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Machine-aided geological interpretation provides an opportunity for rapid and data-driven decision-making. In disciplines such as geostatistics, the integration of machine learning has the potential to improve the reliability of mineral resources and ore reserve estimates. In this study, inspired by existing geostatistical approaches that use radial basis functions to delineate domain boundaries, we reformulate the problem into a machine learning task for automated domain boundary delineation to partition the orebody. We use an actual dataset from an operating mine (Driefontein gold mine, Witwatersrand Basin in South Africa) to showcase our new method. Using various machine learning algorithms, domain boundaries were created. We show that based on a combination of in-discipline requirements and heuristic reasoning, some algorithms/models may be more desirable than others, beyond merely cross-validation performance metrics. In particular, the support vector machine algorithm yielded simple (low boundary complexity) but geologically realistic and feasible domain boundaries. In addition to the empirical results, the support vector machine algorithm is also functionally the most resemblant of current approaches that makes use of radial basis functions. The delineated domains were subsequently used to demonstrate the effectiveness of domain delineation by comparing domain-based estimation versus non-domain-based estimation using an identical automated workflow. Analysis of estimation results indicate that domain-based estimation is more likely to result in better metal reconciliation as compared with non-domained based estimation. Through the adoption of the machine learning framework, we realized several benefits including: uncertainty quantification; domain boundary complexity tuning; automation; dynamic updates of models using new data; and simple integration with existing machine learning-based workflows. Funder: Department of Science and Innovation (DSI)-National Research Foundation (NRF) Thuthuka Grant (UID: 121973); DSI-NRF CIMERA; Wits Mining Institute (WMI)

Although the need to consider acoustics in the built environment is well-accepted, an understanding of 'what' constitutes 'good acoustics' is not. The authors present posteriori-reviews of historical events and of empirical evidence-to develop an understanding of the current landscape of Standards, Guidelines, and Codes. More specifically, special attention is devoted to the development of speech privacy metrics, as well as that of auditory and non-auditory effects of noise and sound on health. With a refreshed understanding of theory, a priori-i.e., an acoustical framework for design and/or performance verification with a special interest in speech privacy-is renewed and its impacts on the ongoing development of Standards, Guidelines and Codes is discussed.

ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.

Deep-water fold-and-thrust belt (DWFTB) systems are gravity-driven collapse structures often found in passive margin settings and are comprised of a linked up-dip extensional domain, central transitional/translational domain, and down-dip compressional domain. Many Late Cretaceous DWFTB systems occur along the SW African passive margin with multiple, over-pressurized, seaward-dipping shale detachment surfaces accommodating gravitational slip. In this study we use 3D reflection seismic data to constrain the strato-structural evolution of the translational and compressional domains of a Late Cretaceous DWFTB system and the overlying Cenozoic deposits in the Orange Basin, South Africa. The stratigraphy and structure of the Late Cretaceous DWFTB system is shown to have controlled fundamental sedimentary processes and the stability of the evolving margin. The compressional domain exhibits large-scale landward-dipping DWFTBs with thrust faults detaching the main Turonian shale detachment surface at depth and terminating at the early Campanian surface. A major ∼ 7 km wide seafloor slump scar reflecting margin instability occurs directly above a syncline of the same width from the buried DWFTB system's compressional domain. The translational domain is imaged as a complex region displaying overprinted features of both extensional and compressional tectonics with the downslope translation of sediment comprising listric normal and then thrust and oblique-slip faults distally. Thrust sheets are segmented along strike by extensive oblique-slip faults which extend from the translational domain into the down-dip compressional domain. Smaller, localized fold-and-thrust belts are found directly below the kilometre-scale DWFTB system in the down-dip compressional domain detaching a lower, Albian shale detachment surface which corresponds to an older gravitational collapse. The upward propagation of normal and oblique-slip faults with progressive sedimentation is hindered by the Oligocene or Miocene stratigraphic markers corresponding to mass erosional processes in the Cenozoic. A large (∼ 2.3 km wide), roughly slope-perpendicular Oligocene submarine canyon formed by turbidity currents is attributed to a major sea-level fall at ∼ 30 Ma. Oceanographic circulation is shown to have held a significant control on the deposition of mid-Miocene to present-day sedimentary sequences. Between 1200 to 1500 m water depths along the upper continental slope well-preserved extensive slope-parallel, sinusoidal channel-like features occur on the Miocene stratigraphic marker. The channels are confined within a ∼ 14 km wide zone at the interface of the upper northward-flowing Antarctic Intermediate Water (AAIW) and deeper southward-flowing North Atlantic Deep Water (NADW) currents. The erosive interaction of these oppositely flowing bottom currents combined with the effects of the Benguela Upwelling System (BUS), all of which formed or intensified at ∼ 11 Ma, are responsible for the creation and preservation of the extensive slope-parallel channels. This study shows the difference in structural styles of the translational and compressional domains of a Late Cretaceous DWFTB system and the processes responsible for mass-scale erosion in the Cenozoic.

Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. Case A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: Genetic analysis After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. Conclusion To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients.Using a panel of gastric adenocarcinoma cell lines (human: MKN 45, SNU-5; murine: NCC-S1M), we demonstrate that prior incubation of GC cells with MA results in a significant ( 1.7-fold) increase in the number of cells capable of adhering to human peritoneal mesothelial cells (HPMC) (p 0.05). We then corroborate these findings using an ex vivo PM model and show that MA also significantly enhances the ability of GC cells to adhere to strips of human peritoneum (p 0.05). Using a multiplex ELISA, we identify MIF and VEGF as consistently elevated across MA samples from GC patients (p 0.05). We demonstrate that agents that block the effects of MIF or VEGF abrogate the ability of MA to stimulate the adhesion of GC cells to adhere to human peritoneum and promote both ex vivo and in vivo metastases.Agents targeting MIF or VEGF may be relevant to the treatment or prevention of PM in GC patients.

The Assen Fe ore deposit is a banded iron formation (BIF)-hosted orebody, occurring in the Penge Formation of the Transvaal Supergroup, located 50 km northwest of Pretoria in South Africa. Most BIF-hosted Fe ore deposits have experienced post-depositional alteration including supergene enrichment of Fe and low-grade regional metamorphism. Unlike most of the known BIF-hosted Fe ore deposits, high-grade hematite (> 60% Fe) in the Assen Fe ore deposit is located along the lithological contacts with dolerite intrusions. Due to the variability in alteration levels, identifying the lithologies present within the various parts of the Assen Fe ore deposit, specifically within the weathering zone, is often challenging. To address this challenge, machine learning was applied to enable the automatic classification of rock types identified within the Assen Fe ore mine and to predict the in-situ Fe grade. This classification is based on geochemical analyses, as well as petrography and geological mapping. A total of 21 diamond core drill cores were sampled at 1 m intervals, covering all the lithofacies present at Assen mine. These were analyzed for major elements and oxides by means of X-ray fluorescence spectrometry. Numerous machine learning algorithms were trained, tested and cross-validated for automated lithofacies classification and prediction of in-situ Fe grade, namely (a) k-nearest neighbors, (b) elastic-net, (c) support vector machines (SVMs), (d) adaptive boosting, (e) random forest, (f) logistic regression, (g) Naïve Bayes, (h) artificial neural network (ANN) and (i) Gaussian process algorithms. Random forest, SVM and ANN classifiers yield high classification accuracy scores during model training, testing and cross-validation. For in-situ Fe grade prediction, the same algorithms also consistently yielded the best results. The predictability of in-situ Fe grade on a per-lithology basis, combined with the fact that CaO and SiO2were the strongest predictors of Fe concentration, support the hypothesis that the process that led to Fe enrichment in the Assen Fe ore deposit is dominated by supergene processes. Moreover, we show that predictive modeling can be used to demonstrate that in this case, the main differentiator between the predictability of Fe concentration between different lithofacies lies in the strength of multivariate elemental associations between Fe and other oxides. Localized high-grade Fe ore along with lithological contacts with dolerite intrusion is indicative of intra-basinal fluid circulation from an already Fe-enriched hematite. These findings have a wider implication on lithofacies classification in weathered rocks and mobility of economic valuable elements such as Fe.

