tbuckley/cabot-search huggingface dataset:
Enhanced osteogenesis of titanium with nano-Mg(OH)2 film and a mechanism study via whole genome expression analysis
Authors: Mengyu Yao, Shi Cheng, Guoqing Zhong, Jielong Zhou, Hongwei Shao, Limin Ma, Chang Du, Feng Peng, Yu Zhang
Journal: Bioactive Materials (2021)

Titanium (Ti) has been the most widely used orthopedic implant in the past decades. However, their inert surface often leads to insufficient osteointegration of Ti implant. To solve this issue, two bioactive Mg(OH)2 films were developed on Ti surfaces using hydrothermal treatment (Ti-M1# and Ti-M2#). The Mg(OH)2 films showed nano-flake structures: sheets on Ti-M1# with a thickness of 14.7 ± 0.7 nm and a length of 131.5 ± 2.9 nm, and on Ti-M2# with a thickness of 13.4 ± 2.2 nm and a length of 56.9 ± 5.6 nm. Both films worked as Mg ions releasing platforms. With the gradual degradation of Mg(OH)2 films, weakly alkaline microenvironments will be established surrounding the modified implants. Benefiting from the sustained release of Mg ions, nanostructures, and weakly alkaline microenvironments, the as-prepared nano-Mg(OH)2 coated Ti showed better in vitro and in vivo osteogenesis. Notably, Ti-M2# showed better osteogenesis than Ti-M1#, which can be ascribed to its smaller nanostructure. Moreover, whole genome expression analysis was applied to study the osteogenic mechanism of nano-Mg(OH)2 films. For both coated samples, most of the genes related to ECM-receptor interaction, focal adhesion, and TGF-β pathways were upregulated, indicating that these signaling pathways were activated, leading to better osteogenesis. Furthermore, cells cultured on Ti-M2# showed markedly upregulated BMP-4 gene expression, suggesting that the nanostructure with Mg ion release ability can better activate BMP-4 related signaling pathways, resulting in better osteogenesis. Nano-Mg(OH)2 films demonstrated a superior osteogenesis and are promising surface modification strategy for orthopedic applications.
Nivolumab as second-line treatment and beyond for metastatic renal cell carcinoma: A real-life experience from Turkish Oncology Group Kidney Cancer Consortium (TKCC) Database.
Authors: Emre Yekeduz, Ismail Erturk, Deniz Tural, Nuri Karadurmus, Serdar Karakaya, Mutlu Hizal, Çağatay Arslan, Hakan Taban, Ahmet Küçükarda, Nihan Şentürk Öztaş, Ozlem Nuray Sever, Gokhan Uçar, Mehmet Ali Nahit Sendur, Umut Demirci, Saadettin Kilickap, Irfan Cicin, Berna Oksuzoglu, Mustafa Ozguroglu, Yuksel Urun
Journal: Journal of Clinical Oncology (2021)

