tbuckley/cabot-search huggingface dataset:
Biofunctionalization of Dental Abutment Surfaces by Crosslinked ECM Proteins Strongly Enhances Adhesion and Proliferation of Gingival Fibroblasts
Authors: Alena L. Palkowitz, Taskin Tuna, Shaza Bishti, Frederik Böke, Nathalie Steinke, Gerhard Müller‐Newen, Stefan Wolfart, Horst Fischer
Journal: Advanced Healthcare Materials (2021)

Abstract To ensure the long‐term success of dental implants, a functional attachment of the soft tissue to the surface of the implant abutment is decisively important in order to prevent the penetration of bacteria into the implant–bone interface, which can trigger peri‐implant disease. Here a surface modification approach is described that includes the covalent immobilization of the extracellular matrix (ECM) proteins fibronectin and laminin via a crosslinker to silanized Ti6Al4V and Y‐TZP surfaces. The surface properties are evaluated using static contact angle, X‐ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The interaction of human gingival fibroblasts (HGFs) with the immobilized ECM proteins is verified by analyzing the localization of focal contacts, cell area, cell morphology, proliferation rate, and integrin expression. It is observed in the presence of fibronectin and laminin an increased cellular attachment, proliferation, and integrin expression of HGFs accompanied by a significantly higher number of focal adhesions. The presented approach holds great potential to enable a stronger bond between soft tissue and implant abutment surface. This could potentially help to prevent the penetration of bacteria in an in vivo application and thus reduce the risk of periimplant disease.
Abstract PR-07: ORCESTRA: A platform for orchestrating and sharing high-throughput multimodal data analyses
Authors: Anthony Mammoliti, Petr Smirnov, Minoru Nakano, Zhaleh Safikhani, Sisira Nair, Arvind Singh Mer, Chantal Ho, Gangesh Beri, Benjamin Haibe-Kains
Journal: Clinical Cancer Research (2021)

Abstract Reproducibility is essential to Open Science. If a finding cannot be reproduced by independent research groups its relevance is extremely limited, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, challenged, and built upon. However, due to recent technological advances in the biological and computational sciences, experimental protocols, data analysis and interpretation have become increasingly complex. This has made reproducing research findings more challenging, with some researchers going as far as suggesting that the biomedical sciences are experiencing a "reproducibility crisis". In order to overcome these issues we developed ORCESTRA, a cloud-based platform that provides a transparent, reproducible and flexible computational framework for processing and sharing high-throughput multimodal biomedical data. The platform enables processing of genomic and pharmacological profiles of cancer samples through the use of automated processing pipelines executed by Pachyderm, a data versioning and orchestration tool. ORCESTRA creates an integrated and fully documented data object known as a PharmacoSet (PSet) for future analyses using the Bioconductor PharmacoGx package. A PSet includes cell line and drug annotations, along with molecular and pharmacological data from the largest studies and consortia. Our platform is currently being expanded to additional data types, which includes toxicogenomics, xenographic pharmacogenomic data, radiomics, and clinical genomic data. The automated pipelines can be accessed via a web interface (www.orcestra.ca). Users can view and download existing dataset or request a new one by selecting pipeline parameters. The web application provides features to improve user experience, and to accommodate different scenarios for ORCESTRA deployment. They include a personal account to save PSets, a dashboard to check the status of a requested pipeline, email notification upon the pipeline completion, handling pipeline requests while the Pachyderm cluster is offline, and “manual push” of the pipeline requests once the cluster becomes online. Funding: This project is supported by CIHR, under the frame of ERA PerMed. Citation Format: Anthony Mammoliti, Petr Smirnov, Minoru Nakano, Zhaleh Safikhani, Sisira Nair, Arvind Singh Mer, Chantal Ho, Gangesh Beri, Benjamin Haibe-Kains. ORCESTRA: A platform for orchestrating and sharing high-throughput multimodal data analyses [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-07.
Abstract PO-066: Data standardization, integration and meta-analysis of preclinical pharmacogenomics studies for gene expression biomarker discovery
Authors: Petr Smirnov, Benjamin Haibe-Kains
Journal: Clinical Cancer Research (2021)

