tbuckley/cabot-search huggingface dataset:
Steroid Hormone Vitamin D
Authors: Linda L. Demer, Jeffrey J. Hsu, Yin Tintut
Journal: Circulation Research (2018)

Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.
Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies
Authors: Na Wang, Xuelian Hu, Wenyue Cao, Chunrui Li, Yi Xiao, Yang Cao, Chaojiang Gu, Shangkun Zhang, Liting Chen, Jiali Cheng, Gaoxiang Wang, Xiaoxi Zhou, Miao Zheng, Xia Mao, Lijun Jiang, Di Wang, Qiuxiang Wang, Yaoyao Lou, Haodong Cai, Dandan Yan, Yicheng Zhang, Tongcun Zhang, Jianfeng Zhou, Liang Huang
Journal: Blood (2019)
Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis
Authors: Min Wang, Miao Zhang, Lianhua Fu, Jing Lin, Xinmin Zhou, Pinghong Zhou, Peng Huang, Hao Hu, Ying Han
Journal: Theranostics (2019)

Mesenchymal stem cells (MSCs) transplantation is a promising antifibrotic strategy but facing clinical controversies. Inspired by advances in nanomedicine, we aimed to bypass these clinical barriers of MSCs by identifying the key antifibrotic molecule of MSCs and developing a specific liver-targeting nanocarrier. Methods: Cytokines secreted by MSCs were examined with serum stimulation of cirrhotic patients. Immunohistochemistry, microarray, immunoblotting, and quantitative real-time PCR (qRT-PCR) were applied to identify the critical antifibrotic cytokine and to discover its role in modulating antifibrotic effects. Biomineralization method was used to prepare calcium phosphate nanoparticles (NPs). The targeting and therapeutic efficiency of NPs were evaluated by in vivo imaging and biochemical studies on fibrotic mice induced by CCl4. Results: The stimulated MSCs exhibited high-level expression of Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6). On animal study, exogenous administration of TSG-6 alone can ameliorate liver fibrosis while TSG-6 knocked MSCs (Lv-TSG-6 MSCs) lost antifibrotic effects. Further studies verified the importance of TSG-6 and identified its antifibrotic mechanism by modulating M2 macrophages and increasing matrix metalloproteinase 12 (MMP12) expression. Additionally, we found a feedback loop between TSG-6, MMP12 and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), which may improve our understanding of the aggravating process of cirrhosis and antifibrotic mechanisms of TSG-6 and MSCs. Based on these findings, we developed calcium phosphate nanoparticles (CaP@BSA NPs) by biomineralization method using bovine serum albumin (BSA) as the biotemplate. Imaging tracking and drug loading studies showed specific liver targeting and high TSG-6 loading efficacy of as-prepared CaP@BSA NPs. In vivo therapeutic study further demonstrated the improved therapeutic effects of TSG-6 loaded CaP@BSA. Conclusions: TSG-6 was a major antifibrotic cytokine of MSCs, TSG-6 loaded CaP@BSA NPs showed specific liver accumulation and improved therapeutic effects, which indicated translational potentials of CaP@BSA as a promising drug carrier for the liver disease management.
Pancreatic Cancer Awareness Issue 2019
Authors: Peter D. Siersema
Journal: Endoscopy (2019)

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. However, its toll is even higher in more developed countries. Reasons for differences in mortality rates for pancreatic cancer include, amongst others, delay in diagnosis, uncertainty about whether a lesion is cancerous or benign, difficulty in determining whether the malignancy is confined to the pancreas or already has grown into surrounding structures, and the presence of advanced disease precluding curative treatment.
Abstract 15408: Elevated Plasma Tgf-β1 Levels Predicted the Development of Hypertension in Normotensives in a General Population: The 14-Year Follow-Up Study in Uku Town
Authors: Erika Nakao, Hisashi Adachi, Mika Enomoto, Ako Fukami, Eita Kumagai, Sachiko Nakamura, Aya Obuchi, Yume Nohara, Nagisa Morikawa, Shoko Kono, Akiko Sakaue, Tomoko Tsuru, Yoshihiro Fukumoto
Journal: Circulation (2016)