Despite availability of effective antiretroviral therapy (ART), many HIV patients still have a detectable viral load (VL). Predictive factors of detectable VL are not well documented. This study was done at two large multidisciplinary HIV outpatient clinics at the Centre hospitalier de l'Université de Montréal (CHUM) and the McGill University Health Centre (MUHC). This is a retrospective case-control study of patients treated between 2016 and 2018. Cases had a VL ≥50 copies/mL in 2018. Controls had an undetectable VL from 2016 to 2018. Matching was based on gender and year of HIV diagnosis. Primary objective was to identify predictive factors of detectable VL. Secondary objectives included to identify predictive factors of virologic failure, low persistent viremia, and viral blip. A forward stepwise model selection by the Akaike Information Criterion of the conditional logistic regression was used to identify predictive factors. Two hundred cases were identified and matched with 200 controls. The cohort was mostly male (68.0%) with a median age of 54 years (21-83 years). Among cases, viral blip was the most common type of detectable VL (43.0%). The strong predictive factors for a detectable VL were adherence to ART and seeking health care services. Asylum seekers were less at risk of detectable VL. Adherence to ART was the only strong predictive factor for virologic failure. Three main predictive factors of detectable VL were identified in two ambulatory clinic hospitals in Montreal. Ascertaining these factors will allow for identification of patients more at risk of detectable VL.

Many features indicative of natural gas and oil leakage are delineated in the deep-water Orange Basin offshore South Africa using 3D reflection seismic data. These features are influenced by the translational and compressional domains of an underlying Upper Cretaceous deep-water fold-and-thrust belt (DWFTB) system detaching Turonian shales. The origin of hydrocarbons is postulated to be from both: (a) thermogenic sources stemming from the speculative Turonian and proven Aptian source rocks at depth; and (b) biogenic sources from organic-rich sediments in the Cenozoic attributed to the Benguela Current upwelling system. The late Campanian surface has a dense population of > 950 pockmarks classified into three groups based on their variable shapes and diameter: giant (> 1500 m), crater (~ 700–900 m) and simple (

People living with Alzheimer’s disease and related dementias (PwADRD) experience declined memory, language, problem-solving and other cognitive functions caused by the disease. They face major challenges in self-care and assistive living, including equitable access to assistive technology and care, the right to choose where to live, protection of privacy and security, and the preserving their personhood and social connections. Fast advances in telecommunication, Internet of Things (IoT) technology, and artificial intelligence make it possible to devise an assistive technology ecosystem to address these challenges. This chapter presents an assistive technology ecosystem that enables autonomy, independence and interdependence among PwADRD, their circle of care and society. Participatory action research and design methodology underpin this ecosystem’s design and implementation. We also discuss funding policy and health system changes needed to facilitate the affordability and sustainability of such an ecosystem and, ultimately, to empower PwADRD and their caregivers to have a meaningful quality of life.

Background In 2020, the Health Resources and Services Administration’s HIV/AIDS Bureau funded an initiative to promote implementation of rapid antiretroviral therapy initiation in 14 HIV treatment settings across the U.S. The goal of this initiative is to accelerate uptake of this evidence-based strategy and provide an implementation blueprint for other HIV care settings to reduce the time from HIV diagnosis to entry into care, for re-engagement in care for those out of care, initiation of treatment, and viral suppression. As part of the effort, an evaluation and technical assistance provider (ETAP) was funded to study implementation of the model in the 14 implementation sites. Method The ETAP has used implementation science methods framed by the Dynamic Capabilities Model integrated with the Conceptual Model of Implementation Research to develop a Hybrid Type II, multi-site mixed-methods evaluation, described in this paper. The results of the evaluation will describe strategies associated with uptake, implementation outcomes, and HIV-related health outcomes for patients. Discussion This approach will allow us to understand in detail the processes that sites to implement and integrate rapid initiation of antiretroviral therapy as standard of care as a means of achieving equity in HIV care.

In some primaries African American race/ethnicity predisposes to higher stage and worse survival. We tested for differences in cancer specific mortality (CSM) and other-cause mortality (OCM) in patients with adrenocortical carcinoma (ACC) according to African American vs. Caucasian race/ethnicity. We hypothesized that African Americans present with higher tumor stage and grade, do not receive the same treatment and benefit of lower survival than Caucasians. Within Surveillance, Epidemiology, and End Results database, we identified 1016 ACC patients: 123 (12.1%) African Americans vs. 893 (87.9%) Caucasians. Propensity score matching (age, sex, marital status, grade, T, N and M stages, treatment type), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Compared to Caucasians, African Americans were more frequently unmarried (56.9% vs. 35.5%, p < 0.001). No clinically meaningful or statistically significant differences were observed for age, grade, T, N, and M stages, as well as for treatment type (all p > 0.05). After propensity score matching (1:4), 123 African Americans and 492 Caucasians remained and were included in CRR analysis. In multivariable CRR models, CSM and OCM rates were not different between the two race/ethnicities (hazard ratio: 0.84, p = 0.3). In African Americans five-year CSM rates were 31.2% and 75.3% in respectively European Network for the Study of Adrenal Tumors (ENSAT) stages I-II and III-IV vs. 32.9% and 75.4% in Caucasians. Overall five-year OCM rates were 11.0% vs. 10.1% in respectively African Americans and Caucasians. Unlike other primaries, in ACC African American race/ethnicity is not associated with higher disease stage at initial diagnosis or worse survival.

