tbuckley/cabot-search huggingface dataset:
Focal infection of periodontal origin
Authors: Jørgen Slots
Journal: Periodontology 2000 (2019)

Periodontology has evolved from a predominantly mechanical to a sophisticated infectious disease-based discipline. Research has paved the way for a greater understanding of the periodontal microbiome, improvement in periodontal diagnostics and therapies, and the recognition of periodontitis being associated with more than 50 systemic diseases. The etiopathology of progressive periodontitis includes active herpesviruses, specific bacterial pathogens, and proinflammatory immune responses. This article points to a role of periodontal herpesviruses in the development of systemic diseases and proposes treatment of severe periodontitis not only to avoid tooth loss, but also to reduce the risk for systemic diseases. An efficient, safe, and reliable anti-infective treatment of severe periodontitis is presented, which targets both herpesviruses and bacterial pathogens and which can be carried out in minimal time with minimal cost.
18F-FDG PET/CT Findings in Disseminated Genital Herpes in an Immunocompetent Patient With Anaplastic Lymphoma Kinase Rearranged Advanced Nonsmall Cell Lung Cancer
Authors: Danijela Dejanovic, Annemarie Gjelstrup Amtoft, Jens Benn Sørensen, Mette Pøhl
Journal: Clinical Nuclear Medicine (2019)

We present the PET/CT findings of extensive disseminated genital herpes simplex virus infection in a 29-year-old woman known with disseminated anaplastic lymphoma kinase-mutated nonsmall lung cancer. PET/CT revealed extensive involvement of the outer and inner genitalia, multiple lymph nodes extending from the porta hepatis to the groins, and involvement of the liver. Disseminated herpes simplex virus infection is well described in neonates and immunocompromised individuals but very rare in immunocompetent adults as was the case with this patient.
AXL Inhibition Extinguishes Primitive JAK2 Mutated Myeloproliferative Neoplasm Progenitor Cells
Authors: Stella Pearson, Rognvald Blance, Tim C.P. Somervaille, Anthony D. Whetton, Andrew Pierce
Journal: HemaSphere (2019)

Myeloproliferative neoplasms (MPN) are clonal stem cell associated disorders inclusive of chronic myeloid leukemia (CML), Polycythaemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET). They are characterized by increased production of myeloid cells with minimal effects on terminal differentiation but can undergo transformation to acute leukemias. PV is the most common chronic myeloproliferative neoplasm and in the majority of cases is characterized by a V617F point mutation in JAK2. This JAK2 activating mutation is also found in about half the patients with MF and ET. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. We have previously used advanced proteomic techniques to identify drug targets and thus develop novel treatment strategies to distinguish the leukemic clone in both CML and PV. Here, we build on our proteomic data sets to characterize a new target, the receptor tyrosine kinase AXL. AXL is overexpressed in acute myeloid leukemia and importantly small molecule inhibitors have been developed which are currently in clinical trial hence offer the opportunity to repurpose this drug for the treatment of MPNs. We demonstrate that AXL is upregulated and activated in JAK2 associated MPNs. Further we show that inhibition of AXL preferentially kills early hemopoietic stem cells from PV patients and as such represents a promising therapeutic approach for JAK2 driven MPNs.
Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema
Authors: Jayashree Sahni, Sunil S. Patel, Pravin U. Dugel, Arshad M. Khanani, Chirag D. Jhaveri, Charles C. Wykoff, Vrinda S. Hershberger, Meike Pauly-Evers, Shamil Sadikhov, Piotr Szczesny, Dietmar Schwab, Everson Nogoceke, Aaron Osborne, Robert Weikert, Sascha Fauser
Journal: Ophthalmology (2019)

