Machine learning techniques have been previously applied for classification of tumors based largely on morphological features of tumor cells recognized in H&E images. Here, we tested the possibility of using numeric data acquired from software-based quantification of certain marker proteins, i.e. key autophagy proteins (ATGs), obtained from immunohistochemical (IHC) images of renal cell carcinomas (RCC). Using IHC staining and automated image quantification with a tissue microarray (TMA) of RCC, we found ATG1, ATG5 and microtubule-associated proteins 1A/1B light chain 3B (LC3B) were significantly reduced, suggesting a reduction in the basal level of autophagy with RCC. Notably, the levels of the ATG proteins expressed did not correspond to the mRNA levels expressed in these tissues. Applying a supervised machine learning algorithm, the K-Nearest Neighbor (KNN), to our quantified numeric data revealed that LC3B provided a strong measure for discriminating clear cell RCC (ccRCC). ATG5 and sequestosome-1 (SQSTM1/p62) could be used for classification of chromophobe RCC (crRCC). The quantitation of particular combinations of ATG1, ATG16L1, ATG5, LC3B and p62, all of which measure the basal level of autophagy, were able to discriminate among normal tissue, crRCC and ccRCC, suggesting that the basal level of autophagy would be a potentially useful parameter for RCC discrimination. In addition to our observation that the basal level of autophagy is reduced in RCC, our workflow from quantitative IHC analysis to machine learning could be considered as a potential complementary tool for the classification of RCC subtypes and also for other types of tumors for which precision medicine requires a characterization.
Contributors:Peters, Daniel, Pettke, Thomas, John, Timm, Scambelluri, Marco
The Erro Tobbio olivine-antigorite serpentinites and associated dehydration veins represent hydrated oceanic mantle rocks that escaped complete dehydration and recycling into the mantle after subduction to ~ 550-600 °C and 2.0-2.5 GPa. These rocks thus offer valuable insights into the petrological evolution of a slice of hydrated oceanic mantle and the geochemical cycling down to intermediate subduction zone depths. Our study emphasises the role of brucite upon rock-buffered hydration and subduction dehydration employing bulk and in situ chemical data sets combined with petrology. Bulk rock data reveal a coherent mantle peridotite slice affected by variable melt depletion and refertilisation. Subsequent fluid-rock interaction stages proceeded isochemically with respect to SiO2, i.e., without significant SiO2 enrichment characteristic for hydrothermal ocean floor serpentinisation. Relicts of low-T mesh textures after olivine and preservation of precursor mineral and low-T hydration geochemical features indicate a lack of subsequent fluid and metamorphic overprinting, even on scales of tens of micrometres. Fluid-mobile element enrichments are modest with exceptions for B and W. Enrichment signatures of U/Cs << 1 and Rb/Cs of 4-26 are characteristic of shallow forearc hydration within or atop the slab by fluids derived from breakdown of clays or first dehydration of altered oceanic crust with a subordinate sedimentary pore fluid component. Overall, the geochemical and petrological changes of the Erro Tobbio peridotites during fluid-rock interactions were rockbuffered, in contrast to fluid-buffered hydration accompanied with significant SiO2 metasomatism at, e.g., mid ocean ridges. Silica-neutral rock-buffered serpentinisation resulted in prominent brucite formation upon olivine hydration. In absence of excess SiO2, subsequent serpentine transformation of chrysotile/lizardite to antigorite likely produced even more brucite. Rock-buffered fluid-rock interactions thus provide a mechanism for stabilising brucite in subduction zone serpentinites, presumably along hydration fronts and within deeper sections of the oceanic lithospheric mantle. Finally, brucite + antigorite dehydration produced up to 40 vol. % of metamorphic olivine and prominent olivine + Ti-clinohumite + magnetite vein networks at temperatures < 550-600 °C, prior to complete antigorite breakdown. Wall rocks released alkali elements, B, Cr, As, Sb, and Ba into the dehydration fluids, along with substantial Sr, REE and HFSE redistribution into vein minerals.
Contributors:Boettiger, David C, Salazar Vizcaya, Luisa Paola, Dore, Gregory J, Gray, Richard T, Law, Matthew G, Callander, Denton, Lea, Toby, Rauch, Andri, Matthews, Gail V
BACKGROUND HIV-positive gay and bisexual men (GBM) in Australia are well engaged in clinical care. We hypothesized that the World Health Organization's hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030 may be reachable ahead of time in this population. METHODS We predicted the effect of treatment and behavioral changes on HCV incidence among HIV-positive GBM up to 2025 using a HCV transmission model parameterized with Australian data. We assessed the impact of changes in behavior that may facilitate HCV transmission in the context of different rates of direct-acting antiviral (DAA) use. RESULTS HCV incidence in our model increased from 0.7 per 100 person years in 2000 to 2.5 per 100 person years in 2016, and had the same trajectory as previously reported clinical data. If the proportion of eligible (HCV RNA positive) patients using DAAs stays at 65%/year between 2016-2025, with high-risk sexual behavior and injecting drug use remaining at current levels, HCV incidence would drop to 0.4 per 100 person years (85% decline from 2016). In the same treatment scenario but with substantial increases in risk behavior, HCV incidence would drop to 0.6 per 100 person years (76% decline from 2016). If the proportion of eligible patients using DAAs dropped from 65%/year in 2016 to 20%/year in 2025 and risk behavior did not change, HCV incidence would drop to 0.7 per 100 person years (70% reduction from 2016). CONCLUSIONS Reaching the World Health Organization HCV elimination target by 2025 among HIV-positive GBM in Australia is achievable.
