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Given the disparate effects of the COVID-19 pandemic on people of color, we hypothesized that patients of color experienced a disproportionate increase in trauma during the COVID-19 pandemic.We compared trauma patients arriving in the 3 y before our statewide stay-at-home mandate on March 20, 2020 (PRE) to those arriving in the year afterward (POST). In addition to race/ethnicity, we assessed patient demographics and other clinical variables. Chi-squared, Fisher's exact, and Mann-Whitney U tests were used for univariate analyses. A multivariable logistic regression was performed to assess for associations with mortality.During the study period, 8583 patients were included in the PRE group and 2883 were included in the POST group. There were increases in penetrating trauma (PRE 14.7%, POST 23.1%; P 0.001) and mortality rates (PRE 3.20%, POST 4.60%; P 0.001). From PRE to POST, the percentage of Black patients increased from 35.0% to 38.3% (P = 0.01) and the percentage of Hispanic patients increased from 19.2% to 23.0% (P 0.001). After a multivariable analysis, Asian patients experienced an independent increase in mortality from PRE to POST (odds ratio 2.00, 95% confidence interval 1.13-3.54, P = 0.02).Penetrating trauma and mortality rates increased during the pandemic. There was a simultaneous increase in the percentage of Black and Hispanic trauma patients. Asian patient mortality increased significantly after the start of the pandemic independent of other variables. Identifying racial/ethnic disparities is the first step in finding ways to improve dissimilar outcomes.

Methane (CH4) emissions estimates from top-down studies over oil and gas basins have revealed systematic under-estimation of CH4 emissions in current national inventories. Sparse but extremely large amounts of CH4 from oil and gas production activities have been detected across the globe, resulting in a significant increase of the overall O&G contribution. However, attribution to specific facilities remains a major challenge unless high-resolution images provide the sufficient granularity within O&G basin. In this paper, we monitor known oil-and-gas infrastructures across the globe using recurrent Sentinel-2 imagery to detect and quantify more than 800 CH4 emissions. In combination with emissions estimates from airborne and Sentinel-5P measurements, we demonstrate the robustness of the fit to a power law from 0.1 tCH4/hr to 600 tCH4/hr. We conclude here that the prevalence of ultra-emitters (> 25tCH4/hr) detected globally by Sentinel-5P directly relates to emission occurrences below its detection threshold. Similar power law coefficients arise from several major oil and gas producers but noticeable differences in emissions magnitudes suggest large differences in maintenance practices and infrastructures across countries., Comment: Preprint version of https://pubs.acs.org/doi/abs/10.1021/acs.est.1c08575

We use a large administrative tax-returns panel dataset merged with a tax audit database to estimate the effect of real-world operational tax audits on subsequent tax behavior of a large sample of Italian self-employed taxpayers. Results from operational audits do not suffer from the fact that taxpayers are aware that they have been randomly selected for research purposes and, then, such audits are viewed as more of a signal about true audit rates by the taxpayer. Our empirical approach relies on fixed-effects difference-in-difference comparisons with an ex-ante matched sample of non-audited taxpayers. To address concerns about the endogenous selection into audit, we provide evidence for the common trends assumption. We find a positive and lasting effect of audits on subsequent reported income. However, in line with theoretical predictions, taxpayers do not increase tax compliance when the tax authority does not assess a positive additional income. Our results are robust to a variety of specifications and samples.

Background In the age of COVID-19 and enforced social distancing, changes in patterns of trauma were observed but poorly understood. Our aim was to characterize traumatic injury mechanisms and acuities in 2020 and compare to years prior at our Level 1 trauma center. Materials and Methods Trauma patients triaged in 2016 through 2020 from January to May were reviewed. Patient demographics, level of activation (1 vs. 2), ISS, and mechanism of injury were collected. Data from 2016 through 2019 was combined, averaged by month, and compared to data from 2020 using Chi-squared analysis. Results During the months of interest, 992 trauma patients were triaged in 2020 and 4,311 in 2016-2019. The numbers of penetrating and Level 1 trauma activations in January – March of 2020 were similar to average numbers for the same months during 2016 through 2019. In April 2020, there was a significant increase in incidence of penetrating trauma compared to the prior four-year average (27% vs. 16%, p

