bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyal2 Expression in Tumor-Associated Myeloid Cells Mediates Cancer-Related Inflammation in Bladder Cancer
Authors: Dominguez-Gutierrez Paul R. , Kwenda Elizabeth P. , Donelan William , O'Malley Padraic , Crispen Paul L. , Kusmartsev Sergei 
Published: November 2020

Abstract

The increased presence of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in tumor tissue has been extensively reported. However, their role in the regulation of hyaluronan (HA) metabolism in the tumor microenvironment has not been established. Here we describe a novel function of tumor-associated myeloid cells related to the enhanced breakdown of extracellular HA in human bladder cancer tissue, leading to the accumulation of small HA fragments with molecular weight (MW) &lt;20 kDa. Increased fragmentation of extracellular HA and accumulation of low molecular weight HA (LMW-HA) in tumor tissue was associated with elevated production of multiple inflammatory cytokines, chemokines, and angiogenic factors. The fragmentation of HA by myeloid cells was mediated by the membrane-bound enzyme hyaluronidase 2 (Hyal2). Increased numbers of Hyal2+CD11b+ myeloid cells were detected in the tumor tissue as well as in the peripheral blood of patients with bladder cancer. Coexpression of CD33 suggested that these cells belong to monocytic myeloid-derived suppressor cells. The HA-degrading function of Hyal2-expressing MDSCs could be enhanced by exposure to tumor-conditioned medium, and IL1β was identified as one of the factors involved in the stimulation of Hyal2 activity. CD44-mediated signaling played an important role in the regulation of HA-degrading activity of Hyal2-expressing myeloid cells, as the engagement of CD44 receptor with specific mAb triggered translocation of Hyal2 enzyme to the cellular surface and stimulated secretion of IL1β. Taken together, this work identifies Hyal2-expressing tumor-associated myeloid cells as key players in the accumulation of LMW-HA in the tumor microenvironment and cancer-related inflammation and angiogenesis.

Significance:
This study identifies Hyal2-expressing tumor-associated myeloid cells of monocyte–macrophage lineage as contributors to hyaluronan degradation in bladder cancer tissue, leading to accumulation of inflammatory and proangiogenic low molecular weight hyaluronan fragments.
Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability
Authors: Chuang Chen-Hua , Dorsch Madeleine , Dujardin Philip , Silas Sukrit , Ueffing Kristina , Hölken Johanna M. , Yang Dian , Winslow Monte M. , Grüner Barbara M. 
Published: November 2020

Abstract

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited.

Significance:
This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.
Axl and Mertk Receptors Cooperate to Promote Breast Cancer Progression by Combined Oncogenic Signaling and Evasion of Host Antitumor Immunity
Authors: Davra Viralkumar , Kumar Sushil , Geng Ke , Calianese David , Mehta Dhriti , Gadiyar Varsha , Kasikara Canan , Lahey Kevin C. , Chang Yun-juan , Wichroski Michael , Gao Chan , De Lorenzo Mariana S. , Kotenko Sergei V. , Bergsbaken Tessa , Mishra Pankaj K. , Gause William C. , Quigley Michael , Spires Thomas E. , Birge Raymond B. 
Published: November 2020

AbstractDespite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis because of their capacities to sustain an immunosuppressive environment. Here, we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment (TME), we observed distinct functions of TAM as oncogenic kinases, as well as inhibitory immune receptors. Depletion of Axl suppressed cell intrinsic oncogenic properties, decreased tumor growth, reduced the incidence of lung metastasis and increased overall survival of mice when injected into mammary fat pad of syngeneic mice, and demonstrated synergy when combined with anti-PD-1 therapy. Blockade of Mertk function on macrophages decreased efferocytosis, altered the cytokine milieu, and resulted in suppressed macrophage gene expression patterns. Mertk-knockout mice or treatment with anti-Mertk–neutralizing mAb also altered the cellular immune profile, resulting in a more inflamed tumor environment with enhanced T-cell infiltration into tumors and T-cell–mediated cytotoxicity. The antitumor activity from Mertk inhibition was abrogated by depletion of cytotoxic CD8α T cells by using anti-CD8α mAb or by transplantation of tumor cells into B6.CB17-Prkdc SCID mice. Our data indicate that targeting Axl expressed on tumor cells and Mertk in the TME is predicted to have a combinatorial benefit to enhance current immunotherapies and that Axl and Mertk have distinct functional activities that impair host antitumor response.Significance:This study demonstrates how TAM receptors act both as oncogenic tyrosine kinases and as receptors that mediate immune evasion in cancer progression.
Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma
Authors: Iorgulescu J. Bryan , Gokhale Prafulla C. , Speranza Maria C. , Eschle Benjamin K. , Poitras Michael J. , Wilkens Margaret K. , Soroko Kara M. , Chhoeu Chhayheng , Knott Aine , Gao Yan , Lim-Fat Mary Jane , Baker Gregory J. , Bonal Dennis M. , Nguyen Quang-Dé , Grant Gareth R. L. , Ligon Keith L. , Sorger Peter K. , Chiocca E. Antonio , Anderson Ana C. , Kirschmeier Paul T. , Sharpe Arlene H. , Freeman Gordon J. , Reardon David A. 
Published: November 2020

