Microdamage generation by tapered and cylindrical mini-screw implants after pilot drilling

Objective:  To investigate the relationship between mini-screw implant (MSI) diameter (1.6 vs 2.0 mm) and shape (tapered vs cylindrical) and the amount of microdamage generated during insertion. Materials and Methods:  Thirty-six cylindrical and 36 tapered MSIs, 6 mm long, were used in this study. Half of each shape was 1.6 mm in diameter, while the other half was 2.0 mm. After pilot drilling, four and five MSIs were inserted, respectively, into fresh cadaveric maxillae and mandibles of dogs. Bone blocks containing the MSIs were sectioned and ground parallel to the MSI axis. Epifluorescent microscopy was used to measure overall cortical thickness, crack length, and crack number adjacent to the MSI. Crack density and total microdamage burden per surface length were calculated. Three-way analysis of variance (ANOVA) was used to test the effects of jaw, and MSI shape and diameter. Pairwise comparisons were made to control the overall significance level at 5%. Results:  The larger (2.0 vs 1.6 mm) cylindrical MSIs increased the numbers, lengths, and densities of microcracks, and the total microdamage burden. The same diameter cylindrical and tapered MSIs generated a similar number of cracks and crack lengths. More total microdamage burden was created by the 2.0-mm cylindrical than the 2.0-mm tapered MSIs. Although higher crack densities were produced by the insertion of 1.6-mm tapered MSIs, there was no difference in total microdamage burden induced by 1.6-mm tapered and 1.6-mm cylindrical MSIs. Conclusions:  Pilot drilling is effective in reducing microdamage during insertion of tapered MSIs. To prevent excessive microdamage, large diameter and cylindrical MSIs should be avoided

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5–10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2–46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0–7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation

Mechanisms of Response and Resistance to Combined Decitabine and Ipilimumab for Advanced Myeloid Disease

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329

Broad chromosomal domains of histone modification patterns in C. elegans

Chromatin immunoprecipitation identifies specific interactions between genomic DNA and proteins, advancing our understanding of gene-level and chromosome-level regulation. Based on chromatin immunoprecipitation experiments using validated antibodies, we define the genome-wide distributions of 19 histone modifications, one histone variant, and eight chromatin-associated proteins in Caenorhabditis elegans embryos and L3 larvae. Cluster analysis identified five groups of chromatin marks with shared features: Two groups correlate with gene repression, two with gene activation, and one with the X chromosome. The X chromosome displays numerous unique properties, including enrichment of monomethylated H4K20 and H3K27, which correlate with the different repressive mechanisms that operate in somatic tissues and germ cells, respectively. The data also revealed striking differences in chromatin composition between the autosomes and between chromosome arms and centers. Chromosomes I and III are globally enriched for marks of active genes, consistent with containing more highly expressed genes, compared to chromosomes II, IV, and especially V. Consistent with the absence of cytological heterochromatin and the holocentric nature of C. elegans chromosomes, markers of heterochromatin such as H3K9 methylation are not concentrated at a single region on each chromosome. Instead, H3K9 methylation is enriched on chromosome arms, coincident with zones of elevated meiotic recombination. Active genes in chromosome arms and centers have very similar histone mark distributions, suggesting that active domains in the arms are interspersed with heterochromatin-like structure. These data, which confirm and extend previous studies, allow for in-depth analysis of the organization and deployment of the C. elegans genome during development

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC

Return relationships among European equity sectors: a comparative analysis across selected sectors in small and large economies

This paper examines return interrelationships between numbers of equity sectors across several European markets. The markets comprise six Member States of the European Union (EU): namely, Belgium, Finland, France, Germany, Ireland and Italy. The five sectors include the consumer discretionary, consumer staples, financial, industrials and materials sectors. Generalised Autoregressive Conditional Heteroskedasticity in Mean (GARCH-M) models are used to consider the impact of returns in other European markets on the returns in each market across each sector. The results indicate that there are relatively few significant interrelationships between sectors in different markets, with most of these accounted for by the larger markets in France, Germany and Italy. The evidence also suggests the consumer discretionary, financial and materials sectors are relatively more interrelated than the consumer staples and industrials sectors. This has clear implications for portfolio diversification and asset pricing in the EU