Introduction: Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine. There is evidence that TGF-β1 is involved in the pathogenesis of hypertension and the development of hypertensive...
Research integrity: UK guidelines are updated to ensure misconduct reporting
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The national guidelines on research integrity have been updated to clarify the requirements for universities and enable sanctions to be enforced when research misconduct takes place.1

The move follows a July 2018 report by the House of Commons Science and Technology Select Committee, which found that a quarter of UK universities failed to produce an annual report on research integrity.2

The committee said that the “lack of consistent transparency” in reporting data on the number of misconduct investigations, …
Efficacy and Safety of Treatment with Bevacizumab (BEV) + Chemotherapy (CT) Beyond First Progression in Patients (PTS) with Metastatic Colorectal Cancer (MCRC) Previously Treated with BEV + CT: Age Subgroup Analysis From a Randomised Phase III Intergroup Study (ML18147)
Authors: O. Bouche, C. Steffens, T. André, J. Bennouna, J. Sastre, P. Österlund, R. von Moos, I. Reyes-Rivera, M.A. Sersch, D. Arnold
Journal: Annals of Oncology (2012)
Renal Clearable Ru-based Coordination Polymer Nanodots for Photoacoustic Imaging Guided Cancer Therapy
Authors: Rui Zhang, Xing Fan, Zhouqi Meng, Haiping Lin, Qiutong Jin, Fei Gong, Ziliang Dong, Youyong Li, Qian Chen, Zhuang Liu, Liang Cheng
Journal: Theranostics (2019)

Rationale: Despite the promises of applying theranostic nanoagents for imaging-guided cancer therapy, the chronic retention of these nanoagents may cause safety concerns that hinder their future clinical applications.The metabolizable nanoagents with rapid renal excretion to avoid long-term toxicity is a possible solution for this issue.Method: Herein, we synthesize ultra-small metal-organic coordination polymer nanodots based on ruthenium ion (Ru 3+ ) / phenanthroline (Phen) (Ru-Phen CPNs) with superior near-infrared (NIR) absorption.The size, photothermal conversion, cytotoxicity, photoacoustic imaging, in vivo & in vitro cancer treatment efficiency and biosafety are tested. Results:The size of the ultra-small Ru-Phen CPNs is 6.5 nm.The photothermal conversion efficiency is measured to be ~ 60.69 %, much higher than that of previously reported photothermal agents.The Ru-Phen CPNs could be employed for photoacoustic (PA, 808 nm) imaging-guided photothermal therapy (PTT, 808 nm, 0.5 W/cm 2 ) with great performance.Notably, the intrinsic PA signals (808 nm) of Ru-Phen CPNs are observed in kidneys of treated mice, illustrating efficient renal clearance of those ultra-small CPNs.Moreover, the clearance of CPNs is further confirmed by detecting Ru levels in urine and feces.Conclusion: Our work presents a new type of ultra-small Ru-based CPNs with a record high photothermal conversion efficiency, efficient tumor retention after systemic administration, and rapid renal excretion to avoid long-term toxicity, promising for imaging-guided photothermal therapy.
Early Detection of Pulmonary Vascular Dysfunction in Neonatal Bronchopulmonary Dysplasia
Authors: Paul M. Hassoun
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

were enumerated in donor tissue in the setting of PGD or non-PGD.The authors are to be congratulated for their protocol of harvesting the tissue and processing the cells in a uniform fashion, freezing the cells, and then performing the flow cytometry concurrently to avoid the confounding factor of variation in flow compensation and other possible cytometer-related differences in the results.Another strength of the analysis is that the flow strategy for cell identification is appropriate based on the current state of the art.Thus, this work adds to a growing body of literature that describes the presence of ILC2s in human diseases.The presence of ILC2s has been described in allergic rhinitis, chronic rhinosinusitis, asthma, atopic dermatitis, pleural effusion, pulmonary fibrosis, psoriasis, and graft versus host disease (10).Although ILC2s are potent producers of cytokines that are critical for the pathophysiology of many diseases, the specific importance of these cells in pathogenesis is unknown given that no methods are currently available to eliminate or suppress the function of these cells without also directly targeting other effector cells.Until such methods are available, investigators are left with the association of ILC2s with a condition, and not a definitive cause-and-effect relationship.
Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats
Authors: Jennifer L. Philip, Diana M. Tabima, Gregory D. Wolf, Andrea L. Frump, Tik-Chee Cheng, David A. Schreier, Timothy A. Hacker, Tim Lahm, Naomi C. Chesler
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

