AXL-Initiated Paracrine Activation of pSTAT3 Enhances Mesenchymal and Vasculogenic Supportive Features of Tumor-Associated Macrophages

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting M2-like phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer

Submicron Structures Technology and Research

Contains reports on fourteen research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908)National Science Foundation (Grant ECS82-05701)Semiconductor Research Corporation (Grant 83-01-033)U.S. Department of Energy (Contract DE-ACO2-82-ER-13019)Lawrence Livermore National Laboratory (Contract 2069209)National Aeronautics and Space Administration (Contract NAS5-27591)Defense Advanced Research Projects Agency (Contract N00014-79-C-0908)National Science Foundation (Grant ECS80-17705)National Aeronautics and Space Administration (Contract NGL22-009-638

Submicron Structures Technology and Research

Contains reports on ten research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)Joint Services Electronics Program (Contract DAAL03-86-K-0002)National Science Foundation (Grant ECS82-05701)National Science Foundation (Grant ECS85-06565)Lawrence Livermore Laboratory (Subcontract 2069209)National Science Foundation (Grant ECS85-03443)U.S. Air Force - Office of Scientific Research (Grant AFOSR-85-0154)National Aeronautics and Space Administration (Grant NGL22-009-638)National Science Foundation (through KMS Fusion, Inc.)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908

Submicron Structures Technology and Research

Contains reports on thirteen research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908)National Science Foundation (Contract ECS82-05701)U.S. Department of Energy (Contract DE-ACO2-82-ER-13019)Lawrence Livermore Laboratory (Contract 2069209)National Aeronautics and Space Administration (Contract NGL-22-009-638)U.S. Navy - Office of Naval Research (Contract N00014-84-K-0073)National Science Foundation (Grant ECS80-17705)National Science Foundation (Grant ENG79-09980

The cadherin–catenin complex in nasopharyngeal carcinoma

Abnormal Wnt signaling and impaired cell–cell adhesion due to abnormal E-cadherin and β-catenin function have been implicated in many cancers, but have not been fully explored in nasopharyngeal carcinoma. The aim of this study was to analyze β-Catenin cellular location and E-cadherin expression levels in nasopharyngeal carcinoma. E-cadherin expression levels were also correlated with clinical data and underlying pathology. β-Catenin and E-cadherin expression were examined in 18 nasopharyngeal carcinoma and 7 non-tumoral inflammatory pharynx tissues using immunohistochemical methods. Patient clinical data were collected, and histological evaluation was performed by hematoxylin/eosin staining. β-catenin was detected in membrane and cytoplasm in all cases of nasopharyngeal carcinoma, regardless of histological type; in non-tumoral tissues, however, β-catenin was observed only in the membrane. As for E-cadherin expression levels, strong staining was observed in most non-tumoral tissues, but staining was only moderate in nasopharyngeal carcinoma tissues. E-cadherin expression was associated with β-catenin localization, study group, metastatic disease, and patient outcomes. Reduced levels of E-cadherin protein observed in nasopharyngeal carinoma may play an important role in invasion and metastasis. Cytoplasmic β-catenin in nasopharyngeal carcinoma may impair cell–cell adhesion, promoting invasive behavior and a metastatic tumor phenotype

Countdown to 2030 : tracking progress towards universal coverage for reproductive, maternal, newborn, and child health

Building upon the successes of Countdown to 2015, Countdown to 2030 aims to support the monitoring and measurement of women's, children's, and adolescents' health in the 81 countries that account for 95% of maternal and 90% of all child deaths worldwide. To achieve the Sustainable Development Goals by 2030, the rate of decline in prevalence of maternal and child mortality, stillbirths, and stunting among children younger than 5 years of age needs to accelerate considerably compared with progress since 2000. Such accelerations are only possible with a rapid scale-up of effective interventions to all population groups within countries (particularly in countries with the highest mortality and in those affected by conflict), supported by improvements in underlying socioeconomic conditions, including women's empowerment. Three main conclusions emerge from our analysis of intervention coverage, equity, and drivers of reproductive, maternal, newborn, and child health (RMNCH) in the 81 Countdown countries. First, even though strong progress was made in the coverage of many essential RMNCH interventions during the past decade, many countries are still a long way from universal coverage for most essential interventions. Furthermore, a growing body of evidence suggests that available services in many countries are of poor quality, limiting the potential effect on RMNCH outcomes. Second, within-country inequalities in intervention coverage are reducing in most countries (and are now almost non-existent in a few countries), but the pace is too slow. Third, health-sector (eg, weak country health systems) and non-health-sector drivers (eg, conflict settings) are major impediments to delivering high-quality services to all populations. Although more data for RMNCH interventions are available now, major data gaps still preclude the use of evidence to drive decision making and accountability. Countdown to 2030 is investing in improvements in measurement in several areas, such as quality of care and effective coverage, nutrition programmes, adolescent health, early childhood development, and evidence for conflict settings, and is prioritising its regional networks to enhance local analytic capacity and evidence for RMNCH

EFL Learners’ Online Reading Strategy Use and Text Comprehension: An Exploratory Study

