Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, ...extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146-5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3'UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target.
The tumor-stromal cross-talk mediated by cancer-associated fibroblast-derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.
•We study the effects of liberal refugee-hosting policies and hosting large numbers of refugees on public goods provision and attitudes towards migration in Uganda from 2001 to 2020.•Uganda’s ...inclusive refugee hosting policies allow refugees to self-settle and have access to local public goods, while also ensuring that host communities benefit from refugee-related aid.•We combine longitudinal geospatial data on refugee settlements, primary and secondary education, healthcare, roads, citizen attitudes, and conflict.•We find that host community parishes that are closer to larger refugee settlements experience substantial positive spillovers, such as improved public school access, greater access to health clinics, more health utilization, and more road density.•While we might expect liberal hosting policies and large numbers of refugees to lead to public backlash, especially among poorer citizens, we find no backlash.
Large arrivals of refugees raise concerns about potential tensions with host communities, particularly if refugees are viewed as an out-group competing for limited material resources and crowding out public services. To address these concerns, calls have increased to allocate humanitarian aid in ways that also benefit host communities. This study tests whether the increased presence of refugees, when coupled with humanitarian aid, improves public service delivery for host communities and dampens potential social conflict. We study this question in Uganda, one of the largest and most inclusive refugee-hosting countries. The data combines geospatial information on refugee settlements with original longitudinal data on primary and secondary schools, road density, health clinics, and health utilization. We report two key findings. First, even after the 2014 arrival of over 1 million South Sudanese refugees, host communities with greater refugee presence experienced substantial improvements in local development. Second, using public opinion data, we find no evidence that refugee presence has been associated with more negative (or positive) attitudes towards migrants or migration policy.
Research Summary
The reach of the modern enterprise relies on the power of information technology (IT) tools such as sensors, databases, and machine learning. But tool improvements must be fueled by ...increased computing power (e.g., faster hardware) or getting more productivity from existing systems (e.g., through better computer algorithms). New research has uncovered that this second source, algorithm progress, is more important than previously realized—sometimes orders of magnitude more important than hardware—and thus could be an important technological stepping‐stone to give competitive advantage to a country's firms. Analyzing this “Algorithm Commons” reveals that the United States has been the largest contributor to algorithm progress, with universities and large private labs (e.g., IBM) leading the way, but that U.S. leadership has faded in recent decades.
Managerial Summary
Companies are increasingly tackling problems with big data and sophisticated analysis techniques (e.g., Machine Learning). To meet the increased computational demands of these approaches, the capability of computers must improve. One important technique for doing this is to redesign algorithms, the recipes that computers follow to perform calculations. As a result, firms that develop better algorithms, or get access to them first, can get important advantages over their competitors. This paper shows that it is U.S. corporations and U.S. universities that have produced most of the important algorithm improvements, and thus suggests that better algorithms may have been a source of advantage for U.S. multinationals.
Denizens of Silicon Valley have called Moore's Law "the most important graph in human history," and economists have found that Moore's Law-powered I.T. revolution has been one of the most important ...sources of national productivity growth. But data substantiating these claims tend to either be abstracted - for example by examining spending on I.T., rather than I.T. itself - or anecdotal. In this paper, we assemble direct quantitative evidence of the impact that computing power has had on five domains: two computing bellwethers (Chess and Go), and three economically important applications (weather prediction, protein folding, and oil exploration). Computing power explains 49%-94% of the performance improvements in these domains. But whereas economic theory typically assumes a power-law relationship between inputs and outputs, we find that an exponential increase in computing power is needed to get linear improvements in these outcomes. This helps clarify why the exponential growth of computing power from Moore's Law has been so important for progress, and why performance improvements across many domains are becoming economically tenuous as Moore's Law breaks down.
Large arrivals of refugees raise concerns about potential tensions with host communities,particularly if refugees are viewed as an out-group competing for limited material resources and crowding ...outpublic services. To address this concern, calls have increased to allocate humanitarian aid in ways that (also)benefit host communities. This study empirically tests whether the presence of refugees in Uganda (one of thelargest refugee-hosting countries) has improved public service delivery, and consequently, dampened potentialsocial conflict. The data com- bines geospatial information on refugee settlements with unique longitudinal data onprimary and secondary schools, road density, health clinics, and health utilization. This study reports two key findings.First, particularly after the 2014 arrival of over 1 million South Sudanese refugees, host communities with greaterlevels of refugee presence experienced substantial improvements in local development. Second, using publicopinion data, we find no evidence that refugee presence is associated with more negative (or positive) attitudestowards migrants or migration policy.