To the Editor: 17b-estradiol (E2), the most abundant female sex steroid, has been implicated in the development and progression of pulmonary arterial hypertension (PAH) (1, 2).Although some studies have found that E2 drives PAH progression, others have found a protective effect (3-6).The majority of these studies used right ventricular (RV) end systolic or mean pulmonary artery (PA) pressure as the primary metric of pulmonary vascular function and RV afterload.However, these endpoints are affected by RV function and do not fully capture RV afterload (7, 8).To accurately determine the impact of E2 in PAH, a comprehensive assessment of pulmonary vascular function, including multipoint pressure-flow relationships and impedance to flow at physiological Intact OVX+Veh OVX+E2
Stephanie Michelle Clarke
Authors: Esther Waterhouse
Journal: BMJ (2019)

Stephanie Michelle Clarke (“Steph”) was a bright and talented young doctor with a stellar career ahead of her. After qualification she had a very happy and successful FY1 year in Cheltenham. She was diagnosed with mesenchymal chondrosarcoma in August 2015, shortly after she started her FY2 year, and returned to work two years later, after her extensive anticancer treatment.

Her family and friends describe a bright, multitalented child and young woman. Whatever she did—be it playing for Aston Villa Ladies’ football team, beach volleyball at university, mess social rep at Cheltenham, piano playing, …
Improving accessibility of EPR-insensitive tumor phenotypes using EPR-adaptive strategies: Designing a new perspective in nanomedicine delivery
Authors: Alexander Dhaliwal, Gang Zheng
Journal: Theranostics (2019)

The enhanced permeability and retention (EPR) effect has underlain the predominant nanomedicine design philosophy for the past three decades. However, growing evidence suggests that it is over-represented in preclinical models, and agents designed solely using its principle of passive accumulation can only be applied to a narrow subset of clinical tumors. For this reason, strategies that can improve upon the EPR effect to facilitate nanomedicine delivery to otherwise non-responsive tumors are required for broad clinical translation. EPR-adaptive nanomedicine delivery comprises a class of chemical and physical techniques that modify tumor accessibility in an effort to increase agent delivery and therapeutic effect. In the present review, we overview the primary benefits and limitations of radiation, ultrasound, hyperthermia, and photodynamic therapy as physical strategies for EPR-adaptive delivery to EPR-insensitive tumor phenotypes, and we reflect upon changes in the preclinical research pathway that should be implemented in order to optimally validate and develop these delivery strategies.
Fabrication of Curcumin‐Modified TiO<sub>2</sub> Nanoarrays via Cyclodextrin Based Polymer Functional Coatings for Osteosarcoma Therapy
Authors: Meng Zhang, Jiting Zhang, Jisheng Chen, Yan Zeng, Zhihong Zhu, Ying Wan
Journal: Advanced Healthcare Materials (2019)

