Prognostic Significance of KN Motif and Ankyrin Repeat Domains 1 (KANK1) in Invasive Breast Cancer

Background: KN Motif and Ankyrin Repeat Domains 1 (KANK1) plays an important role in cytoskeleton maintenance and contributes to the regulation of cell proliferation, adhesion and apoptosis. KANK1 is involved in progression of a variety of solid tumours, however, its role in invasive breast cancer (BC) remains unknown. This study aims to evaluate the clinicopathological and prognostic value of KANK1 expression in operable BC.Methods: KANK1 expression was assessed at the transcriptomic level using multiple BC cohorts; the Molecular Taxonomy of BC International Consortium cohort (METABRIC; n=1980), The Cancer Genome Atlas BC cohort (TCGA; n=949) and the publicly available BC transcriptomic data hosted by BC Gene-Expression Miner (bc- GenExMiner v4.0) and Kaplan Meier-plotter?. The Nottingham BC cohort (n=1500) prepared as tissue microarrays was used to assess KANK1 protein expression using immunohistochemistry (IHC). The association between clinicopathological variables and patient outcome was investigated.Results: In the METABRIC cohort, high expression of KANK1 mRNA was associated with characteristics of good prognosis including lower grade, absence of lymphovascular invasion and HER2 negativity (all;

Utility of Ankyrin 3 as a Prognostic Marker in Androgen-Receptor-Positive Breast Cancer Running Title: Prognostic Value of ANK3 in AR-Positive Breast Cancer

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Purpose: Androgen receptor (AR) and AR signaling pathways are thought to play a role in breast cancer (BC) and are potentially related to treatment responses and outcomes. Ankyrin 3 (ANK3) is associated with AR stability in cancer cells. In the present study, we investigated the clinicopathological utility of ANK3 expression with emphasis on AR and its associated signalling pathway at transcriptomic and proteomic phases. Patients and methods: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1980) and The Cancer Genome Atlas (TCGA) dataset (n = 1039) were used to assess the expression and significance of ANK3 mRNA and other AR signalling pathway-associated gene signature. Using immunohistochemistry, ANK3 protein expression was evaluated in large (n = 982) cohort of early-stage BC with long-term follow-up and compared with clinicopathological characteristics and its prognostic value in the whole cohort and the subgroups stratified by AR protein expression. Results: An AR-related gene signature was developed, comprising 20 genes, which included ANK3. This AR-related gene signature was significantly associated with AR mRNA expression, oestrogen receptor, human epidermal growth factor receptor 2 (HER2) status and the patients’ outcomes. In tumours with high AR protein expression (n = 614), high ANK3 protein expression was significantly associated with progesterone receptor positivity and it was independently associated with the good outcomes (p = 0.025). Conclusions: This study indicates that ANK3 is related to AR signalling pathway and is associated with BC prognosis

Visual histological assessment of morphological features reflects the underlying molecular profile in invasive breast cancer : a morpho‐molecular study

Background: Tumour genotype and phenotype are related and can predict outcome. In this study, we hypothesised that the visual assessment of breast cancer (BC) morphological features can provide valuable insight into underlying molecular profiles. Methods: The Cancer Genome Atlas (TCGA) BC cohort was used (n=743) and morphological features including Nottingham grade and its components and nucleolar prominence were assessed utilising whole slide images (WSIs). Two independent scores were assigned, and discordant cases were utilised to represent cases with intermediate morphological features. Differentially expressed genes (DEGs) were identified for each feature, compared among concordant/discordant cases and tested for specific pathways. Results: Concordant grading was observed in 467/743 (63%) of cases. Among concordant case groups, 8 common DEGs (UGT8, DDC, RGR, RLBP1, SPRR1B, CXorf49B, PSAPL1, and SPRR2G) were associated with overall tumour grade and its components. These genes are related mainly to cellular proliferation, differentiation and metabolism. The number of DEGs in cases with discordant grading was larger than those identified in concordant cases. The largest number of DEGs was observed in discordant grade 1:3 cases (n=1185). DEGs were identified for each discordant component. Some DEGs were uniquely associated with well‐defined specific morphological features, whereas expression/co‐expression of other genes was identified across multiple features and underlined intermediate morphological features. Conclusion: Morphological features are likely related to distinct underlying molecular profiles that drive both morphology and behaviour. This study provides further evidence to support the use of image‐based analysis of WSIs, including artificial intelligence algorithms, to predict tumour molecular profiles and outcome