Abstract The sparsity of predictive biomarkers for drug response remains a major impediment to the clinical success of precision oncology. Over the past decade, massive studies combining in-vitro drug screening with high-throughput molecular profiling of cancer cell lines have been published, with the goal of discovering novel predictive biomarkers for drug response. Unfortunately, inconsistencies in the data, as well as a lack of standards in the field, has effectively siloed the findings of these studies away from the clinical researchers working in precision medicine. In our previous work developing the PharmacoGx/PharmacoDB platform, we have reprocessed and curated the 7 largest pharmacogenomic studies released to date. Together, these studies profiled 760 compounds across ~1600 cell lines, in over 650,000 drug dose response experiments. Here, we present an update of this database, and describe our preliminary findings from a statistical meta-analysis of these data for the discovery of gene expression biomarkers. Our meta-analysis looked for markers consistently associated with drug response across 11 tissue types and 70 compounds found in at least 3 studies in the examined dataset. From these data, we find approximately 4338 consistent associations across studies surviving multiple hypothesis correction, in 1946 genes, across 8 tissues and 34 different drugs. The results show evidence of both drug-mechanism specific markers of response, as well as markers of multi-drug resistance phenotypes. Within lung cancer cell lines, we observe an enrichment of TGF-β signalling related genesets among markers of multi-drug sensitivity and resistance. We discuss our approach to validate these markers using organoid, in vivo and clinical datasets. Finally, we detail tools we are building for researchers to explore our database of putative biomarkers and the data supporting them; focusing on exposing our findings to the clinical precision medicine research community. Ultimately, our goal is to extract a database of high confidence preclinical associations from the consensus of published pharmacogenomic studies. This database would be the first step in translating findings from these massive preclinical studies towards novel clinically actionable biomarkers for use in the pursuit of precision cancer care. Citation Format: Petr Smirnov, Benjamin Haibe-Kains. Data standardization, integration and meta-analysis of preclinical pharmacogenomics studies for gene expression biomarker discovery [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-066.
A clear pathway to tubulointerstitial disease: is an exclusive focus on fibrosis justified?
Authors: Robert Safirstein
Journal: Journal of Clinical Investigation (2021)

Tubulointerstitial accumulation of matrix proteins in human kidney biopsies is the best predictor of renal survival. In this issue of the JCI, Yen-Ting Chen et al. elegantly show that an endoplasmic reticulum resident protein, thioredoxin domain containing 5 (TXNDC5), is a key mediator of experimental kidney fibrosis. The researchers used knockout or conditional knockout animals to reduce Txndc5 expression, which reduced the accumulation of fibrous tissue in three models of chronic kidney disease (CKD), including unilateral ureteral obstruction, unilateral ischemia reperfusion injury, and folic acid nephropathy. More importantly, the studies demonstrate that the activated fibroblasts are almost exclusively responsible for producing matrix proteins. The study also showed that reducing Txndc5 in mice after tubulointerstitial fibrosis (TIF) was established mitigated the fibrosis. These experiments have obvious clinical importance but warrant caution because a key question remains unanswered. The impact of reducing TXNDC5 on renal function itself, the very heart of CKD, demands further exploration.
Allele-specific recombinase polymerase amplification for real-time detection of sickle cell anaemia in low-resource settings: evaluation of an isothermal nucleic acid amplification test to detect the βS globin point mutation in paediatric patients
Authors: Mary Natoli, Megan Chang, Kathryn Kundrod, Jackson Coole, Gladstone Airewele, Venée N Tubman, Rebecca Richards-Kortum
Journal: The Lancet Global Health (2021)

