tbuckley/cabot-search huggingface dataset:
The Silence and Sorrow of Miscarriage
Authors: Altaf Saadi
Journal: JAMA (2020)

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Covid-19: Is the UK carrying out more tests than anywhere else in Europe?
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Last week at Prime Minister's Questions Boris Johnson claimed that the UK was now carrying out more covid-19 tests than anywhere else in Europe.In response to a question from the Labour Party leader, Keir Starmer, the prime minister said, "Not only are we getting the pandemic under control, with deaths down and hospital admissions way, way down, but we will continue to tackle it, with local lockdowns and with our superlative test and trace system, which, before opposition members sneer and mock it, has now conducted more tests than any other country in Europe."
Pharmacological inhibition of mTORC1 increases CCKBR-specific tumor uptake of radiolabeled minigastrin analogue [<sup>177</sup>Lu]Lu-PP-F11N
Authors: Michal Grzmil, Yun Qin, Carina Schleuniger, Stephan Frank, Stefan Imobersteg, Alain Blanc, Martin Spillmann, Philipp Berger, Roger Schibli, Martin Behe
Journal: Theranostics (2020)

Rationale: A high tumor-to-healthy-tissue uptake ratio of radiolabeled ligands is an essential prerequisite for safe and effective peptide receptor radionuclide therapy (PRRT). In the present study, we searched for novel opportunities to increase tumor-specific uptake of the radiolabeled minigastrin analogue [177Lu]Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2 ([177Lu]Lu-PP-F11N), that targets the cholecystokinin B receptor (CCKBR) in human cancers. Methods: A kinase inhibitor library screen followed by proliferation and internalization assays were employed to identify compounds which can increase uptake of [177Lu]Lu-PP-F11N in CCKBR-transfected human epidermoid carcinoma A431 cells and natural CCKBR-expressing rat pancreatic acinar AR42J cells. Western blot (WB) analysis verified the inhibition of the signaling pathways and the CCKBR level, whereas the cell-based assay analyzed arrestin recruitment. Biodistribution and SPECT imaging of the A431/CCKBR xenograft mouse model as well as histological analysis of the dissected tumors were used for in vivo validation. Results: Our screen identified the inhibitors of mammalian target of rapamycin complex 1 (mTORC1), which increased cell uptake of [177Lu]Lu-PP-F11N. Pharmacological mTORC1 inhibition by RAD001 and metformin increased internalization of [177Lu]Lu-PP-F11N in A431/CCKBR and in AR42J cells. Analysis of protein lysates from RAD001-treated cells revealed increased levels of CCKBR (2.2-fold) and inhibition of S6 phosphorylation. PP-F11N induced recruitment of β-arrestin1/2 and ERK1/2 phosphorylation. In A431/CCKBR-tumor bearing nude mice, 3 or 5 days of RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N (ratio [RAD001/Control] of 1.56 or 1.79, respectively), whereas metformin treatment did not show a significant difference. Quantification of SPECT/CT images confirmed higher uptake of [177Lu]Lu-PP-F11N in RAD001-treated tumors with ratios [RAD001/Control] of average and maximum concentration reaching 3.11 and 3.17, respectively. HE staining and IHC of RAD001-treated tumors showed a significant increase in necrosis (1.4% control vs.10.6% of necrotic area) and the reduction of proliferative (80% control vs. 61% of Ki67 positive cells) and mitotically active cells (1.08% control vs. 0.75% of mitotic figures). No significant difference in the tumor vascularization was observed after five-day RAD001 or metformin treatment. Conclusions: Our data demonstrates, that increased CCKBR protein level by RAD001 pretreatment has the potential to improve tumor uptake of [177Lu]Lu-PP-F11N and provides proof-of-concept for the development of molecular strategies aimed at enhancing the level of the targeted receptor, to increase the efficacy of PRRT and nuclear imaging.
SP0049 Raising priority for the needs of the individual
Authors: AD Woolf
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Musculoskeletal conditions (MSC) have an enormous and growing impact recognised by WHO Europe in "Health 21" yet national health care priorities in most European countries do not include them. The aim of the Bone and Joint Decade is to redress this imbalance by advocacy supported by evidence. To improve the outcome for the individual greater priority has to be given to the provision of existing proven interventions that meet the needs and wishes of the person with a MSC, and better interventions need to be developed through research. Education of public, people with MSC, health care providers, politicians and health professionals is fundamental to changing the negative perception of what can be achieved and in improving standards of care. Any campaign to meet these objectives needs to be supported by relevant data of the impact of MSC and evidence based solutions to reduce this. Key messages that highlight the issues, priorities and these solutions need to be developed for the decision-makers and any other relevant audiences. These messages should be conveyed by the powerful alliance of those with MSC and those who provide their care. The potent image of advocates must be used to attract media attention that is central to the strength of any campaign. Finally targets must be set to measure the success of any campaign. The Bone and Joint Decade is identifying the burden of MSC with the WHO and developing evidence based strategies for prevention with the support of the EU. National and local campaigns are necessary that use this evidence to achieve change and fulfil the aim of the Decade, which is to improve the health-related quality of life for those with musculoskeletal conditions.
Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi
Authors: Hang-Korng Ea, Alan Gauffenic, Quang Dinh Nguyen, Nhu G Pham, Océane Olivier, Vincent Frochot, Dominique Bazin, Nghia H Le, Caroline Marty, Agnès Ostertag, Martine Cohen-Solal, Jean-Denis Laredo, Pascal Richette, Thomas Bardin
Journal: Arthritis & Rheumatology (2020)