The incomplete removal of bone tumors leads to increased local recurrence and poor prognosis. To prevent ostoperative tumor recurrence and simultaneously repair surgery-caused bone defects, there is a need of great significance to develop implantable biomaterials possessing both cancer cell-killing ability and excellent bioactivity. In this work, a functionalized titanium-based implant is successfully fabricated by loading curcumin (CUR) onto cyclodextrin based polymer (pCD) modified titanium dioxide (TiO2 ) nanorod arrays. Herein, a polydopamine (pDA) assisted film is implemented as a first coating layer onto the surface of the TiO2 nanoarrays to guarantee the robust anchorage of the pCD. The pCD coating acts as a reservoir for CUR, allowing for efficient drug loading and sustained release of anticancer drugs. Studies show that the CUR-modified surfaces (TiO2 /pDA/pCD/CUR) can significantly promote apoptosis of osteosarcoma cells in vitro by inducing mitochondrial dysfunction caused by the ROS overproduction, and meanwhile, effectively inhibit the tumor growth in vivo. Moreover, such functionalized implants with surface density of loaded CUR at 22.48 µg cm-2 or lower support the attachment and proliferation of osteoblasts in vitro. These results successfully demonstrate that as-prepared TiO2 /pDA/pCD/CUR constructs have combined anticancer performance and good biocompatibility, which has great promise for the surgical therapy of bone tumors.
The harm of high-frequency oscillatory ventilation (HFOV) in ARDS is not related to a high baseline risk of acute cor pulmonale or short-term changes in hemodynamics
Authors: Federico Angriman, Bruno L. Ferreyro, Lachlan Donaldson, Brian H. Cuthbertson, Niall D. Ferguson, Casper W. Bollen, Thomas E. Bachman, François Lamontagne, Neill K. J. Adhikari
Journal: Intensive Care Medicine (2019)
TB vaccine is hailed as ground breaking, though confirmatory trials are needed
Authors: Jacqui Thornton
Journal: BMJ (2019)

A new vaccine against tuberculosis has shown more than 50% efficacy in protecting people with latent disease from developing the deadly and infectious pulmonary form of the disease, a study has found.1

It is the first time that a vaccine against TB has demonstrated the ability to stop progression, which was “ground breaking” and could save tens of millions of lives, the TB Science conference in Hyderabad, India, heard.

At present the 100 year old BCG jab is given to children to prevent the illness but it does not protect adults consistently against the infection.

The study of vaccine candidate M72/AS01 E, made by GlaxoSmithKline, was carried out in 11 sites in TB endemic regions in Kenya, South Africa, and Zambia and involved 3573 adults aged 18-50 who had latent TB. The participants were randomised to receive two doses of the vaccine 30 days apart or placebo as part of the phase 2b double blind trial and the results reported in the New England Journal of Medicine .1

During the three year follow-up, 13 participants in …
A 25 micron-thin microscope for imaging upconverting nanoparticles with NIR-I and NIR-II illumination
Authors: Hossein Najafiaghdam, Efthymios Papageorgiou, Nicole A. Torquato, Bining Tian, Bruce E. Cohen, Mekhail Anwar
Journal: Theranostics (2019)

Rationale: Intraoperative visualization in small surgical cavities and hard-to-access areas are essential requirements for modern, minimally invasive surgeries and demand significant miniaturization.However, current optical imagers require multiple hard-to-miniaturize components including lenses, filters and optical fibers.These components restrict both the form-factor and maneuverability of these imagers, and imagers largely remain stand-alone devices with centimeter-scale dimensions.Methods: We have engineered INSITE (Immunotargeted Nanoparticle Single-Chip Imaging Technology), which integrates the unique optical properties of lanthanide-based alloyed upconverting nanoparticles (aUCNPs) with the time-resolved imaging of a 25-micron thin CMOS-based (complementary metal oxide semiconductor) imager.We have synthesized core/shell aUCNPs of different compositions and imaged their visible emission with INSITE under either NIR-I and NIR-II photoexcitation.We characterized aUCNP imaging with INSITE across both varying aUCNP composition and 980 nm and 1550 nm excitation wavelengths.To demonstrate clinical experimental validity, we also conducted an intratumoral injection into LNCaP prostate tumors in a male nude mouse that was subsequently excised and imaged with INSITE.Results: Under the low illumination fluences compatible with live animal imaging, we measure aUCNP radiative lifetimes of 600 µs -1.3 ms, which provides strong signal for time-resolved INSITE imaging.Core/shell NaEr 0.6 Yb 0.4 F 4 aUCNPs show the highest INSITE signal when illuminated at either 980 nm or 1550 nm, with signal from NIR-I excitation about an order of magnitude brighter than from NIR-II excitation.The 55 µm spatial resolution achievable with this approach is demonstrated through imaging of aUCNPs in PDMS (polydimethylsiloxane) micro-wells, showing resolution of micrometer-scale targets with single-pixel precision.INSITE imaging of intratumoral NaEr 0.8 Yb 0.2 F 4 aUCNPs shows a signal-to-background ratio of 9, limited only by photodiode dark current and electronic noise.Conclusion: This work demonstrates INSITE imaging of aUCNPs in tumors, achieving an imaging platform that is thinned to just a 25 µm-thin, planar form-factor, with both NIR-I and NIR-II excitation.Based on a highly paralleled array structure INSITE is scalable, enabling direct coupling with a wide array of surgical and robotic tools for seamless integration with tissue actuation, resection or ablation.
The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients
Authors: K. Phakhounthong, M. Mukaka, S. Dittrich, A. Tanganuchitcharnchai, N.P.J. Day, L.J. White, P.N. Newton, S.D. Blacksell
Journal: Clinical Microbiology and Infection (2019)