321 Background: Immune checkpoint inhibitors (ICIs) started a new era in the treatment of metastatic renal cell carcinoma (mRCC). CheckMate-025 and CheckMate-214 trials established the effect of ICIs in the second-line and upfront therapy of mRCC, respectively. This study aimed to share a real-life experience regarding nivolumab in the second-line treatment and beyond in mRCC Methods: We retrospectively searched the Turkish Oncology Group Kidney Cancer Consortium (TKCC) database, which is the multicenter registry system, and extracted patients treated with nivolumab in the second line and beyond. The patients treated with nivolumab plus targeted therapy or ipilimumab were excluded. The primary endpoint was overall survival (OS). The secondary endpoints were response rates and safety. Results: A total of 134 patients were included in this study. The median age at the starting of nivolumab treatment was 61 years (Inter Quartile Range (IQR):55-67). Three out of four patients were male. One hundred four patients (78%) had previous nephrectomy. The majority of patients had clear-cell pathology (83%). Thirteen patients (10%) had sarcomatoid features. According to International Metastatic RCC Database Consortium (IMDC) risk score, seventy patients (52%) were in the intermediate and poor prognostic group. The previous drugs administered in each line before nivolumab are shown in the table below. The number of patients treated with nivolumab was 63(47%), 45(33%), 17(13%), and 9(7%) in the second-, third-, fourth-, and fifth-line setting, respectively. The median OS was 34 months (95% Confidence Interval (CI): 24.1-43.8)) with the 15 months (IQR:5-26) median follow-up. Objective response rate (ORR) and disease control rate (DCR) was 33% and 57%, respectively. The most common grade 3 or higher AEs leading to treatment discontinuation were pneumonitis (%1.4) and colitis (&lt;%1). Conclusions: In compliance with the CheckMate-025 trial results, nivolumab improved OS for mRCC patients treated in the second line and beyond. The median OS was slightly higher in our study than the CheckMate-025 (34 months versus 25.8 months). It may be associated with the patient population in our study. Patients up to the fifth-line setting of mRCC treatment were included in this study. Of note, there was no additional safety concern for nivolumab. [Table: see text]
The Preventable Productivity Burden of Kidney Disease in Australia
Authors: Feby Savira, Zanfina Ademi, Bing H. Wang, Andrew R. Kompa, Alice J. Owen, Danny Liew, Ella Zomer
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Kidney disease is associated with reduced work productivity. The authors describe the preventable productivity burden of kidney disease in Australia over 10 years (2020–2029), using the novel metric “productivity-adjusted life year” (PALY). The PALY resembles the quality-adjusted life year, but it adjusts years of life lived for productivity loss resulting from ill health instead of quality-of-life impairment. They demonstrate that, if 10% of future cases of kidney disease can be prevented over this period, &gt;7500 PALYs could be saved, equivalent to a gain of US$1.1 billion in gross domestic product. These results have potential to inform policy makers regarding the need and the substantial financial incentive for the prevention of kidney disease. Background Kidney disease is associated with impaired work productivity. However, the collective effect of missed work days, reduced output at work, and early withdrawal from the workforce is rarely considered in health-economic evaluations. Methods To determine the effect on work productivity of preventing incident cases of kidney disease, using the novel measure “productivity-adjusted life year” (PALY), we constructed a dynamic life table model for the Australian working-age population (aged 15–69 years) over 10 years (2020–2029), stratified by kidney-disease status. Input data, including productivity estimates, were sourced from the literature. We ascribed a financial value to the PALY metric in terms of gross domestic product (GDP) per equivalent full-time worker and assessed the total number of years lived, total PALYs, and broader economic costs (GDP per PALY). We repeated the model simulation, assuming a reduced kidney-disease incidence; the differences reflected the effects of preventing new kidney-disease cases. Outcomes were discounted by 5% annually. Results Our projections indicate that, from 2020 to 2029, the estimated number of new kidney-disease cases will exceed 161,000. Preventing 10% of new cases of kidney disease during this period would result in &gt;300 premature deaths averted and approximately 550 years of life and 7600 PALYs saved—equivalent to a savings of US$1.1 billion in GDP or US$67,000 per new case avoided. Conclusions Pursuing a relatively modest target for preventing kidney disease in Australia may prolong years of life lived and increase productive life years, resulting in substantial economic benefit. Our findings highlight the need for investment in preventive measures to reduce future cases of kidney disease.
Metabolic Reprogramming of Dendritic Cells Is Controlled By the Mir-142
Authors: Yaping Sun, Thomas Saunders, Katherine Oravecz-Wilson, Sydney Bridges, Richard McEachin, Julia Wu, Stephanie Kim, Cynthia Zajac, Tomomi Toubai, Hideaki Fujiwara, Israel Henig, Dan Peltier, Pavan Reddy
Journal: Blood (2017)
The battle for COVID-19 vaccines highlights the need for a new global governance mechanism
Authors: Anna Mia Ekström, Camilla Berggren, Göran Tomson, Lawrence O. Gostin, Peter Friberg, Ole Petter Ottersen
Journal: Nature Medicine (2021)

To the Editor—Although the rapid development of several vaccines against COVID-19 is an unparalleled scientific accomplishment, one made possible through the collaboration of researchers, industry and funding bodies, the absence of a system that secures equitable access to vaccines has uncovered deep fissures in the global governance systems for health, as noted in a recent Nature Medicine Editorial.