Visual histological assessment of morphological features reflects the underlying molecular profile in invasive breast cancer: a morphomolecular study

© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd Aims: Tumour genotype and phenotype are related and can predict outcome. In this study, we hypothesised that the visual assessment of breast cancer (BC) morphological features can provide valuable insight into underlying molecular profiles. Methods and results: The Cancer Genome Atlas (TCGA) BC cohort was used (n=743) and morphological features, including Nottingham grade and its components and nucleolar prominence, were assessed utilising whole-slide images (WSIs). Two independent scores were assigned, and discordant cases were utilised to represent cases with intermediate morphological features. Differentially expressed genes (DEGs) were identified for each feature, compared among concordant/discordant cases and tested for specific pathways. Concordant grading was observed in 467 of 743 (63%) of cases. Among concordant case groups, eight common DEGs (UGT8, DDC, RGR, RLBP1, SPRR1B, CXorf49B, PSAPL1 and SPRR2G) were associated with overall tumour grade and its components. These genes are related mainly to cellular proliferation, differentiation and metabolism. The number of DEGs in cases with discordant grading was larger than those identified in concordant cases. The largest number of DEGs was observed in discordant grade 1:3 cases (n=1185). DEGs were identified for each discordant component. Some DEGs were uniquely associated with well-defined specific morphological features, whereas expression/co-expression of other genes was identified across multiple features and underlined intermediate morphological features. Conclusion: Morphological features are probably related to distinct underlying molecular profiles that drive both morphology and behaviour. This study provides further evidence to support the use of image-based analysis of WSIs, including artificial intelligence algorithms, to predict tumour molecular profiles and outcome