Abstract

Purpose:
Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.

Experimental Design:
We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.

Results:
Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti–PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti–PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; &lt;2 mg HR, 2.16; 95% confidence interval (CI), 1.30–3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23–3.16; P = 0.005].

Conclusions:
Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.
Rethinking “Economic Fundamentals” in an Era of Global Physical Shocks: Insights from the Philippines Experience with COVID-19*
Authors: Monsod Toby Melissa C. , Gochoco-Bautista Maria Socorro 
Published: November 2020

AbstractHaving “strong macroeconomic fundamentals,” as the Philippines supposedly did pre-COVID-19, matters much less (if at all), in and of itself, to economic outcomes in the context of a physical shock. Using a model for 21 countries including ASEAN+3, developing East Asia and South Asia, as well as Australia and New Zealand to explain the difference in actual 2019 and forecasted 2020 GDP growth, we find that, ceteris paribus, stronger national capacities to detect and respond to emerging outbreaks (in particular, laboratory capacity) are associated with better short term economic outcomes. For the Philippines, up to 3.6 percentage points in lost GDP growth forecasted in 2020 could have been saved. Our results suggest that a dearth in health system capacity should be prioritized over and above any other type of spending, including traditional stimulus (e.g., large-scale infrastructure) spending. Our results also underscore the need to rethink what is necessary for the stability and resilience of an economy—what are the “economic fundamentals”—in an era of global physical shocks, including those brought about by climate hazards. Given physical shocks, efficient and prepared government institutions matter. A macro economy is not resilient if these are not.
COVID-19 in Korea: Success Based on Past Failure*
Authors: Lim Byeongho , Kyoungseo Hong Emma , Mou Jinjin , Cheong Inkyo 
Published: November 2020

Abstract
This paper analyzes how the Republic of Korea (Korea) halted the massive transmission of COVID-19 in just two months. The quarantine was achieved successfully without any need for a national lockdown because, simply, Korean citizens actively followed quarantine guidelines. During the 2015 Middle East Respiratory Syndrome (MERS) outbreak, the country recognized the importance of an early response in the form of a systematic approach and adopted the necessary procedures. Comparing the spread of COVID-19 among different countries, Korea demonstrated several distinct characteristics. First, the duration of the coronavirus crisis was relatively short, and Korea was able to flatten the coronavirus curve in a brief period. Second, Korea blocked expanded transmission of the virus without implementing a national lockdown. Third, the coronavirus pandemic did not lead to economic panic. Korea, which had developed an institutional response to infectious diseases prior to COVID-19, used a strategy of balancing quarantine measures with economic policies. The paper summarizes the specific measures Korea implemented to overcome COVID-19, and discusses the sustainability of the economy after overcoming the virus.
Financial Spillover in Emerging Asia: A Tale of  Three Crises
Authors: Azis Iwan J. , Virananda I. G. Sthitaprajna , Estiko Fauzi I. 
Published: November 2020