Intersecting Art and Reconciliation

As art develops more traction and consideration in the peacebuilding field, there remains a gap in the theory, research and analysis of the synthesis of the two. Currently, there are many examples of art making for peacebuilding in recent post war societies. For Cambodians, 31 years after the genocide, peacebuilding and reconciliation remains unfinished. Even more absent is looking at the potential of art making for reconciliation and peacebuilding. The objective of this inquiry is to illustrate the possible relationship between art and reconciliation /healing through the personal opinions and experiences of three artists. As a Cambodian genocide survivor and refugee, this inquiry emerges from ten years of personal exploration of reconciliation practices. I include my personal voice and experiences throughout the empirical inquiry as a point of departure for discussion and to contextualize. Nevertheless, this paper explores reconciliation and art in a larger societal level. The main conclusions from this research are 1) Art can be an effective means to affirm one’s experiences 2) Art can serve as an important vehicle to witness and acknowledge other’s experiences 3) Contextualizing the art is important to decreasing the disconnection between the artist’s intent and audience’s reaction. Suggestions for further research are 1) Under what conditions can art most likely foster reconciliation/healing and reduce the discrepancy between the artist’s intention and audience’s interpretation 2) What preventive measures can reduce the risks of retraumatization while addressing painful past through art, and 3) under what conditions can being a witness be counterproductive to acknowledgement and validation of other’s experiences

An economic and neuroscientific comparison of strategic decision making

Economic decision- making is traditionally based on the assumptions of the predominant existence of Homo economicus (Latin: economic human being). The framework of this theory is known as the Rational Choice Theory (RC Theory). It includes assumptions such as utility maximization, opportunism, bounded rationality, complete information and rational facts. Thus, everything that can be measured is integrated into the decisions of homo economicus, and the decision is rationally made. But the decision model of the homo economicus is subject to criticism by many economists as this agent’s decisions are supposed to be based on comprehensiveness and quantitative factors (Camerer et al., 2005). What is missing in this decision model are soft factors such as motivations and emotions as well as context and interdependencies between the factors of decision- making. The need to improve the decisive power of the homo economicus is refl ected in the diff erent derivates coming from various fi elds, for example, Homo sapiens, Homo sociologicus, Homo ludens, Homo reciprocans, Homo politicus, Homo religiousus, Homo europaeus and many more. Still even these derivatives are criticized as not being satisfyingly adequate and comprehensive for decision models. One basic reason for this is that behavioral models are harder to develop than traditional economic models; building models of rational, unemotional agents is easier than building models of quasi- rational emotional humans. Neuroeconomics is a newly recognized fi eld of interest that aims to open the ‘black box’ of economic decision- making and might help to formulate new economic models of decision- making that are more realistic compared to traditional models, thus making them more effi cient (Fehr et al., 2005; Zak, 2004). In this chapter we focus on strategic decision- making and two of its important aspects and ask the following research question: can results of neuroscientifi c research help to better manage aspects of uncertainty and reward in strategic decision- making? In order to answer this question, we fi rst compare strategic decisionmaking in economics with strategic decision- making in neuroscience regarding uncertainty and reward. Second, we integrate these results and show how they accord (or do not) with each other. Lastly, we give implications on how strategic decisions can be made more effi cient by integrating results from neuroeconomics and give propositions for future research

An economic and neuroscientific comparison of strategic decision making

Economic decision- making is traditionally based on the assumptions of the predominant existence of Homo economicus (Latin: economic human being). The framework of this theory is known as the Rational Choice Theory (RC Theory). It includes assumptions such as utility maximization, opportunism, bounded rationality, complete information and rational facts. Thus, everything that can be measured is integrated into the decisions of homo economicus, and the decision is rationally made. But the decision model of the homo economicus is subject to criticism by many economists as this agent’s decisions are supposed to be based on comprehensiveness and quantitative factors (Camerer et al., 2005). What is missing in this decision model are soft factors such as motivations and emotions as well as context and interdependencies between the factors of decision- making. The need to improve the decisive power of the homo economicus is refl ected in the diff erent derivates coming from various fi elds, for example, Homo sapiens, Homo sociologicus, Homo ludens, Homo reciprocans, Homo politicus, Homo religiousus, Homo europaeus and many more. Still even these derivatives are criticized as not being satisfyingly adequate and comprehensive for decision models. One basic reason for this is that behavioral models are harder to develop than traditional economic models; building models of rational, unemotional agents is easier than building models of quasi- rational emotional humans. Neuroeconomics is a newly recognized fi eld of interest that aims to open the ‘black box’ of economic decision- making and might help to formulate new economic models of decision- making that are more realistic compared to traditional models, thus making them more effi cient (Fehr et al., 2005; Zak, 2004). In this chapter we focus on strategic decision- making and two of its important aspects and ask the following research question: can results of neuroscientifi c research help to better manage aspects of uncertainty and reward in strategic decision- making? In order to answer this question, we fi rst compare strategic decisionmaking in economics with strategic decision- making in neuroscience regarding uncertainty and reward. Second, we integrate these results and show how they accord (or do not) with each other. Lastly, we give implications on how strategic decisions can be made more effi cient by integrating results from neuroeconomics and give propositions for future research