Objective The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits. Methods Twenty‐five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and μ Fourier transform infrared (μFTIR) spectroscopy. Results Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign‐body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and μFTIR. Compared to patients without CPPD, those with CPPD‐containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer‐term gout duration (mean 17.0 years versus mean 9.0 years; P &lt; 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P &lt; 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist. Conclusion CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long‐lasting urate‐lowering therapy.
Synergistic effects of fructose and glucose on lipoprotein risk factors for cardiovascular disease in young adults
Authors: Bettina Hieronimus, Valentina Medici, Andrew A. Bremer, Vivien Lee, Marinelle V. Nunez, Desiree M. Sigala, Nancy L. Keim, Peter J. Havel, Kimber L. Stanhope
Journal: Metabolism (2020)

Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors.Adults (18-40 years; BMI 18-35 kg/m2) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc.145 subjects (26.0 ± 5.8 years; body mass index 25.0 ± 3.7 kg/m2) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [-0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [-0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340).A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption.
The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease
Authors: Marine Berquez, Jonathan R. Gadsby, Beatrice Paola Festa, Richard Butler, Stephen P. Jackson, Valeria Berno, Alessandro Luciani, Olivier Devuyst, Jennifer L. Gallop
Journal: Kidney International (2020)

Loss-of-function mutations in the OCRL gene, which encodes the phosphatidylinositol [PI] 4,5-bisphosphate [PI(4,5)P
Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia
Authors: Runxia Gu, Fang Liu, Dehui Zou, Yingxi Xu, Yang Lu, Bingcheng Liu, Wei Liu, Xiaojuan Chen, Kaiqi Liu, Ye Guo, Xiaoyuan Gong, Rui Lv, Xia Chen, Chunlin Zhou, Mengjun Zhong, Huijun Wang, Hui Wei, Yingchang Mi, Lugui Qiu, Lulu Lv, Min Wang, Ying Wang, Xiaofan Zhu, Jianxiang Wang
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8 + naïve T cells was an independent factor associated with a shorter period of relapse-free survival ( p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8 + naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687
Do PROMS improve outcomes in patients with depression in primary care?
Authors: Tony Kendrick, Emma Maund
Journal: BMJ (2020)

### What you need to know

Patient reported outcome measures (PROMs) are questionnaires or brief interviews assessing patients’ symptoms, social functioning, and health related quality of life.1 PROMs provide feedback on patients’ responses to treatment, so healthcare practitioners may then adjust treatment or refer for alternative interventions.1 Their use in the assessment of severity of depression and monitoring is widely promoted in primary care, psychological therapy, and mental healthcare settings in the UK, US, and Europe (box 1). In the NHS England Improving Access to Psychological Therapies (IAPT) programme, PROMs for depression, anxiety, and social functioning are routinely administered at every treatment session.2

Box 1 
### Organisations recommending the use of PROMs for monitoring outcomes in the treatment of depressionRETURN TO TEXT

PROMs are relatively quick surrogate measures for longer, interview-based assessments of symptoms and functioning. PROMs provide standardised results, readily understandable to other practitioners, and to patients themselves after brief explanations of their meaning. Similar measures can be used to screen for depression and aid …
Carrier‐Free Nanoassembly of Curcumin–Erlotinib Conjugate for Cancer Targeted Therapy
Authors: Chen Cheng, Binglin Sui, Mingming Wang, Xiangxiang Hu, Shanshan Shi, Peisheng Xu
Journal: Advanced Healthcare Materials (2020)

Anticancer drug-loaded nanoparticles have been explored extensively to decrease side effects while improving their therapeutic efficacy. However, due to the low drug loading content, premature drug release, nonstandardized carrier structure, and difficulty in predicting the fate of the carrier, only a few nanomedicines have been approved for clincial use. Herein, a carrier-free nanoparticle based on the self-assembly of the curcumin-erlotinib conjugate (EPC) is developed. The EPC nanoassembly exhibits more potent cell killing, better antimigration, and anti-invasion effects for BxPC-3 pancreatic cancer cells than the combination of free curcumin and erlotinib. Furthermore, benefiting from both passive and active tumor targeting effect, EPC nanoassembly can effectively accumulate in the tumor tissue in a xenograft pancreatic tumor mouse model. Consequently, EPC effectively reduces the growth of pancreatic tumors and extends the median survival time of the tumor-bearing mice from 22 to 68 days. In addition, no systemic toxicity is detected in the mice receiving EPC treatment. Attributed to the uniformity of the curcumin-erlotinib conjugate and easiness of scaling up, it is expected that the EPC can be translated into a powerful tool in fighting against pancreatic cancer and other epidermal growth factor receptor positive cancers.
Racial Differences in Genomic Profiling of Prostate Cancer
Authors: Brandon A Mahal, Mohammed Alshalalfa, Kevin H Kensler, Ilkania Chowdhury-Paulino, Philip Kantoff, Lorelei A Mucci, Edward M Schaeffer, Daniel Spratt, Kosj Yamoah, Paul L Nguyen, Timothy R Rebbeck
Journal: New England Journal of Medicine (2020)