PurposeThe phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME).DesignThe BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States.ParticipantsThe trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 μm or more.MethodsAnti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability.Main Outcome MeasuresThe prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment.ResultsThe trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals.ConclusionsThe BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.
Visual tools to assess the plausibility of algorithm-identified infectious disease clusters: an application to mumps data from the Netherlands dating from January 2009 to June 2016
Authors: Loes Soetens, Jantien A. Backer, Susan Hahné, Rob van Binnendijk, Sigrid Gouma, Jacco Wallinga
Journal: Eurosurveillance (2019)

IntroductionWith growing amounts of data available, identification of clusters of persons linked to each other by transmission of an infectious disease increasingly relies on automated algorithms. We propose cluster finding to be a two-step process: first, possible transmission clusters are identified using a cluster algorithm, second, the plausibility that the identified clusters represent genuine transmission clusters is evaluated.AimTo introduce visual tools to assess automatically identified clusters.MethodsWe developed tools to visualise: (i) clusters found in dimensions of time, geographical location and genetic data; (ii) nested sub-clusters within identified clusters; (iii) intra-cluster pairwise dissimilarities per dimension; (iv) intra-cluster correlation between dimensions. We applied our tools to notified mumps cases in the Netherlands with available disease onset date (January 2009 - June 2016), geographical information (location of residence), and pathogen sequence data (n = 112). We compared identified clusters to clusters reported by the Netherlands Early Warning Committee (NEWC).ResultsWe identified five mumps clusters. Three clusters were considered plausible. One was questionable because, in phylogenetic analysis, genetic sequences related to it segregated in two groups. One was implausible with no smaller nested clusters, high intra-cluster dissimilarities on all dimensions, and low intra-cluster correlation between dimensions. The NEWC reports concurred with our findings: the plausible/questionable clusters corresponded to reported outbreaks; the implausible cluster did not.ConclusionOur tools for assessing automatically identified clusters allow outbreak investigators to rapidly spot plausible transmission clusters for mumps and other human-to-human transmissible diseases. This fast information processing potentially reduces workload.
An Interactive Resource to Probe Genetic Diversity and Estimated Ancestry in Cancer Cell Lines
Authors: Julie Dutil, Zhihua Chen, Alvaro N. Monteiro, Jamie K. Teer, Steven A. Eschrich
Journal: Cancer Research (2019)

Abstract Recent work points to a lack of diversity in genomics studies from genome-wide association studies to somatic (tumor) genome analyses. Yet, population-specific genetic variation has been shown to contribute to health disparities in cancer risk and outcomes. Immortalized cancer cell lines are widely used in cancer research, from mechanistic studies to drug screening. Larger collections of cancer cell lines better represent the genomic heterogeneity found in primary tumors. Yet, the genetic ancestral origin of cancer cell lines is rarely acknowledged and often unknown. Using genome-wide genotyping data from 1,393 cancer cell lines from the Catalogue of Somatic Mutations in Cancer (COSMIC) and Cancer Cell Line Encyclopedia (CCLE), we estimated the genetic ancestral origin for each cell line. Our data indicate that cancer cell line collections are not representative of the diverse ancestry and admixture characterizing human populations. We discuss the implications of genetic ancestry and diversity of cellular models for cancer research and present an interactive tool, Estimated Cell Line Ancestry (ECLA), where ancestry can be visualized with reference populations of the 1000 Genomes Project. Cancer researchers can use this resource to identify cell line models for their studies by taking ancestral origins into consideration.
HMGB1-Induced p62 Overexpression Promotes Snail-Mediated Epithelial-Mesenchymal Transition in Glioblastoma Cells via the Degradation of GSK-3β
Authors: Hong Li, Junjie Li, Guozhong Zhang, Qian Da, Lei Chen, Shishi Yu, Qiang Zhou, Zhijian Weng, Zong Xin, Linyong Shi, Liyi Ma, Annie Huang, Songtao Qi, Yuntao Lu
Journal: Theranostics (2019)