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

A influência das características do CFO nas decisões financeiras: caso do Egito

Tese de doutoramento em Ciências EmpresariaisEsta tese tem como objetivo estudar diferentes fatores que podem influenciar as decisões financeiras dentro da empresa, explorando as características comportamentais e não comportamentais dos CFOs egípcios, juntamente com seus traços de personalidade e nível de literacia financeira, além das características tradicionais de suas empresas. O objetivo é, portanto, identificar esses fatores e analisar a influência de tais fatores em três decisões financeiras inter-relacionadas, a saber: a estrutura de capital, o custo de capital e a decisão de investimento. Além disso, este estudo modera a participação do CFO no Conselho de Administração para testar se o comportamento do CFO muda em relação à tomada de decisões, quando este faz parte do Conselho. Um questionário é distribuído aos CFOs das empresas não financeiras listadas na EGX e a amostra final é de 96 empresas. Os dados primários são coletados para medir as características comportamentais e não comportamentais de gestão, além disso, os dados secundários são coletados para medir variáveis como as características da empresa, as decisões financeiras e a participação no Conselho de Administração do CFO. A análise inclui uma regressão hierárquica, análise de componentes principais e regressão stepwise. Os resultados da regressão hierárquica mostram que os modelos com preditores tradicionais e demográficos explicam melhor a variação nas três decisões financeiras do que o modelo que inclui fatores comportamentais. No entanto, a inclusão do moderador da participação do CFO no Conselho de Administração no modelo revelou um impacto na decisão de estrutura de capital e alguns fatores comportamentais revelam impacto significativo na decisão de custo de capital. A análise de componentes principais mostra a importância dos fatores da empresa apenas para explicar a variação nas decisões financeiras, enquanto a análise stepwise demonstra que as variáveis em estudo estão impactando as decisões financeiras, incluindo fatores comportamentais e não comportamentais. Assim, a evidência deste estudo revela a importância de incluir características comportamentais e outros nos modelos corporativos, ao invés de depender apenas dos determinantes tradicionais e isso sustenta a teoria de finanças comportamentais. Este estudo contribui para a literatura ao explorar características pouco estudadas em um contexto de finanças corporativas, além de focar nos CFOs de um mercado em desenvolvimento como o Egito.This thesis aims to study different factors that might be impacting financial decisions within the firm by exploring behavioral and non-behavioral characteristics of Egyptian CFOs along with their personality traits and financial literacy level, in addition to the traditional characteristics of the firms. The objective is therefore to identify these factors and to then analyze the influence of such factors on three interrelated financial decisions namely: the capital structure, the cost of capital and the investment decision. In addition, this study moderates for the CFO board membership to test if the CFO´s behavior changes towards taking decisions, when on board. A questionnaire is distributed to the CFOs of the non-financial firms listed on the EGX and the final sample accounts for 96 firms. Primary data is collected to measure managerial behavioral and non-behavioral characteristics, moreover, secondary data is gathered to measure variables such as the firm characteristics, the financial decisions, and the CFO board membership. The analysis includes a hierarchical regression, principal component analysis and stepwise regression. The results of a hierarchical regression show that the models with traditional and demographic predictors explain the variation in the three financial decisions better than the model that includes behavioral factors. However, including the moderator in the model revealed an impact on the capital structure decision and few behavioral factors report significant impact on the cost of capital decision. The principal component analysis reveals the importance of firm factors only in explaining the variation in financial decisions, while the stepwise analysis reveals that the variables under study are impacting the financial decisions, including behavioral and non-behavioral factors. Thus, the findings of this study reveal the importance of including behavioral characteristics and other determinants to the corporate models, rather than just depending on traditional determinants and this supports the behavioral finance theory. This study contributes to the literature by exploring characteristics that are understudied in a corporate finance context, in addition to focusing on the CFOs of a developing market such as Egypt

Role of Circ-ITCH Gene Polymorphisms and Its Expression in Breast Cancer Susceptibility and Prognosis

Introduction/Objective: Breast cancer (BC) is the first leading cause of cancer-related mortality in females worldwide. We have investigated the correlation between circ-ITCH gene polymorphisms, circ-ITCH expression, and their effect on β-catenin levels and BC development. Methods: Participants included 62 BC and 62 controls matched in terms of age. The circ-ITCH polymorphisms rs10485505 and rs4911154 were genotyped using whole blood samples. In addition, mRNA expression analysis of circ-ITCH was performed on BC tissues. The β-catenin levels in serum samples were measured using ELISA. Results: The qRT-PCR results demonstrated that circ-ITCH was significantly downregulated in BC compared to normal healthy tissues. The genotype distribution of rs10485505 and rs4911154 were significantly associated with BC risk. For rs10485505, genotype CT and TT were significantly associated with an increased BC risk. In contrast, there was a significant association between rs4911154, genotypes GA and AA, and an increased BC risk. Regarding the rs10485505 genotype, carriers of the T allele frequently have a poor prognosis compared to carriers of the CC genotype. Serum β-catenin in the BC patients’ group was significantly higher than in the control group. The relative expression levels of circ-ITCH were remarkably decreased in the BC samples of patients carrying the A allele at rs4911154 compared to patients with a GG genotype. Conversely, β-catenin protein levels were increased in patients carrying the A allele, while rs10485505 genotype carriers of the CT and TT genotypes showed downregulation of circ-ITCH expression fold compared to the CC genotype. Contrarily, β-catenin levels markedly increased in TT and CT genotypes compared with the CC genotype. Conclusions: Our research showed that the rs10485505 polymorphism (T allele) and the rs4911154 polymorphism (A allele) are associated with the risk and prognosis of BC. This finding may be due to the effect on the level of circ-ITCH mRNA expression in BC tissues as well as the level of β-catenin in BC patients