The late Holocene Bonneville landslide, a 15.5 km2 rockslide-debris avalanche, descended 1000 m from the north side of the Columbia River Gorge and dammed the Columbia River where it bisects the Cascade Range of Oregon and Washington, USA. The landslide, inundation, and overtopping created persistent geomorphic, ecologic, and cultural consequences to the river corridor, reported by Indigenous narratives and explorer accounts, as well as scientists and engineers. From new dendrochronology and radiocarbon dating of three trees killed by the landslide, one entrained and buried by the landslide and two killed by rising water in the impounded Columbia River upstream of the blockage, we find (1) the two drowned trees and the buried tree died the same year, and (2) the age of tree death, and hence the landslide (determined by combined results of nine radiocarbon analyses of samples from the three trees), falls within AD 1421–1455 (3σ confidence interval). This result provides temporal context for the tremendous physical, ecological, and cultural effects of the landslide, as well as possible triggering mechanisms. The age precludes the last Cascadia Subduction Zone earthquake of AD 1700 as a landslide trigger, but not earlier subduction zone or local crustal earthquakes.

Biomineralized structures in animals can undergo remodeling, altering the original construction of the structure. Remodeling such structures could enhance plastic inducible defenses and mitigate some hypothesized limits to adaptive phenotypic plasticity. Predator-induced shell thickening in marine snails, already a model for studies of adaptive plasticity, provides a potentially good system to study the role of hardened structure remodeling for enhancing the adaptive value of phenotypically plastic responses. However, studies on predator-induced shell plasticity tend to examine only recent shell growth, and plastic remodeling of older regions of the shell has been previously unexplored. Therefore, we examined the potential for shell remodeling by the marine snail Nucella lamellosa in response to its major predator, the shell-breaking predatory crab Cancer productus. For snails exposed to chemical cues from C. productus, shell thickness and microstructure in the newest parts of the shell differed from controls. In response to chemical cues from C. productus, snails also remodeled older parts of the shell, producing overall thicker shells toward the apex compared to controls. This predator-induced shell remodeling may provide a new model for examining inducible defenses and the role of reversibility and epi-phenotype limits to adaptive phenotypic plasticity.

Introduction While paramacular retinal atrophy (PRA) is known to be found in 48% of eyes of adults and 42% of eyes of children with homozygous SCD (SS-SCD), the aim of this study is to assess the association between PRA and red blood cell (RBC) deformability, hematological markers and brain imaging abnormalities in SS-SCD. Methods This study is a subset of DREAM2, a prospective observational study performed between August 2015 and August 2016. Children (5–17 years) with SS-SCD and no history of large vessel vasculopathy, were included. Ophthalmological characteristics including visual acuity, fundus examination, OCT of central and temporal retina (with several retinal thickness measurements) were explored in relation with RBC deformability (ektacytometry), hematological and biochemical (hemolysis parameters), and neurological (cerebral oxygenation estimated by Near Infrared Spectroscopy, brain magnetic resonance imaging) investigations. Results 17 children (5 boys; mean age: 13 years) with complete ophthalmological investigations were included in the analysis; 8 exhibited PRA. RBC deformability was found to be significantly lower in children with PRA for measurements made at 1.69 Pa (0.16 a.u ± 0.02 vs 0.21 a.u ± 0.03, p = 0.02) and above, as well as cerebral oxygenation (59.25% ± 9.9 vs 71.53% ± 4.9, p = 0.02). A significant positive correlation was found between temporal retinal thickness and hemoglobin level (ρ = 0.65, p = 0.007), hematocrit (ρ = 0.53, p = 0.04) and RBC deformability at 3 Pa (ρ = 0.75, p = 0.005) and above. Conclusions These results suggest that PRA could be an early marker of systemic severity and cerebral oxygenation in SCD. Whether it could help predicting cerebral vasculopathy requires further investigations.