[[abstract]]The bulk of L2 reading research has shown that prospective readers use various reading strategies to facilitate comprehension, but relatively few studies have centered on online reading strategy use and its effects on the reading comprehension of students with different language proficiencies. This study aimed to investigate EFL learners’ online reading strategies, to study the effects of strategy use on comprehension, and to evaluate a web-based reading program, English Reading Online, which was constructed to fulfill the first two purposes of this study. The design of this online reading program echoed reading strategy patterns found in L2 reading literature and the action of clicking on a certain strategy function button online was traced to reflect a reader’s particular strategy use. There were 15 strategy buttons: Global strategy design provided students with previews, keywords, and outlines of the reading texts as well as chances to make predictions. Problem-solving strategy mechanisms included online summary services, reading-rate training, text-to-speech software, and semantic mapping tools. Support strategy functions were provided by online dictionaries, online grammar resources, an online translation mechanism, highlighting tools, and individualized electronic notebooks. Socio-affective strategies were displayed by online chatrooms, discussion boards, email services, and music boxes. Thirty Applied English majors, divided into a High group and a Low group based on their proficiency levels, were asked to read a total of four authentic online texts of two difficulty levels. They also completed a post-task survey, wrote written recalls, and attended interview sessions after reading. Each participant’s navigation path in doing these four reading tasks was tracked by the computer system to collect their pre-defined strategies; each navigation path was also videotaped by a screen-capturing software to collect newly emerging strategy patterns. Strategy use data was analyzed by the Chi-square test to examine if strategy use was influenced by language proficiency, the text topic, and the text difficulty levels. Written recalls were scored according to two categories: main ideas and details. The relationship between students’ strategy use and comprehension was computed using multiple regression. The post-task survey on program feedback was analyzed by descriptive statistics. Finally, qualitative investigations of four case studies gathered from videotaping and interviews were used to supplement the quantitative data mentioned above. The results showed that due to learners’ concern of convenience and immediacy, Support strategies made up the overwhelming proportion of strategy use and Problem-solving strategies were used the least. Other strategies emerging from qualitative investigation—including Navigating strategies, Information gathering strategies, Interface changing strategies, and Usability problem reporting strategies—assisted readers in navigating online texts smoothly, finding relevant information to build up background knowledge, establishing a personal environment to facilitate online reading, and making suggestions for user-friendly web design. Additionally, four factors that influenced online reading strategy use were language proficiency, the text topic and difficulty level, computer skills, and background knowledge. In relating strategy use with comprehension, the use of Support strategies dominated the strategy use and contributed to most of the comprehension gains, but an exclusive dependence on Support strategies did not successfully predict the increase in scores on main ideas and details when the students were reading more challenging texts. It was the use of Global strategies that significantly contributed to better comprehension. The effects of Global strategies were most evident among the Low group, who often confined themselves to the use of Support strategies and Socio-affective strategies in reading. Finally, students provided positive feedback on this program in terms of the design of the strategy tools, interface design, and learning effects. They also welcomed the possibility of including online reading in the existing curriculum. Findings of this study bear important pedagogical implications. First, strategy instruction needs to be integrated into reading classes. Online reading strategies about how to find and synthesize information and how to increase social interaction need to be addressed. Second, Global strategies, which aided low achievers’ comprehension of difficult texts, should be encouraged. Third, more personalized features and more choices for text selection should be included in the future program design.

The von Hippel–Lindau Tumor Suppressor Protein Is Destabilized by Src: Implications for Tumor Angiogenesis and Progression

The von Hippel–Lindau tumor suppressor protein (VHL), when mutated and inactivated, has been associated with renal and CNS cancer development. VHL normally plays an important role in targeting for degradation of the HIF-1α (hypoxia inducible factor-1α) transcription factor, a primary positive regulator of vascular endothelial growth factor (VEGF) production. In this report we demonstrate that VHL destabilization can be induced by Src kinase and may be involved in other cancers, including breast cancer. We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome-mediated degradation of VHL. The Src-induced degradation of VHL protein leads to increased HIF-1α levels and transcriptional activity and increased VEGF production. In this manner, Src regulation of VHL protein stability may play an important role in promoting VEGF expression, tumor angiogenesis, and cancer progression

TCT CONNECT-184 Impact of Sex and Timing of Impella Support in Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock

Background: Randomized controlled trials studying Impella (Abiomed, Danvers, Massachusetts) usage in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) are limited. Retrospective data from the catheter-based Ventricular Assist Device Registry has demonstrated that pre-percutaneous coronary intervention (PCI) implantation of the device in AMICS patients is associated with a significant mortality benefit (odds ratio [OR]: 0.49, p = 0.04). Whether this effect varies by sex remains understudied. Methods: In-hospital data was collected from all AMICS patients prospectively enrolled in the RECOVER III post market approval observational study of the Impella device from 2017 to 2019. Univariate logistic regression models were used to identify the effects of baseline and procedural characteristics on in-hospital mortality. Identified statistically significant predictors and sex were included in the final multivariate logistic regression model. Results: Data were available for 82 females (41 with pre-PCI Impella vs. 41 with post-PCI Impella) and 266 males (167 pre-PCI vs. 99 post-PCI). Females had a survival benefit with Impella implantation pre-PCI compared to post-PCI (59% vs. 34%, p = 0.03); males did not (56% vs. 50%, p = 0.40). Survival for patients on 0, 1 to 2, or \u3e2 inotropes pre-Impella was 71%, 43%, and 19% for females (p = 0.001) and 64%, 54%, and 31% for males (p = 0.004), respectively. The multivariate regression found that the following were significant independent predictors of in-hospital mortality: pre-PCI Impella implantation (OR: 0.516, p = 0.03), previously diagnosed renal insufficiency (OR: 2.482, p = 0.02), heart rate (OR: 1.013, p = 0.03), and systolic blood pressure (OR: 1.013, p = 0.03). However, sex was not an independent predictor (p = 0.59) and there was not a significant interaction between sex and pre-PCI Impella usage (p = 0.13). Conclusion: Early implantation of Impella provides a significant survival benefit, particularly to females. Sex discrepancies appear to be the result of differing baseline and hemodynamic characteristics at presentation. Taking these factors into consideration may help identify patients most likely to benefit from Impella support