AbstractBy measuring time-varying financial spillovers of five asset classes, we analyze the propagation of shocks originating in the United States and Japan into countries of emerging Asia (EA). We compare the scale and nature of spillovers during the 2008–09 global financial crisis (GFC), the 2013 “taper tantrum” (TT), and the ongoing COVID-19 pandemic (C-19). Based on the direct and indirect spillovers, the intensity of the spillover effect was largest during C-19 due to its global and multidimensional nature, and the United States was a net transmitter of spillovers particularly in bonds and equity markets. TT was an important episode for EA as it marked the beginning of the region's financial volatility and increased spillovers especially in bonds market. The impulse responses reveal that most spillovers were transmitted rapidly, in a matter of days. In times of recession whereby financial stability is in danger of being affected by spillovers, a concrete financial cooperation remains absent in EA although formal institutions designed to deal with the contagion have been put in place.
Mahāyāna Sūtras in Khotan
Authors: Chen Ruixuan , Loukota Diego 
Published: November 2020

Abstract
The present paper continues a serial article dealing with the identifications of sources for Chapter 6 of the Book of Zambasta, a Mahāyāna Buddhist poem in Khotanese. The first installment of this serial article was published in 2018 by the same authors in this journal. In this installment, we report on new identifications made in the interim, and offer a detailed analysis of four additional identified quotations, underlining their significance in historical and cross-cultural perspective.
Scepticism and Self-Detachment
Authors: Perin Casey 
Published: November 2020

Abstract
This paper takes up two questions. Is there a sense in which the Sceptic as described by Sextus Empiricus is detached from himself? Does this self-detachment by itself make the Sceptic’s way of life undesirable? I sketch two conceptions of self-detachment, and then conclude that the Sceptic faces a dilemma: either he is more detached from himself than the non-Sceptic or he is vulnerable to a non-standard version of the apraxia objection.
The Threat of Aerial Bombing in World War Two Lagos, 1938–1943
Authors: Coates Oliver 
Published: November 2020

Abstract
The spectre of air bombing attacks on West African cities during World War Two remains an unexplored dimension of World War Two history. Lagos had long been perceived as vulnerable to attack from neighbouring Dahomey (Benin), and the Fall of France in June 1940 intensified these threats, while increasing anxiety concerning potential Axis raids. Focusing on air-raid planning in Lagos particularly, this article will argue that the possibility of aerial bombing exposed not simply the incapacity of the colonial government and officials’ limited understanding of housing and employment in 1940s Lagos, but also the inadequacy of measures to protect African lives. Conversely, the air-raid threat motivated Africans to critique limited government provision and propose their own interpretations of this new and deadly threat. Although the feared aerial raids never materialised, the crisis and anxiety they provoked yield significant insights into wartime Nigeria, local participation in civil defence, and African responses to World War Two more generally.
Typography for a Modern World? The Ways of Chinese Movable Types
Authors: Bussotti Michela , Qi Han 
Published: November 2020

This article presents a brief history and poses questions about traditional Chinese movable type printing. This is a technology that developed in the pre-modern period and never underwent in the mechanization in the ways that Western movable type printing did. Nevertheless, even today, Chinese traditional movable types continue to be used in some places in China. The authors not only describe the chronology of but also analyse significant cultural, political, and social factors affecting the development traditional Chinese typography.
The first part of this article discusses the movable type made of earthenware and of wood, which are described in various sources written by scholar-officials. In the case of movable type for the Tangut script, however, the main evidence come from chiefly religious imprints which provide information about material evidence as well as a few about printers, typesetters, etc. The second section describes the long hiatus from the Yuan until the second half of the fifteenth century in the utilization of metallic typography in the private circles in Wuxi in Jiangnan, whose publications still survive, and how during the last dynasty, the movable type production reflects some trends in book publishing in general, with the important engagement of some of the Manchu emperors. In the last section of the paper, the authors explain why although wooden types existed in the Kingdom of Xixia (1032-1227) and in the Yuan dynasty (1279-1368), it was only in the Ming (1368-1644) to Qing (1644-1911) periods that their use became more widespread in China. Wooden movable type played a key role in the printing of genealogies in various areas (e.g. Zhejiang, Anhui, Jiangsu, Hunan, and Fujian). That all also indicates that wood is the “material medium” of traditional Chinese printing, never mind if employed in blocks or types.
The Qing Imperial Academy of Medicine: Its Institutions and the Physicians Shaped by Them
Authors: Chang Che-chia 
Published: November 2020