Contributors:Bonetti, Sara, Hirschi, Stephan, Bosshart, Patrick D.
l-lactate plays an important role as metabolite and signaling molecule in eukaryotes and bacteria. Monocarboxylate transporters (MCTs) of the SLC16 solute carrier family are responsible for the transport of l-lactate across eukaryotic and bacterial cell membranes. Here we report an efficient protocol for the expression and purification of an SLC16 family homologue in milligram amounts. The purified protein is stable and can thus be used for biochemical and structural studies as shown by successful crystallization.
Contributors:Hampel, B, Kusejko, K, Kouyos, R D, Böni, J, Flepp, M, Stöckle, M, Conen, A, Béguelin, C, Künzler-Heule, P, Nicca, D, Schmidt, A J, Nguyen, H, Delaloye, J, Rougemont, M, Bernasconi, E, Rauch, A, Günthard, H F, Braun, D L, Fehr, J
OBJECTIVES Chemsex refers to the use of sex-enhancing drugs among men who have sex with men (MSM) in combination with specific sexual and social behaviours. Longitudinal data on this development and the associated health risks are scarce. METHODS Data on all recreational drugs reported in the Swiss HIV Cohort Study (SHCS) from 2007 to 2017 were collected. Drug use was analysed longitudinally for all drug classes. In addition, potential associations between patient characteristics and the consumption of methamphetamine, γ-hydroxybutric acid/γ-butyrolactone (GHB/GBL), 3,4-methylenedioxymethamphetamine (MDMA/XTC), cocaine and amphetamine were analysed. RESULTS We analysed 166 167 follow-up entries for 12 527 SHCS participants, including 7101 free text field entries containing information about recreational drugs other than cannabis, cocaine and heroin. Overall, we observed a stable percentage (9.0%) of recreational drug use (excluding cannabis, amyl nitrite and prescription drugs). For MSM, however, there was an increase in overall drug use from 8.8% in 2007 to 13.8% in 2017, with particularly large increases for methamphetamine (from 0.2 to 2.4%; P
PURPOSE To conduct a meta-analysis to determine specific computed tomography (CT) patterns and clinical features that discriminate between nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). MATERIALS AND METHODS The PubMed/Medline and Embase databases were searched for studies describing the radiological patterns of UIP and NSIP in chest CT images. Only studies involving histologically confirmed diagnoses and a consensus diagnosis by an interstitial lung disease (ILD) board were included in this analysis. The radiological patterns and patient demographics were extracted from suitable articles. We used random-effects meta-analysis by DerSimonian & Laird and calculated pooled odds ratios for binary data and pooled mean differences for continuous data. RESULTS Of the 794 search results, 33 articles describing 2,318 patients met the inclusion criteria. Twelve of these studies included both NSIP (338 patients) and UIP (447 patients). NSIP-patients were significantly younger (NSIP: median age 54.8 years, UIP: 59.7 years; mean difference (MD) -4.4; p = 0.001; 95% CI: -6.97 to -1.77), less often male (NSIP: median 52.8%, UIP: 73.6%; pooled odds ratio (OR) 0.32; p<0.001; 95% CI: 0.17 to 0.60), and less often smokers (NSIP: median 55.1%, UIP: 73.9%; OR 0.42; p = 0.005; 95% CI: 0.23 to 0.77) than patients with UIP. The CT findings from patients with NSIP revealed significantly lower levels of the honeycombing pattern (NSIP: median 28.9%, UIP: 73.4%; OR 0.07; p<0.001; 95% CI: 0.02 to 0.30) with less peripheral predominance (NSIP: median 41.8%, UIP: 83.3%; OR 0.21; p<0.001; 95% CI: 0.11 to 0.38) and more subpleural sparing (NSIP: median 40.7%, UIP: 4.3%; OR 16.3; p = 0.005; 95% CI: 2.28 to 117). CONCLUSION Honeycombing with a peripheral predominance was significantly associated with a diagnosis of UIP. The NSIP pattern showed more subpleural sparing. The UIP pattern was predominantly observed in elderly males with a history of smoking, whereas NSIP occurred in a younger patient population.
INTRODUCTION The objective of this systematic review was to assess the available evidence in the literature for the effects of fixed orthodontic retainers on periodontal health. METHODS The following databases were searched up to August 31, 2019: Medline, EMBASE, the Cochrane Oral Health Group's Trials Register, CENTRAL, ClinicalTrials.gov, the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis database. Randomized controlled trials (RCTs), controlled clinical trials, cohort studies of prospective and retrospective design, and cross-sectional studies reporting on periodontal measurements of patients who received fixed retention after orthodontic treatment were eligible for inclusion. The quality of the included RCTs was assessed per the revised Cochrane risk of bias tool for randomized trials (RoB 2.0), whereas the risk of bias of the included cohort studies was assessed using the Risk Of Bias In Nonrandomized Studies of Interventions tool. A modified version of the Newcastle-Ottawa scale was used for cross-sectional studies. RESULTS Eleven RCTs, 4 prospective cohort studies, 1 retrospective cohort study, and 13 cross-sectional studies fulfilled the inclusion criteria. The quality of evidence was low for most of the included studies. In contrast to the general consensus, 2 RCTs, 1 prospective cohort study, and 2 cross-sectional studies reported poorer periodontal conditions in the presence of a fixed retainer. The results of the included studies comparing different types of fixed retainers were heterogeneous. CONCLUSIONS According to the currently available literature, orthodontic fixed retainers seem to be a retention strategy rather compatible with periodontal health, or at least not related to severe detrimental effects on the periodontium.