For example, advance purchase agreements for vaccines against COVID-19 have favored affluent countries, allowing them to secure 150–500% of their predicted needs, while many citizens of low-and middle-income countries (LMICs) will remain unvaccinated until 2024. Additionally, the power of patent-holders and pharmaceutical companies to place conditions on the use of vaccines prices out access for LMICs, and bilateral purchasing deals are rarely disclosed.

By affording priority on the basis of economic or political power, today’s discourse clearly deviates from previous ethical and public-health principles of maximizing lives or life-years saved, and the sentiment that “people’s entitlement to lifesaving resources should not depend on nationality”.

The COVID-19 pandemic has tested wealthy nations’ commitments to Agenda 2030 and to ‘leaving no one behind’ at the same time that it has revealed democratic deficits, institutional rigidity, weak accountability systems, and inadequate policy space that protects health-governance systems from economic goals. Thus, the as-yet-limited support for the vaccine-sharing and allocation principles of the COVAX initiative may be a sign not only of a moral catastrophe, to quote the director-general of the World Health Organization (WHO), but also of inadequate global accountability mechanisms that exposes the consequences of commercial determinants of health.
UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.
Authors: Craig Gedye, David William Pook, Laurence Eliot Miles Krieger, Carole A. Harris, Jeffrey C. Goh, Ganessan Kichenadasse, Howard Gurney, Craig Underhill, Francis Parnis, Anthony M. Joshua, Tom Ferguson, Felicia Roncolato, Michelle L. Harrison, Stephen Begbie, Michelle Frances Morris, Elizabeth J. Hovey, Mathew George, Prashanth Prithviraj, Elizabeth Chien Hern Liow, Ian D. Davis
Journal: Journal of Clinical Oncology (2021)

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .
SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation
Authors: Esther Redin, Irati Garmendia, Teresa Lozano, Diego Serrano, Yaiza Senent, Miriam Redrado, Maria Villalba, Carlos E De Andrea, Francisco Exposito, Daniel Ajona, Sergio Ortiz-Espinosa, Ana Remirez, Cristina Bertolo, Cristina Sainz, Juana Garcia-Pedrero, Ruben Pio, Juan Lasarte, Jackeline Agorreta, Luis M Montuenga, Alfonso Calvo
Journal: Journal for ImmunoTherapy of Cancer (2021)