Rationale: Glioblastoma (GBM) is the most common and aggressive brain tumor, characterized by its propensity to invade the surrounding brain parenchyma. The effect of extracellular high-mobility group box 1 (HMGB1) protein on glioblastoma (GBM) progression is still controversial. p62 is overexpressed in glioma cells, and has been associated with the malignant features and poor prognosis of GBM patients. Hence, this study aimed to clarify the role of p62 in HMGB1-induced epithelial-mesenchymal transition (EMT) of GBM both in vitro and in vivo. Methods: Immunoblotting, immunofluorescence and qRT-PCR were performed to evaluate EMT progression in both human GBM cell line and primary GBM cells. Transwell and wound healing assays were used to assess the invasion and migration of GBM cells. shRNA technique was used to investigate the role of p62 in HMGB1-induced EMT both in vitro and in vivo orthotopic tumor model. Co-immunoprecipitation assay was used to reveal the interaction between p62 and GSK-3β (glycogen synthase kinase 3 beta). Immunohistochemistry was performed to detect the expression levels of proteins in human GBM tissues. Results: In this study, GBM cells treated with recombinant human HMGB1 (rhHMGB1) underwent spontaneous EMT through GSK-3β/Snail signaling pathway. In addition, our study revealed that rhHMGB1-induced EMT of GBM cells was accompanied by p62 overexpression, which was mediated by the activation of TLR4-p38-Nrf2 signaling pathway. Moreover, the results demonstrated that p62 knockdown impaired rhHMGB1-induced EMT both in vitro and in vivo. Subsequent mechanistic investigations showed that p62 served as a shuttling factor for the interaction of GSK-3β with proteasome, and ultimately activated GSK-3β/Snail signaling pathway by augmenting the degradation of GSK-3β. Furthermore, immunohistochemistry analysis revealed a significant inverse correlation between p62 and GSK-3β, and a combination of the both might serve as a more powerful predictor of poor survival in GBM patients. Conclusions: This study suggests that p62 is an effector for HMGB1-induced EMT, and may represent a novel therapeutic target in GBM.
MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma
Authors: Edward Kim, Beth E. Zucconi, Muzhou Wu, Sarah E. Nocco, David J. Meyers, Jean S. McGee, Samantha Venkatesh, Daniel L. Cohen, Estela C. Gonzalez, Byungwoo Ryu, Philip A. Cole, Rhoda M. Alani
Journal: Cancer Research (2019)

Abstract Histone modifications, largely regulated by histone acetyltransferases (HAT) and histone deacetylases, have been recognized as major regulatory mechanisms governing human diseases, including cancer. Despite significant effort and recent advances, the mechanism by which the HAT and transcriptional coactivator p300 mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. Direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions was coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed forkhead box M1 (FOXM1) as a key effector of the p300–MITF axis driving cell growth that is selectively activated in human melanomas. Targeted chemical inhibition of p300 acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. Collectively, these data confirm the critical role of the p300–MITF–FOXM1 axis in melanoma and support p300 as a promising novel epigenetic therapeutic target in human melanoma. Significance: These results show that MITF is a major downstream target of p300 in human melanoma whose expression is predictive of melanoma response to small-molecule inhibition of p300 HAT activity.
Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis
Authors: Liyuan Fan, Qiang Cao, Jia Liu, Junpeng Zhang, Baosheng Li
Journal: Molecular Cancer (2019)