BackgroundSickle cell anaemia is a common, life-threatening disorder caused by a point mutation in the β globin gene. The high cost and complexity of conventional diagnostic methods limit the scope and sustainability of newborn screening for sickle cell anaemia and other haemoglobin disorders in resource-limited areas. Although several point-of-care tests are commercially available, most are antibody-based tests, which cannot be used in patients who have recently received a blood transfusion. Additionally, very low levels of sickle haemoglobin (HbS) in premature babies and some newborns may cause errors in immunoassays. DNA analysis provides the most reliable approach to diagnose haemoglobin disorders. However, DNA analysis is not currently available at the point of care due to its cost and complexity. Here, we describe a rapid, low-cost nucleic acid test that uses real-time fluorescence to detect the point mutation encoding HbS in one round of isothermal recombinase polymerase amplification.MethodsVenous and capillary blood samples were obtained from healthy volunteers who were recruited by word of mouth. Venous blood samples from patients with varying genotypes seen in the Sickle Cell Disease Program at Texas Children's Hematology Center were collected and deidentified under IRB-approved exemption. Genotypes, as determined by qualitative isoelectric focusing combined with quantitative high performance liquid chromatography (HPLC) to confirm a diagnosis, were provided with the blood samples. The assay was evaluated with genomic DNA extracted from a set of blood samples of varying genotypes using the Axxin T8-ISO, a low-cost, field-deployable benchtop fluorimeter.FindingsThe developed assay demonstrated 100% sensitivity for both the βA globin and βS globin alleles, and 94·7% and 97·1% specificity for the βA globin allele and βS globin allele, respectively (n=91). We also demonstrate a complete sample-to-answer workflow using a two-step lysis method and direct input of lysate into the allele-specific assay, and genotyping of blood samples in an open-source, custom built fluorimeter whose components cost less than US$850.InterpretationThis sample-to-answer nucleic acid test has the potential to be adapted to other disease-causing point mutations in genomic DNA. The technology described could streamline diagnosis in resource-limited settings of patients with sickle cell anaemia who have recently undergone a blood transfusion, with a comparable cost to protein-based tests.FundingNIH K23-HL148548-01A1.
Abstract IA-22: Automated treatment planning and quality assurance in radiation oncology
Authors: Thomas G. Purdie
Journal: Clinical Cancer Research (2021)

Abstract The delivery of radiation for the treatment of cancer is a complicated process that requires both clinical and technical expertise to ensure radiation treatments are safe and effective. Sub-optimal radiation treatments have the potential to result in significant detriment to the patient and several studies have shown radiation treatments, which deviate from established clinical guidelines, result in worse patient outcomes. Therefore, the current radiation treatment process requires substantial multi-disciplinary resources to both generate and verify radiation treatments are of high-quality. In this talk, a previously validated machine learning platform customized for radiation oncology will be presented. The method automatically learns based on data from thousands of previously treated patients which relationships and patterns in radiation oncology image and treatment data and has been applied for automated data mining activities, automated quality assurance to support expedited radiation treatment review, and for radiation dose prediction to develop new radiation treatments by best deciding where dose should be placed and how dose should be delivered without requiring any manual intervention. Therefore, the method can be used to both generate personalized radiation treatments and to quantitatively score radiation treatments for quality and classify radiation treatments that have errors. The automated platform can readily be integrated into current clinical process to improve efficiency in the radiation treatment planning and plan review processes and to better utilize the vast data we have to ensure we are providing patients with highly personalized radiation treatments. Citation Format: Thomas G. Purdie. Automated treatment planning and quality assurance in radiation oncology [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-22.
Rechallenge of nivolumab in metastatic renal cell carcinoma, an ambispective multicenter study (RENIVO).
Authors: Charles Vauchier, Edouard Auclin, Philippe Barthelemy, Lucia Carril, Thomas Ryckewaert, Delphine Borchiellini, Zahra Ajgal, Mostefa Bennamoun, Luca Campedel, Antoine Thiery-Vuillemin, Elodie Coquan, Laurence Crouzet, Jean Francois Berdah, Christine Chevreau, Raffaele Ratta, Aude Flechon, Felix Lefort, Marine Gross-Goupil, Constance Thibault, Stephane Oudard
Journal: Journal of Clinical Oncology (2021)