Objective: Students’ enrollment intensity during their first academic semester and year are highly influential in their success and decisions to persist in community college. Limited research, however, has focused on understanding how students navigate the decision-making process of determining their credit load or how institutional support services, such as academic advising, influence these decisions. Our objective was to advance knowledge on this topic by examining the implementation of a 15 to Finish campaign to promote full-time enrollment at a large, racially/ethnically diverse community college system in Texas. Methods: We interviewed 24 students and eight academic advisors to identify key factors that influence recommendations for, and selection of, course load. The collection and analysis of the data employed the critical qualitative inquiry method, and data were analyzed through low- and high-level coding processes using reconstructive analysis. Results: The factors influencing student decision-making fall into three major areas: (1) academic performance, (2) financial considerations and other costs, and (3) advising experiences, with academic performance framing students’ discussion. Academic advisors agreed with the importance of full-time enrollment for students’ success and recognized the importance of reducing time-to-degree, but believed many students were not academically prepared or had too many commitments to enroll in 15 credits each semester. Conclusion: Consequently, a “one-more-course” approach may be more attractive for both students and advisors. We outline recommendations that better enable community college students to make optimal credit load decisions, which in turn can increase their academic momentum and chances for degree completion.

Purpose: The preplanned exploratory analysis of the BERIL-1 trial presented here aimed to identify biomarkers of response to the combination of buparlisib and paclitaxel.Patients and Methods: BERIL-1 was a multicenter, randomized, double-blind, placebo-controlled phase II study. Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on/after one previous platinum-based chemotherapy regimen in the recurrent or metastatic setting were treated with either buparlisib plus paclitaxel or placebo plus paclitaxel. Archival tumor tissue and ctDNA samples were analyzed for molecular alterations and immune infiltration using next-generation sequencing or immunohistochemistry.Results: Biomarker analyses were performed in randomized patients (n = 158) with available biomarker data. The most frequently (>5%) mutated genes were TP53, FAT1, TET2, KMT2D, PIK3CA, NOTCH1, NFE2L2, NOTCH2, CCND1, and CDKN2A. Patients with SCCHN tumors (from various primary sites) having HPV-negative status (HR = 0.51), TP53 alterations (HR = 0.55) or low mutational load (HR = 0.57) derived overall survival (OS) benefit with the combination of buparlisib and paclitaxel. OS benefit with this combination was also increased in patients with presence of intratumoral TILs ≥10% (HR = 0.51), stromal TILs ≥15% (HR = 0.53), intratumoral CD8-positive cells ≥5% (HR = 0.45), stromal CD8-positive cells ≥10% (HR = 0.47), or CD8-positive cells in invasive margins >25% (HR = 0.37). A trend for improved progression-free survival with the combination of buparlisib and paclitaxel was also observed in these patients.Conclusions: The BERIL-1 biomarker analyses showed that patients with TP53 alterations, HPV-negative status, low mutational load, or high infiltration of TILs or CD8-positive cells derived survival benefit with the combination of buparlisib and paclitaxel. Clin Cancer Res; 24(11); 2505–16. ©2018 AACR.

Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53–SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence. Mass spectrometry confirmed SOCS1 Y80 phosphorylation in cells, and a new mAb was generated to detect its presence in tissues by IHC. A tyrosine kinase library screen identified the SRC family as Y80-SOCS1 kinases. SRC family kinase inhibitors potentiated the SOCS1–p53 pathway and reinforced SOCS1-induced senescence. Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. Collectively, these results reveal a mechanism that inactivates the SOCS1–p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful.Significance:These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.

Supplementary methods and results Supplementary Table 1: Mutational profiles of patients with HPV-positive vs HPV-negative tumors Supplementary Figure 1: Interaction between immune markers and other biomarkers

Legends for 8 supplementary figures

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Disabling RB bypasses PML-induced senescence in normal human fibroblasts (S1); Cyclin-dependent kinase inhibitors p21 and p16INK4A cooperate with PML to inhibit cancer cell proliferation (S2); CDK inhibitors enhance PML-mediated growth arrest and senescence in tumor cell lines (S3); Gene Set Enrichment Analysis (GSEA) showing homology to our gene expression profiling (S4); Gene Set Enrichment Analysis (GSEA) showing homology to our gene expression profiling (S5); Palbociclib or 5-Aza-dC sensitise cells to PML-induced irreversible growth arrest (S6); palbociclib decreased DNMT1 levels in a dose dependent manner (S7).

