Cox proportional hazard regression. Results: Baseline characteristics were similar in SU and PBO arms and in pts with and without gene expression data; effect of SU was numerically similar to that in the entire trial (DFS HR 0.78, 95% CI 0.48–1.24; P= 0.29). RS predicted TTR and DFS in both treatment arms with the strongest results observed in PBO arm where high RS group had significantly higher risk (Table). Interaction of RS with treatment was not significant (TTR P= 0.192; DFS P= 0.219); however, the number of events was relatively low. Conclusions: The prognostic value of the 16-gene assay was confirmed in S-TRAC. RS is now validated with consistent results in 2 separate studies (level IB evidence). RS results may help identify patients at high risk who could derive higher absolute benefit from adjuvant treatment. The predictive value of RS to select patients for adjuvant SU requires further investigation in independent adjuvant trials. [Table: see text]
Intensive consolidation with G‐CSF support: Tolerability, safety, reduced hospitalization, and efficacy in acute myeloid leukemia patients ≥60 years
Authors: Wolfgang R. Sperr, Susanne Herndlhofer, Karoline Gleixner, Michael Girschikofsky, Ansgar Weltermann, Sigrid Machherndl‐Spandl, Thamer Sliwa, Rainer Poehnl, Veronika Buxhofer‐Ausch, Karin Strecker, Gregor Hoermann, Paul Knoebl, Ulrich Jaeger, Klaus Geissler, Michael Kundi, Peter Valent
Journal: American Journal of Hematology (2017)

The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA-C in cycle 1 and intermediate-dose ARA-C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction-chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC-P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation-cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC-P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC-P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.
Epidemiology of human infections with highly pathogenic avian influenza A(H7N9) virus in Guangdong, 2016 to 2017
Authors: Min Kang, Eric H Y Lau, Wenda Guan, Yuwei Yang, Tie Song, Benjamin J Cowling, Jie Wu, Malik Peiris, Jianfeng He, Chris Ka Pun Mok
Journal: Eurosurveillance (2017)

We describe the epidemiology of highly pathogenic avian influenza (HPAI) A(H7N9) based on poultry market environmental surveillance and laboratory-confirmed human cases (n = 9) in Guangdong, China. We also compare the epidemiology between human cases of high- and low-pathogenic avian influenza A(H7N9) (n = 51) in Guangdong. Case fatality and severity were similar. Touching sick or dead poultry was the most important risk factor for HPAI A(H7N9) infections and should be highlighted for the control of future influenza A(H7N9) epidemics.
Accelerometry: Improving Objective Assessments of Therapeutic Impact in Pediatric Pulmonary Arterial Hypertension
Authors: Eric D. Austin, Jeffrey A. Feinstein
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

which pathways to prioritize in future studies.Given the great efforts it takes to generate such rich datasets and the importance of the information contained within them, I would implore the authors of both of these innovative and well performed studies to attempt to replicate each other's findings on the datasets they have, or, even better, come together to perform a meta-analysis.Despite this weakness, which can easily be overcome through further collaboration and data sharing, these studies have revealed the importance of microbe-host interactions in the progression of IPF, and represent a significant step forward in defining the role of infection in the development of pulmonary fibrosis.Whether infection is an etiological factor for pulmonary fibrosis, and whether antimicrobial treatment can alter the course of progressive pulmonary fibrosis, are fundamental questions that still need to be definitively answered, but these studies raise the realistic prospect of replacing "IPF" in some with the diagnosis of this disease with a more meaningful label: infectious pulmonary fibrosis.