Esophageal squamous cell cancer (ESCC) is a high incidence and mortality disease worldwide. However, specificity and sensitivity of its diagnostic and prognostic biomarkers are still unsatisfactory. Recently, circular RNAs (circRNAs) as biomarkers have been studied extensively while the expression profile and clinical significance of circRNAs in ESCC have rarely been studied. We performed circular RNA microarray in 3 pairs of ESCC frozen tumor and non-tumor tissues to identify ESCC-related circRNAs and found 1045 up-regulated and 1032 down-regulated circRNAs among which 6 circRNAs (hsa_circ_0062459, hsa_circ_0076535, hsa_circ_0072215, hsa_circ_0042261, hsa_circ_0001946, and hsa_circ_0043603) displayed consistency with microarray results by qRT-PCR. 3 circRNAs (hsa_circ_0062459, hsa_circ_0001946, and hsa_circ_0043603) were also detected in plasma and 2 of them except hsa_circ_0062459 could be used as diagnostic biomarkers and found in exosome of cell-conditioned culture conditioned media. The AUC, sensitivity and specificity of hsa_circ_0001946 were 0.894, 92, 80%, of hsa_circ_0043603 were 0.836, 64, 92% while a signature combining them were 0.928, 84 and 98%. Hsa_circ_0001946 was confirmed to predict the recurrence, overall survival (OS) and disease-free survival (DFS) in frozen and FFPE tissues, while its overexpression decreased cell proliferation, migration, and invasion.
Research on implants and osseointegration
Authors: María B. Guglielmotti, Daniel G. Olmedo, Rómulo L. Cabrini
Journal: Periodontology 2000 (2019)

Abstract Osseointegration was originally defined as a direct structural and functional connection between ordered living bone and the surface of a load‐carrying implant. It is now said that an implant is regarded as osseointegrated when there is no progressive relative movement between the implant and the bone with which it is in direct contact. Although the term osseointegration was initially used with reference to titanium metallic implants, the concept is currently applied to all biomaterials that have the ability to osseointegrate. Biomaterials are closely related to the mechanism of osseointegration; these materials are designed to be implanted or incorporated into the living system with the aims to substitute for, or regenerate, tissues and tissue functions. Objective evaluation of the properties of the different biomaterials and of the factors that influence bone repair in general, and at the bone tissue–implant interface, is essential to the clinical success of an implant. The Biomaterials Laboratory of the Oral Pathology Department of the School of Dentistry at the University of Buenos Aires is devoted to the study and research of the properties and biological effects of biomaterials for dental implants and bone substitutes. This paper summarizes the research work resulting from over 25 years’ experience in this field. It includes studies conducted at our laboratory on the local and systemic factors affecting the peri‐implant bone healing process, using experimental models developed by our research team. The results of our research on corrosion, focusing on dental implants, as well as our experience in the evaluation of failed dental implants and bone biopsies obtained following maxillary sinus floor augmentation with bone substitutes, are also reported. Research on biomaterials and their interaction with the biological system is a continuing challenge in biomedicine, which aims to achieve optimal biocompatibility and thus contribute to patient health.
Prevention of Dysbiosis Complications with Autologous Fecal Microbiota Transplantation (auto-FMT) in Acute Myeloid Leukemia (AML) Patients Undergoing Intensive Treatment (ODYSSEE study): First Results of a Prospective Multicenter Trial
Authors: Mohamad Mohty, Florent Malard, Evelyne D'Incan, Xavier Thomas, Christian Recher, Anne-Sophie Michallet, Pierre Peterlin, Anne Vekhoff, Norbert Vey, Emilie Plantamura, Philippe Lehert, Joel Doré, Ollivier Legrand
Journal: Blood (2017)
Private health screening: NHS must not be left to “pick up the pieces,” say LMCs
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Private screening providers should be mandated to provide follow-up appointments with patients to discuss abnormal results and should not offload responsibility to the NHS, local medical committees (LMCs) have argued.

The annual conference of LMCs, held in Belfast on 19 March, carried a motion arguing that GPs should be empowered to invoice private screening providers directly for their time if, as NHS GPs, they provide follow-up appointments to patients who had undergone privately funded scans.