Supplementary Table 1. List of antibodies and conditions. Supplementary Table 2. List of qPCR primers. Supplementary Table 3. Oligonucleotide sequences

Supplementary Fig 1. Identification of hepatic cells that express TNFR2. Supplementary Fig 2. Loss of TNFR2 expression does not affect the induction of CAM expression on LSEC. Supplementary Fig 3. Additional characterization of MDSC isolated from wild type and TNFR2-/- mice. Supplementary Fig 4. The recruitment of Treg cells to the liver is not reduced in TNFR1-/- mice. Supplementary Fig 5. TNFR2 expression is not required for tumor or TNF-α - induced upregulation of hepatic CXCR2 chemokines. Supplementary Fig 6. Loss of TNFR2 does not affect the expression of CXCR1 and CXCR2 on MDSC. Supplementary Fig 7. Reduced TNFR2 expression in the livers of mice treated with TNFR2 ASO. Supplementary Fig 8. HLA-DR is widely expressed in the normal liver.

Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models. Complete senescence correlated with an increase in autophagy, repression of E2F target genes, and an gene expression signature of blocked DNA methylation. Accordingly, treatment of tumor cells with inhibitors of DNA methylation reversed resistance to PML-induced senescence. Further, CDK inhibition with palbociclib promoted autophagy-dependent degradation of the DNA methyltransferase DNMT1. Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization. Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells. Cancer Res; 76(11); 3252–64. ©2016 AACR.

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities.Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden.

Ricœur (1992, 172) defined ethics as “aiming at a good life lived with and for others in just institutions.” Donal Ryan’s novel From a Low and Quiet Sea (2018) examines what this “good life” means while exploring human relationships in the contemporary Irish context, as it portrays characters who are in turn hospitable, hosted, hostile and victims of hostility. The novel focuses on human ambivalence and invites its readers to confront it along with the ethical questions thereby raised. It also points to the changing narratives of migration in Ireland in recent years, highlighting how matters of inclusiveness and exclusion are interlaced with stories and storytelling. This article thus examines the narratives of hostility and hospitality at work in From a Low and Quiet Sea and their correlation with both ethical and aesthetic preoccupations. It briefly reviews the character relationships on display, before focusing on Irish national identity and its narrative. Since, in the novel narrative choices shape the ambivalence of the dialectics of hospitality and hostility, it finally asks whether the text is a hostile or a hospitable one, examining how storytelling modes and intentions—which turn out to be at the core of the novel—are fundamentally linked to inclusiveness. Ricœur (1992, 172) définit l’éthique comme « la visée d’une vie bonne, avec et pour autrui, dans des institutions justes ». Le roman de Donal Ryan From a Low and Quiet Sea (2018) explore ce que signifie cette « bonne vie » en examinant les rapports humains dans le contexte irlandais contemporain ; il met en effet en scène des personnages qui, tour à tour, font preuve d’hospitalité, bénéficient de celle d’autrui, doivent faire face à l’hostilité, et en sont victimes. Le roman se penche sur l’ambivalence des êtres humains ; il invite ses lecteurs à s’y confronter, ainsi qu’aux questions éthiques qu’elle soulève. Il met également en évidence la manière dont les récits de la migration ont évolué en Irlande au cours de ces dernières décennies, montrant ainsi que les thématiques d’inclusion et d’exclusion sont liées aux histoires et aux récits. Cet article étudie donc les récits d’hostilité et d’hospitalité à l’œuvre dans From a Low and Quiet Sea, leurs modes de narration et leur corrélation avec des préoccupations à la fois éthiques et esthétiques. Il passe brièvement en revue les relations entre les personnages, avant d’examiner l’identité nationale irlandaise telle qu’elle est ici racontée. Enfin, et puisque ce sont les choix narratifs qui modèlent l’ambivalence de la dialectique hospitalité/hostilité dans le roman, la dernière partie de l’article se demande si, pour son lectorat, le texte est caractérisé par l’hostilité ou l’hospitalité, en examinant le lien intrinsèque entre d’une part les intentions et modes narratifs, qui s’avèrent être au cœur du roman, et de l’autre la question de l’inclusion.