330 Background: Immune checkpoint inhibitors (ICIs) in combination with another ICI or an antiangiogenic targeted therapy have been approved for frontline therapy in metastatic renal cell carcinoma (mRCC). However, progression disease (PD) often occurs and subsequent therapies are needed. Rechallenge of ICI may then be an option, but there is a lack of data regarding this strategy. Methods: This ambispective multicenter study included patients who received a rechallenge of Nivolumab (ICI-2) between January 2014 and September 2020, after a first-ICI therapy (ICI-1), regardless of the reason of the discontinuation. Patients could have either a non-ICI therapy or have a prolonged free-interval (≥ 12 weeks) between ICI regimens. Those with ongoing rechallenge at inclusion were followed prospectively. Primary endpoint was investigator-assessed best ORR. Results: 45 rechallenges were included from 16 centers. Median age was 60 years (range, 42-90), 64% were male. Most of them had clear cell histology (91%) and a Fuhrman or ISUP grade ≥ 3 (80%). Single-agent Nivolumab and Nivolumab-Ipilimumab association were used in 78% and 11% during ICI-1 and in 93% and 7% during ICI-2, respectively. Discontinuation for PD, toxicity or clinical decision occurred in 49%, 27% and 24% for ICI-1 and in 94%, 3% and 3% for ICI-2, respectively. The ORR were 51% (n = 23) at ICI-1 and 16% (n = 7) at ICI-2. One patient had a complete response during both ICI-1 and ICI-2 and two had a partial response at ICI-2 although they had PD as best ICI-1 response. After a median follow-up of 14.9 months (mo), median duration of response for ICI-2 was 5.1 mo (95% CI, 2.7-not reached [NR]). For ICI-1 and ICI-2: median progression-free survival (PFS) was 11.4 mo (95% CI, 9.8-23.5) and 3.5 mo (95% CI, 2.8-9.7); median overall survival was NR (95% CI, 37.8-NR) and 24 mo (95% CI, 9.9-NR). Poor prognostic factors for PFS at ICI-2 were Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2, presence of liver metastases, inflammatory syndrome and PFS under ICI-1 &gt; 6 months. Grade ≥ 3 immune-related adverse events occurred in 24% (n = 11) during ICI-1 but only in 4% (n = 2) during ICI-2. There was no treatment-related death. Conclusions: Our study suggests that resumption of ICI with Nivolumab has a moderate efficacy in mRCC and acceptable tolerance. Predictive factors of response are needed to propose this strategy to selected mRCC patients. Larger prospective cohorts are needed to confirm these results. [Table: see text]
<i>QuickStats:</i> Death Rates* from Unintentional Falls† Among Persons Aged ≥65 Years, by Age Group — National Vital Statistics System, United States, 1999–2018
Authors: Matthew Garnett, R Spencer, Holly Hedegaard
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

† Deaths from unintentional falls are identified using the International Classification of Diseases, Tenth Revision underlying cause of death codes W00-W19.From 1999 to 2018, death rates from unintentional falls among persons aged ≥65 years increased among all age groups.The largest increase occurred among persons aged ≥85 years, from 110.2 per 100,000 in 1999 to 270.5 in 2018.For persons aged 75-84 years, the rate increased from 31.5 to 63.1, and among those aged 65-74 years, the rate increased from 9.0 to 16.8.Throughout the period, rates were highest among persons aged ≥85 years, followed by rates among persons aged 75-84 years, and were lowest among persons aged 65-74 years.
TCF3-Hlf Hijacks ERG to Activate Leukemia-Critical Super-Enhancers in t(17;19) Leukemia
Authors: Yun Huang, Brice Mouttet, Hans-Jörg Warnatz, Maria Pamela Dobay, Blerim Marovca, Silvia Jenni, Martin Schrappe, Martin Stanulla, Marie-Laure Yaspo, Beat Bornhauser, Jean-Pierre Bourquin
Journal: Blood (2017)
YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases
Authors: Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Journal: Journal of Clinical Investigation (2021)

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.
An FDA pooled analysis: Characteristics and outcomes of patients with nonmetastatic castration-resistant prostate cancer, based on prior history of prostatectomy and/or radiation therapy.
Authors: Jaleh Fallah, Lijun Zhang, Chana Weinstock, Daniel L. Suzman, Shenghui Tang, Kirsten B. Goldberg, Paul Gustav Kluetz, Julia A. Beaver, Richard Pazdur, Amna Ibrahim, Laleh Amiri-Kordestani
Journal: Journal of Clinical Oncology (2021)