The conference also voted on a separate stem of the motion saying it believed that health …
Evidence for Faster X Chromosome Evolution in Spiders
Authors: Jesper Bechsgaard, Mads Fristrup Schou, Bram Vanthournout, Frederik Hendrickx, Bjarne Knudsen, Virginia Settepani, Mikkel Heide Schierup, Trine Bilde
Journal: Molecular Biology and Evolution (2019)

In species with chromosomal sex determination, X chromosomes are predicted to evolve faster than autosomes because of positive selection on recessive alleles or weak purifying selection. We investigated X chromosome evolution in Stegodyphus spiders that differ in mating system, sex ratio, and population dynamics. We assigned scaffolds to X chromosomes and autosomes using a novel method based on flow cytometry of sperm cells and reduced representation sequencing. We estimated coding substitution patterns (dN/dS) in a subsocial outcrossing species (S. africanus) and its social inbreeding and female-biased sister species (S. mimosarum), and found evidence for faster-X evolution in both species. X chromosome-to-autosome diversity (piX/piA) ratios were estimated in multiple populations. The average piX/piA estimates of S. africanus (0.57 [95% CI: 0.55-0.60]) was lower than the neutral expectation of 0.75, consistent with more hitchhiking events on X-linked loci and/or a lower X chromosome mutation rate, and we provide evidence in support of both. The social species S. mimosarum has a significantly higher piX/piA ratio (0.72 [95% CI: 0.65-0.79]) in agreement with its female-biased sex ratio. Stegodyphus mimosarum also have different piX/piA estimates among populations, which we interpret as evidence for recurrent founder events. Simulations show that recurrent founder events are expected to decrease the piX/piA estimates in S. mimosarum, thus underestimating the true effect of female-biased sex ratios. Finally, we found lower synonymous divergence on X chromosomes in both species, and the male-to-female substitution ratio to be higher than 1, indicating a higher mutation rate in males.
HSR19-092: Adjuvant Radiotherapy Is Associated with Improved Overall Survival for Resected Alveolar Ridge Squamous Cell Carcinoma With Adverse Pathologic Features
Authors: Corbin D. Jacobs, Daniel J. Rocke, Russel R. Kahmke, Hannah Williamson, Gita Suneja, Yvonne M. Mowery
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Alveolar ridge (AR) squamous cell carcinoma (SCC) is poorly represented on prospective clinical trials. Adjuvant management is extrapolated from more common head and neck SCC, including those with a stronger influence from the human papillomavirus. The objective of this analysis is to determine the association between adjuvant radiotherapy (RT) and overall survival (OS) for resected ARSCC based on adverse pathologic features. Methods: Adult subjects in the National Cancer Database diagnosed with invasive nonmetastatic ARSCC between 2010–2014 were identified. Exclusion criteria included prior malignancy, no/unknown surgery, unknown receipt of RT, RT dose &lt;50 Gy or &gt;80 Gy, RT fractions &gt;68, T1–2N0 disease without identifiable NCCN-defined risk factors (positive margin, lymphovascular invasion, pT3–4, N2–3, extranodal extension, or level IV/V nodal metastasis), and unknown/missing NCCN risk factor data. Log-rank test stratified by RT and Cox regression analyses with respect to OS were performed. Results: 1,450 subjects met inclusion criteria, of which 825 (57%) received RT. Median follow-up was 27 months. Adjuvant RT was associated with improved OS (72% vs 65% at 2 years, log-rank P =.004). Stratified by number of NCCN-defined risk factors, adjuvant RT was associated with improved OS for subjects with 2 (74% vs 58% at 2 years, log-rank P &lt;.001) and ≥3 (54% vs 29% at 2 years, log-rank P &lt;.001) risk factors. Adjuvant RT was significantly associated with improved OS on univariate (HR, 0.80; 95% CI, 0.68–0.94; P =.008) and multivariate (HR, 0.72; 95% CI, 0.60–0.87; P =.001) analyses, the latter adjusted for age, comorbidity score, and adverse pathologic features. Each NCCN-defined risk factor, high tumor grade, primary tumor ≥3 cm, and ≥5% nodal positivity (number of pathologic nodes positive among nodes resected) were significantly associated with worse OS on univariate and multivariate analyses. Conclusions: Adjuvant RT for resected ARSCC with adverse pathologic features is associated with significantly improved OS. Subjects with a primary tumor ≥3 cm, high tumor grade, and ≥5% nodal positivity in addition to the NCCN-defined risk factors should be considered for adjuvant RT.