This paper is intended to explain the changes in the activities of the Imperial Academy of Medicine during the Qing dynasty (1644-1911). By tracing its precedents and comparing their functions, I will explain its role during the Qing dynasty. Furthermore, the seemingly hidebound institutional codes in fact reveal interesting information about the dynamics of the Academy. Through examining the impacts of the regulations on personnel and their careers, we are able to explain the very different requirements of the Qing rulers for their medical service. Up until the Ming period (1368-1644) there was an institutional boundary between medical services for the palace and those for the state, even though they shared the same personnel. The Qing was the first dynasty in which even this unclear line disappeared. In this sense, the Qing Academy did not simply copy the tradition of its predecessors. Instead, the services for the emperor’s individual needs became more and more central to its mission. Thus, the common people’s rather critical perceptions of the bureau were largely true.
In spite of its increased emphasis on serving the imperial household, the Qing Academy retained its connections with the government. As an alien regime, the Manchu court’s concern for the security of its rulers was much higher than during the previous dynasty. To meet the needs of the new regime, the device of the Qing Academy emphasized fostering elites rather than selecting them. Now the Academy not only provided medical education to the junior members as in earlier periods, but also shaped them in behavior. This affected both the organization of the Imperial Medical Academy, and the strategies of the physicians employed in it.
Outlook for Exploiting Artificial Intelligence in the Earth and Environmental Sciences
Authors: Boukabara Sid-Ahmed , Krasnopolsky Vladimir , Penny Stephen G. , Stewart Jebb Q. , McGovern Amy , Hall David , Ten Hoeve John E. , Hickey Jason , Allen Huang Hung-Lung , Williams John K. , Ide Kayo , Tissot Philippe , Haupt Sue Ellen , Casey Kenneth S. , Oza Nikunj , Geer Alan J. , Maddy Eric S. , Hoffman Ross N. 
Published: November 2020

AbstractPromising new opportunities to apply artificial intelligence (AI) to the Earth and environmental sciences are identified, informed by an overview of current efforts in the community. Community input was collected at the first National Oceanic and Atmospheric Administration (NOAA) workshop on “Leveraging AI in the Exploitation of Satellite Earth Observations and Numerical Weather Prediction” held in April 2019. This workshop brought together over 400 scientists, program managers, and leaders from the public, academic, and private sectors in order to enable experts involved in the development and adaptation of AI tools and applications to meet and exchange experiences with NOAA experts. Paths are described to actualize the potential of AI to better exploit the massive volumes of environmental data from satellite and in situ sources that are critical for numerical weather prediction (NWP) and other Earth and environmental science applications. The main lessons communicated from community input via active workshop discussions and polling are reported. Finally, recommendations are presented for both scientists and decision-makers to address some of the challenges facing the adoption of AI across all Earth science.
Seasonality and Trends of Drivers of Mesoscale Convective Systems in Southern West Africa
Authors: Klein Cornelia , Nkrumah Francis , Taylor Christopher M. , Adefisan Elijah A. 
Published: November 2020

AbstractMesoscale convective systems (MCSs) are the major source of extreme rainfall over land in the tropics and are expected to intensify with global warming. In the Sahel, changes in surface temperature gradients and associated changes in wind shear have been found to be important for MCS intensification in recent decades. Here we extend that analysis to southern West Africa (SWA) by combining 34 years of cloud-top temperatures with rainfall and reanalysis data. We identify clear trends in intense MCSs since 1983 and their associated atmospheric drivers. We also find a marked annual cycle in the drivers, linked to changes in the convective regime during the progression of the West African monsoon. Before the peak of the first rainy season, we identify a shear regime where increased temperature gradients play a crucial role for MCS intensity trends. From June onward, SWA moves into a less unstable, moist regime during which MCS trends are mainly linked to frequency increase and may be more influenced by total column water vapor. However, during both seasons we find that MCSs with the most intense convection occur in an environment with stronger wind shear, increased low-level humidity, and drier midlevels. Comparing the sensitivity of MCS intensity and peak rainfall to low-level moisture and wind shear conditions preceding events, we find a dominant role for wind shear. We conclude that MCS trends are directly linked to a strengthening of two distinct convective regimes that cause the seasonal change of SWA MCS characteristics. However, the convective environment that ultimately produces the most intense MCSs remains the same.