Background
Both anlotinib and programmed death-1 (PD-1) blockade have been approved for the second-line treatment of metastatic esophageal squamous cell carcinoma (ESCC). However, the combination of ...these two therapies has not been evaluated. This study investigated the efficacy and safety of anlotinib, a novel multitarget tyrosine kinase inhibitor targeting tumor angiogenesis, combined with PD-1 blockade as second or further-line treatment for advanced ESCC.
Methods
Between January 2019 and February 2021, 98 advanced ESCC patients receiving anlotinib plus PD-1 blockade or anlotinib monotherapy as second or further-line treatment at Henan Cancer Hospital were retrospectively analyzed. Patients receiving anlotinib plus PD-1 blockade were grouped as cohort A (n=48), while those receiving anlotinib monotherapy were grouped as cohort B (n=50). The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR) and toxicity. Furthermore, independent prognostic factors were identified by Cox regression analysis. A two-sided p-value of <0.05 was considered statistically significant.
Results
Data was collected until May 1, 2021, with a median follow-up time of 9.30 months (8.23–10.37 months) in cohort A and11.10months (7.82–14.38 months) in cohort B. For patients with advanced ESCC, cohort A resulted in significantly longer PFS (5.40 vs. 3.00 months, P<0.001) and higher DCR (71.7% vs. 47.9%, P=0.019) than cohort B. The ORR indicated no significant difference between cohort A (23.9%) and cohort B (10.4%) (P=0.082). Adverse reactions were mainly grade1/2 in the two groups. Compared with cohort B, a significantly higher rate of grade 1–2 hypothyroidism was observed in patients in cohort A (P= 0.034). Three patients (6.3%) developed grade 1/2 immune-related pneumonia. There was no significant difference in the incidence of grade 3-4 toxicities. Multivariable Cox regression analysis showed that the drug regimen (P<0.001), Eastern Cooperative Oncology Group Performance Status (P=0.002), distant organ metastasis (P=0.008), and metastatic sites (P=0.032) were independent prognostic factors for PFS.
Conclusions
Anlotinib plus PD-1 blockade showed promising anti-tumor activity and manageable toxicity as second or further-line treatment of advanced ESCC.
Trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with poor prognosis in coronary heart disease. ...However, the role and underlying mechanisms of TMAO in the cardiac fibrosis after myocardial infarction (MI) remains unclear.
We used mouse MI models and primary cardiac fibroblasts cultures to study the role of TMAO in the heart and in cardiac fibroblasts. C57BL/6 mice were fed a control diet, high choline (1.2%) or/and DMB diet or a diet containing TMAO (0.12%) starting 3 weeks before MI. DMB, a structural analogue of choline, inhibited microbial TMA lyases and reduced the level of TMAO in mice. Cardiac function was measured 7 days after MI using echocardiography. One week post MI, myocardial tissues were collected to evaluate cardiac fibrosis, and blood samples were evaluated for TMAO levels. The expression of TGF-β receptor, P-Smad2, α-SMA or collagen I in myocardial tissues and fibroblasts were analyzed by western blot or immunocytochemistry.
We demonstrated that cardiac function and cardiac fibrosis were significantly deteriorated in mice fed either TMAO or high choline diets compared with the control diet, and DMB reversed the cardiac function damage of high choline diet (p < .05). Cardiomyocyte necrosis, apoptosis and macrophage infiltration after MI was significantly increased after treatment with TMAO or high choline diets. The size and migration of fibroblasts were increased after TMAO treatment compared with non-treated fibroblasts in vitro. Furthermore, TMAO increased TGF-β receptor I expression, which promoted the phosphorylation of Smad2 and up-regulated the expression of α-SMA and collagen I. The ubiquitination of TGF-βRI was decreased in neonatal mouse fibroblasts after TMAO treatment. TMAO also inhibited the expression of smurf2. Inhibition of TGF-β1 receptor with the small molecule inhibitor SB431542 decreased TGF-β receptor I expression, reduced the phosphorylation of Smad2, down-regulated TMAO-induced α-SMA and collagen I expression in cardiac fibroblasts.
Cardiac function and cardiac fibrosis were significantly exacerbated in mice fed diets supplemented with either choline or TMAO, probably through accelerating the transformation of fibroblasts into myofibroblasts, indicating activation of TGF-βRI/Smad2 pathway.
•TMAO or high choline diets increased cardiac fibrosis after MI, and DMB reversed choline related cardiac fibrosis.•TMAO accelerated the transformation of fibroblasts into myofibroblasts by activating of TGF-βRI/Smad2 pathway.•TMAO activated the TGF-β signaling pathway by inhibiting the ubiquitination of TGF-βRI and preventing its degradation.
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