Large scale data on single-cell gene expression have the potential to unravel the specific transcriptional programs of different cell types. The structure of these expression datasets suggests a similarity with several other complex systems that can be analogously described through the statistics of their basic building blocks. Transcriptomes of single cells are collections of messenger RNA abundances transcribed from a common set of genes just as books are different collections of words from a shared vocabulary, genomes of different species are specific compositions of genes belonging to evolutionary families, and ecological niches can be described by their species abundances. Following this analogy, we identify several emergent statistical laws in single-cell transcriptomic data closely similar to regularities found in linguistics, ecology or genomics. A simple mathematical framework can be used to analyze the relations between different laws and the possible mechanisms behind their ubiquity. Importantly, treatable statistical models can be useful tools in transcriptomics to disentangle the actual biological variability from general statistical effects present in most component systems and from the consequences of the sampling process inherent to the experimental technique.Author summaryGene expression profiles represent how different cells use their genetic information. Similarly, books are specific collections of words chosen from a shared vocabulary, and many complex systems can be ultimately described by the statistics of their basic components. Leveraging on this analogy, we identified several emergent statistical laws in single-cell transcriptomic data that are universally found in complex component systems. A simple mathematical description sets these laws in a treatable quantitative framework and represents a useful tool for dissecting the different sources of gene expression variability.

In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro. Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo. Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966–76. ©2018 AACR.

Toxicology analysis. Liver transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured after Antartina{trade mark, serif} treatment and H&E stained tissues from BALB/c mice untreated (n= 5) or treated with 5 mg/kg (n=5) and 50 mg/kg (n=5) of Antartina{trade mark, serif}

Preconditioning of DCs derived from (A) cancer patients and healthy donors, and (B) mice using10 μg/ml Antartina{trade mark, serif} enhances the expression of activation markers

Chronic infections of the human immunodeficiency virus (HIV) create a very complex coevolutionary process, where the virus tries to escape the continuously adapting host immune system. Quantitative details of this process are largely unknown and could help in disease treatment and vaccine development. Here we study a longitudinal dataset of ten HIV-infected people, where both the B-cell receptors and the virus are deeply sequenced. We focus on simple measures of turnover, which quantify how much the composition of the viral strains and the immune repertoire change between time points. At the single-patient level, the viral–host turnover rates do not show any statistically significant correlation, however, they correlate if one increases the amount of statistics by aggregating the information across patients. We identify an anti-correlation: large changes in the viral pool composition come with small changes in the B-cell receptor repertoire. This result seems to contradict the naïve expectation that when the virus mutates quickly, the immune repertoire needs to change to keep up. However, a simple model of antagonistically evolving populations can explain this signal. If it is sampled at intervals comparable with the sweep time, one population has had time to sweep while the second cannot start a counter-sweep, leading to the observed anti-correlation. This article is part of the theme issue ‘Interdisciplinary approaches to predicting evolutionary biology’.

In vivo efficacy of Tricin and 5-FU

Information about experimental procedure to obtain Antartina

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.Experimental Design: IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non–small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Clin Cancer Res; 20(22); 5697–707. ©2014 AACR.

Supplementary Figure 4. Comparison of IL-8 serum concentrations with the serum concentration of IL-6 and c-reactive protein (CRP) in available samples from 14 melanoma and 19 RCC patients from Figure 2A. (**, p

Supplementary Figure 1B. Time course of the serum concentrations of IL-8 (lower panels) and tumor volume (upper panels) in Rag2-/-IL2Rγc-/- mice xenografted with the indicated cell lines. Individual mice are represented and at the time point indicated by the arrow the tumor was surgically removed. Serum IL-8 concentrations are depicted at 2h and 24h after surgery.

Supplementary Figure 2. Serum IL-8 levels before (day -1) and after (day 5-7) disease-reduction surgery of 7 patients: 1 hepatocellular carcinoma (HCC); 2 colorectal carcinoma (CRC); 1 pancreatic cancer (PC); 3 renal cell carcinoma (RCC).

Purpose: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC).Experimental Design: We cloned an A33 promoter fragment (A33Pr) that extends from −105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo.Results: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs.Conclusions: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC.