The use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate the immune cytotoxic activity, in combination with antiprogrammed cell death 1 (PD-1) antibody, are a great promise to overcome resistance. We evaluated the impact of the SRC family kinases (SFKs) on NSCLC prognosis, and the immunomodulatory effect of the SFK inhibitor dasatinib, in combination with anti-PD-1, in clinically relevant mouse models of NSCLC.A cohort of patients from University Clinic of Navarra (n=116) was used to study immune infiltrates by multiplex immunofluorescence (mIF) and YES1 protein expression in tumor samples. Publicly available resources (TCGA, Km Plotter, and CIBERSORT) were used to study patient's survival based on expression of SFKs and tumor infiltrates. Syngeneic NSCLC mouse models 393P and UNSCC680AJ were used for in vivo drug testing.Among the SFK members, YES1 expression showed the highest association with poor prognosis. Patients with high YES1 tumor levels also showed high infiltration of CD4+/FOXP3+ cells (regulatory T cells (Tregs)), suggesting an immunosuppressive phenotype. After testing for YES1 expression in a panel of murine cell lines, 393P and UNSCC680AJ were selected for in vivo studies. In the 393P model, dasatinib+anti-PD-1 treatment resulted in synergistic activity, with 87% tumor regressions and development of immunological memory that impeded tumor growth when mice were rechallenged. In vivo depletion experiments further showed that CD8+ and CD4+ cells are necessary for the therapeutic effect of the combination. The antitumor activity was accompanied by a very significant decrease in the number of Tregs, which was validated by mIF in tumor sections. In the UNSCC680AJ model, the antitumor effects of dasatinib+anti-PD-1 were milder but similar to the 393P model. In in vitro assays, we demonstrated that dasatinib blocks proliferation and transforming growth factor beta-driven conversion of effector CD4+ cells into Tregs through targeting of phospholymphocyte-specific protein tyrosine kinase and downstream effectors pSTAT5 and pSMAD3.YES1 protein expression is associated with increased numbers of Tregs in patients with NSCLC. Dasatinib synergizes with anti-PD-1 to impair tumor growth in NSCLC experimental models. This study provides the preclinical rationale for the combined use of dasatinib and PD-1/programmed death-ligand 1 blockade to improve outcomes of patients with NSCLC.
Wave-Complex-Dependent Actin Dynamics Controls Hematopoietic Stem Cell Bone Marrow Retention and Orderly Differentiation into Mature Hematopoietic Lineages
Authors: Eliza Wiercinska, David de Gorter, Eva Danner, Sabine Harenkamp, Andre Gorgens, Anja Schwiebs, Theresia Stradal, Halvard Bonig
Journal: Blood (2017)
Robust Benchmark Structural Variant Calls of an Asian Using State-of-the-Art Long-Read Sequencing Technologies
Authors: Xiao Du, Lili Li, Fan Liang, Sanyang Liu, Wenxin Zhang, Shuai Sun, Yuhui Sun, Fei Fan, Linying Wang, Xinming Liang, Weijin Qiu, Guangyi Fan, Ou Wang, Weifei Yang, Jiezhong Zhang, Yuhui Xiao, Yang Wang, Depeng Wang, Shoufang Qu, Fang Chen, Jie Huang
Journal: Genomics Proteomics & Bioinformatics (2021)

The importance of structural variants (SVs) for human phenotypes and diseases is now recognized. Although a variety of SV detection platforms and strategies that vary in sensitivity and specificity have been developed, few benchmarking procedures are available to confidently assess their performances in biological and clinical research. To facilitate the validation and application of these SV detection approaches, we established an Asian reference material by characterizing the genome of an Epstein-Barr virus (EBV)-immortalized B lymphocyte line along with identified benchmark regions and high-confidence SV calls. We established a high-confidence SV callset with 8938 SVs by integrating four alignment-based SV callers, including 109× Pacific Biosciences (PacBio) continuous long reads (CLRs), 22× PacBio circular consensus sequencing (CCS) reads, 104× Oxford Nanopore Technologies (ONT) long reads, and 114× Bionano optical mapping platform, and one de novo assembly-based SV caller using CCS reads. A total of 544 randomly selected SVs were validated by PCR amplification and Sanger sequencing, demonstrating the robustness of our SV calls. Combining trio-binning-based haplotype assemblies, we established an SV benchmark for identifying false negatives and false positives by constructing the continuous high-confidence regions (CHCRs), which covered 1.46 gigabase pairs (Gb) and 6882 SVs supported by at least one diploid haplotype assembly. Establishing high-confidence SV calls for a benchmark sample that has been characterized by multiple technologies provides a valuable resource for investigating SVs in human biology, disease, and clinical research.
PTU-032 Endoscopic stenting – a five year retrospective study
Authors: T Johnston, R Matull
Journal: Gut (2017)