Genetic Alterations in Prostate Cancer Among nearly 2400 men with prostate cancer, next-generation sequencing of 474 genes showed differences among racial groups in the frequency of mutations in ce...
Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation
Authors: Gunjan L. Shah, Susan DeWolf, Yeon Joo Lee, Roni Tamari, Parastoo B. Dahi, Jessica A. Lavery, Josel Ruiz, Sean M. Devlin, Christina Cho, Jonathan U. Peled, Ioannis Politikos, Michael Scordo, N. Esther Babady, Tania Jain, Santosha Vardhana, Anthony Daniyan, Craig S. Sauter, Juliet N. Barker, Sergio A. Giralt, Cheryl Goss, Peter Maslak, Tobias M. Hohl, Mini Kamboj, Lakshmi Ramanathan, Marcel R.M. van den Brink, Esperanza Papadopoulos, Genovefa Papanicolaou, Miguel-Angel Perales
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.
MosaicBase: A Knowledgebase of Postzygotic Mosaic Variants in Noncancer Disease-Related and Healthy Human Individuals
Authors: Xiaoxu Yang, Changhong Yang, Xianing Zheng, Luoxing Xiong, Yutian Tao, Meng Wang, Adam Yongxin Ye, Qixi Wu, Yanmei Dou, Junyu Luo, Liping Wei, August Yue Huang
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Mosaic variants resulting from postzygotic mutations are prevalent in the human genome and play important roles in human diseases. However, except for cancer-related variants, there is no collection of postzygotic mosaic variants in noncancer disease-related and healthy individuals. Here, we present MosaicBase, a comprehensive database that includes 6698 mosaic variants related to 266 noncancer diseases and 27,991 mosaic variants identified in 422 healthy individuals. Genomic and phenotypic information of each variant was manually extracted and curated from 383 publications. MosaicBase supports the query of variants with Online Mendelian Inheritance in Man (OMIM) entries, genomic coordinates, gene symbols, or Entrez IDs. We also provide an integrated genome browser for users to easily access mosaic variants and their related annotations for any genomic region. By analyzing the variants collected in MosaicBase, we find that mosaic variants that directly contribute to disease phenotype show features distinct from those of variants in individuals with mild or no phenotypes, in terms of their genomic distribution, mutation signatures, and fraction of mutant cells. MosaicBase will not only assist clinicians in genetic counseling and diagnosis but also provide a useful resource to understand the genomic baseline of postzygotic mutations in the general human population. MosaicBase is publicly available at http://mosaicbase.com/ or http://49.4.21.8:8000.
Death after Kidney Transplantation: An Analysis by Era and Time Post-Transplant
Authors: Tracey Ying, Bree Shi, Patrick J. Kelly, Helen Pilmore, Philip A. Clayton, Steven J. Chadban
Journal: Journal of the American Society of Nephrology (2020)

Mortality risk after kidney transplantation can vary significantly during the post-transplant course. A contemporary assessment of trends in all-cause and cause-specific mortality at different periods post-transplant is required to better inform patients, clinicians, researchers, and policy makers.We included all first kidney-only transplant recipients from 1980 through 2018 from the Australia and New Zealand Dialysis and Transplant Registry. We compared adjusted death rates per 5-year intervals, using a piecewise exponential survival model, stratified by time post-transplant or time post-graft failure.Of 23,210 recipients, 4765 died with a functioning graft. Risk of death declined over successive eras, at all periods post-transplant. Reductions in early deaths were most marked; however, recipients ≥10 years post-transplant were 20% less likely to die in the current era compared with preceding eras (2015-2018 versus 2005-2009, adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.90). In 2015-2018, cardiovascular disease was the most common cause of death, particularly in months 0-3 post-transplant (1.18 per 100 patient-years). Cancer deaths were rare early post-transplant, but frequent at later time points (0.93 per 100 patient-years ≥10 years post-transplant). Among 3657 patients with first graft loss, 2472 died and were not retransplanted. Death was common in the first year after graft failure, and the cause was most commonly cardiovascular (50%).Reductions in death early and late post-transplant over the past 40 years represent a major achievement. Reductions in cause-specific mortality at all time points post-transplant are also apparent. However, relatively greater reductions in cardiovascular death have increased the prominence of late cancer deaths.