This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA).Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR.For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from <400 to ≥3200. The median half-life of R. typhi IgM was 126 days (interquartile range 36-204 days) and IgG was 177 days (interquartile range 134-355 days). Overall median patient titres for R. typhi IgM and IgG were significantly different (p < 0.0001) and at each temporal sample collection point (range p < 0.0001 to p 0.0411). Using Bayesian latent class model analysis, the optimal diagnostic cut-off reciprocal IFA titer on patient admission for IgM was 800 (78.6%, 95% CI 71.6%-85.2% sensitivity; 89.9%, 95% CI 62.5%-100% specificity), and for IFA IgG 1600 (77.3%; 95% CI 68.2%-87.6% sensitivity; 99%, 95% CI 95%-100% specificity).This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.
Fine balance between pragmatism and rigidness in system approaches to acute care
Authors: Damian T Roland, Andrew Rowland, Sarah Cotterill, Calvin Heal, Steve Woby, Natalie Garratt, Stephen Brown, Tony Long
Journal: BMJ (2019)

Social cues, such as eye gaze and pointing fingers, can increase the prioritisation of specific locations for cognitive processing.A previous study using a manual reaching task showed that, although both gaze and pointing cues altered target prioritisation (reaction times [RTs]), only pointing cues affected action execution (trajectory deviations).These differential effects of gaze and pointing cues on action execution could be because the gaze cue was conveyed through a disembodied head; hence, the model lacked the potential for a body part (i.e., hands) to interact with the target.In the present study, the image of a male gaze model, whose gaze direction coincided with two potential target locations, was centrally presented.The model either had his arms and hands extended underneath the potential target locations, indicating the potential to act on the targets (Experiment 1), or had his arms crossed in front of his chest, indicating the absence of potential to act (Experiment 2).Participants reached to a target that followed a nonpredictive gaze cue at one of three stimulus onset asynchronies.RTs and reach trajectories of the movements to cued and uncued targets were analysed.RTs showed a facilitation effect for both experiments, whereas trajectory analysis revealed facilitatory and inhibitory effects, but only in Experiment 1 when the model could potentially act on the targets.The results of this study suggested that when the gaze model had the potential to interact with the cued target location, the model's gaze affected not only target prioritisation but also movement execution.
Gastric bypass versus sleeve gastrectomy in patients with type 2 diabetes (Oseberg): a single-centre, triple-blind, randomised controlled trial
Authors: Dag Hofsø, Farhat Fatima, Heidi Borgeraas, Kåre Inge Birkeland, Hanne Løvdal Gulseth, Jens Kristoffer Hertel, Line Kristin Johnson, Morten Lindberg, Njord Nordstrand, Milada Cvancarova Småstuen, Darko Stefanovski, Marius Svanevik, Tone Gretland Valderhaug, Rune Sandbu, Jøran Hjelmesæth
Journal: The Lancet Diabetes & Endocrinology (2019)