Introduction  Oesophageal, duodenal, gastric (UGI) and colorectal stenting are procedures performed every week in Musgrove Park Hospital Taunton, (a 700 bed District General Hospital in the Southwest of England).  Division of labour betweeen Gastroenterology, Radiology and Surgical Teams.  Most stenting performed for palliative symptom relief in malignant obstruction and a small proportion of cases are for benign peptic stricturing.  We examined our current practice including patient symptoms, morbidity and mortality. Established standards not well defined in this area and so compared our outcomes against our historic practice and against other centres.  Method  Retrospective analysis of procedures between June 2011 and June 2016 and survival up until November 2016.  289 recorded cases over this period (a representative sample of cases cases performed). These detailed both colorectal stenting and UGI stenting.  Data taken from endoscopy records, patient‘s letters, MDT outcomes and the Somerset Cancer Register..  30 day mortality, 8 day readmission rates, survival post stent and designation of the endoscopist or operator in this cohort examined.  In subcohort of 159 cases (cases from November 2013 until June 2016) patient‘s pain score post procedure as well and dysphagia scores pre and post procedure (within the upper gastro-intestinal stenting cohort) examined. Select cohort chosen because previously patients symptoms not consistently recorded. Dysphagia score was derived from the National Oesophago-gastric Cancer Audit. Pain score was classified numerically 0 (no pain) - 3 (breakthrough pain despite opiates.  Results  Key findings (all cases):  Survival range 0–1219 days  Mean age of patient 73  Male 203, Female 86  30 day mortality - 23% (excluding benign cases)  8 day readmission rate: 5.9% (11.9% if including those remaining in hospital for ongoing care)  Procedures performed:-  Oesophageal (including gastro-oesophageal): 176  Stomach: 3  Duodenal (including gastric pylorus): 40  Colorectal: 70  Patient Symptoms (Upper GI):-  - Any dysphagia at one month 42% (96% pre stent), mean dysphagia score 0.85 (2.86 pre stent)  - Any dysphagia at 3 months 39%, mean dysphagia score 0.39  - Mean pain score pre stent 0.58, 0.46 one month post stent.  Patient symptoms (Colorectal):-  - Mean pain score 1.03 pre stent to 0.11 one month post stent.  Specific Mortality Data:-  Oesophageal: 30 day mortality 20.1% Mean survival 135 days  Duodenal: 30 day mortality 17.1% Mean survival 147 days  Colorectal 30 day mortality 20.0% Mean survival 239 days  Complication and failure rates:-  Failure of procedure: 14.4%, Minor Complication:1.9%  Serious Complications: 3.1% (Of which 2.5% could have contributed to death)  Conclusion  UGI stenting leads to improvement in dysphagia but no change in pain score. Lower GI stenting leads to gross improvement in pain score. Our survival data is comparable to similar published data although our average age of patient is higher than comparable studies.  Disclosure of Interest  None Declared
In patients with CAD, adding colchicine to evidence-based therapies reduces MACE without increasing adverse outcomes
Authors: Eric R. Bates
Journal: Annals of Internal Medicine (2021)

ACP Journal ClubMarch 2021In patients with CAD, adding colchicine to evidence-based therapies reduces MACE without increasing adverse outcomesEric R. Bates, MDEric R. Bates, MDUniversity of Michigan, Ann Arbor, Michigan, USA (E.R.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202103160-030 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationXia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-8. https://pubmed.ncbi.nlm.nih.gov/33137319Clinical Impact RatingsGIM/FP/GP: Cardiology: References1 Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-31. [PMID: 28845751] Google Scholar2 Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380:752-62. [PMID: 30415610] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Michigan, Ann Arbor, Michigan, USA (E.R.B.)Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7314.This article was published at Annals.org on 2 March 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAssociation of Pericardiac Adipose Tissue With Coronary Artery Disease March 2021Volume 174, Issue 3Page: JC30KeywordsAcute coronary syndromeAntiplatelet therapyColchicineDrug therapyDrugsMyocardial infarctionRevascularizationStable coronary artery diseaseTreatment guidelinesType 2 diabetes ePublished: 2 March 2021 Issue Published: March 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...