197 Background: Patients (pts) enrolled in trials of androgen receptor inhibitors (ARI) in the non-metastatic castration resistant prostate cancer (nmCRPC) setting may or may not have received definitive treatment with prostatectomy and/or radiation therapy (Surg/RT). We investigated the characteristics and outcomes of pts with nmCRPC based on prior history of Surg/RT. Methods: Data were pooled from all trials of ARI in nmCRPC submitted to the FDA as of October 2020. Pts baseline characteristics were summarized by prior history of Surg/RT. The Kaplan-Meier method was used to estimate median metastatic-free survival (MFS) and overall survival (OS) of each treatment arm by prior history of Surg/RT status. Hazard Ratios (HR) with corresponding 95% confidence intervals (CI) were estimated using a Cox proportional hazards model stratified by trial and adjusted for baseline characteristics. Results: Three trials met the inclusion criteria. Of 4117 pts enrolled, 2251 (55%) had prior surg/RT. The median age at the time of enrollment was 72 and 76 years in pts with and without prior Surg/RT, respectively. The median time from initial diagnosis of prostate cancer to enrollment on the trials of ARI was 9.1 and 5.7 years in pts with and without prior Surg/RT, respectively. PSA doubling time and number of prior hormonal therapies were similar between the two groups with and without prior Surg/RT. History of prior Surg/RT varied by geographic region: 76% (N = 611/807) in North America, 50% (N = 1110/2229) in Europe, 39% (N = 220/570) in Asia/Pacific, 52% (135/262) in South America, and 73% (171/233) in Australia/New Zealand. ECOG performance status (PS) at the time of enrollment was 0 and 1 in 80% and 20% of the pts with prior Surg/RT, respectively. In pts without prior Surg/RT, ECOG PS was 0 in 65% and 1 in 35% of pts. Gleason score was ≥8 in 36% and 47% of pts with and without prior Surg/RT, respectively. MFS and OS results in pts with and without prior Surg/RT are in the table. Conclusions: In this retrospective analysis, MFS and OS was improved in pts who received ARIs compared to placebo, regardless of prior history of Surg/RT. Any relative differences based on prior history of Surg/RT can only be considered hypothesis generating. [Table: see text]
Vitamin D and bacterial pneumonias: the question of causality
Authors: Richard James Allen
Journal: Thorax (2021)

Vitamin D controls calcium and phosphates in the body, maintains healthy bones and muscles, and has been shown to play an important role in the regulation of the innate immune system. Vitamin D is found in some foods, but the main source for most people comes from sunlight. Over recent years, there has been much debate as to the benefit of vitamin D supplementation and the UK’s National Health Service now advises everyone to consider vitamin D supplementation during winter months.1

A recent systematic review2 of 25 randomised controlled trials (collectively containing over 11 000 individuals) found that vitamin D supplementation showed an association with reduced acute-respiratory tract infections, particularly in those with baseline circulating 25-hydroxyvitamin D levels less than 25 nmol/L. These results are supported by observational studies that suggest low vitamin D levels are associated with an increased risk of respiratory tract infections.3 4 Pneumonia (a common lower respiratory tract infection) may be caused by bacterial, viral or fungal infections, and the discussion around the benefit of vitamin D supplementation to reduce the risk of viral pneumonias has intensified this year due to the coronavirus pandemic.5 6

However, observational studies only allow us to study associations and do not test for causation, as there may be confounding factors. For example, smoking may lead to lower vitamin D levels …
The AF9-Binding Domain of DOT1L Is Critical for Its Recruitment By MLL Fusion Proteins in Leukemia and Contributes to Its Functions in Normal Hematopoiesis
Authors: Sierrah Marie Grigsby, James Ropa, Justin Serio, Jennifer Chase, Chenxi Shen, Andrew G. Muntean, Ivan Maillard, Zaneta Nikolovska-Coleska
Journal: Blood (2017)