Supplementary Data from Aprataxin Tumor Levels Predict Response of Colorectal Cancer Patients to Irinotecan-based Treatment

Supplementary Data from A Novel A33 Promoter–Based Conditionally Replicative Adenovirus Suppresses Tumor Growth and Eradicates Hepatic Metastases in Human Colon Cancer Models

Supplementary Figure 3. Quantitative RT-PCR analyses of the mRNA encoding IL-8 in malignant cells from the biopsy of three melanoma patients. The serum IL-8 levels at the time of the biopsy from each patient is provided under the graph.

Supplementary Table 2. Surgical patient description 2

Supplemental Legend

Purpose: Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond.Experimental Design: Here we used microarray analysis of a panel of 30 colorectal cancer cell lines and immunohistochemistry to identify and validate a new biomarker of response to irinotecan.Results: A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair. Moreover, using an isogenic in vitro system deficient in APTX, we show that aprataxin directly regulates the cellular sensitivity to camptothecin, suggesting that it could be used to predict patient response to irinotecan. We constructed a tissue microarray containing duplicate tumor samples from 135 patients that received irinotecan for the treatment of advanced colorectal cancer. Immunohistochemical assessment of the tumor levels of aprataxin showed a significant association with treatment response and patient survival. Patients with low aprataxin had longer progression-free (9.2 versus 5.5 months; P = 0.03) and overall survival (36.7 versus 19.0 months; P = 0.008) than patients with high tumor aprataxin. No associations were found between coding APTX variants and aprataxin levels or camptothecin sensitivity.Conclusions: These results show that aprataxin tumor levels can be used to identify patients with low probability of response to irinotecan-based therapy who are ideal candidates to receive treatment with alternative agents in an attempt to improve patient survival. Clin Cancer Res; 16(8); 2375–82. ©2010 AACR.

Supplementary Table 1. Patient description 1

Legends to supplementary figures

Timing of peripheral tissue infiltration by transferred human T-lymphocytes into Rag2-/-IL2Rgcnull mice.

Urelumab and Nivolumab bind to hCD137 and hPD-1 expressed on human T-lymphocytes engrafted in Rag2-/-IL2Rgcnull mice.

Anti-hCD137 (Urelumab) and anti-hPD-1 (Nivolumab) treatment as single agents or in combination show antitumor effects against a xenografted human gastric cancer transferred with autologous lymphocytes drawn from the same patient.

Human T cells acquire an activated phenotype after being transferred into Rag2-/-IL2Rgcnull mice.

Supplementary Figures 1-6, Tables 1-6 from The Receptor Tyrosine Kinase EPHB4 Has Tumor Suppressor Activities in Intestinal Tumorigenesis

hPD-1 expression on TILs and PD-L1/B7-H1 expression in tumor compartment.

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Supplementary methods Appendix

PDF file - 214K, Fig S1: Inhibition of several cytokines does not modify pneumonitis lethality in mice treated with pSushi-IL15-Apo. Fig S2: Pharmacokinetics, bioactivity and incorporation into HDL of Sushi-IL15. Fig. S3: Time course follow-up of lymphocyte numbers in lung liver and spleen after pSushi-IL15-Apo liver gene transfer. Fig. S4: Liver gene transfer of pSushi-IL15-Apo results in intense proliferation of NK and CD8 T lymphocytes. Fig. S5: In vivo bioactivity of rSushi-IL15-Apo. Fig. S6: Repeated hydrodynamic injections achieve similar effects

Anti-mCD137 and anti-mPD-1 combined antitumor effects are solely CD8 T-cells dependent in a murine colon cancer model.

xGVHD and human IFN-γ elevation in plasma are dependent on human CD4 T cells.

PD-L1/B7-H1 expression on tumor cells is preferentially observed in tumors of the Combo group mice.

hCD137 and hPD1 expression in human T-lymphocytes infiltrating spleen and liver.

A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4+ T cell–mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. Cancer Res; 75(17); 3466–78. ©2015 AACR.

Airborne Wind Energy is a lightweight technology that allows power extraction from the wind using airborne devices such as kites and gliders, where the airfoil orientation can be dynamically controlled in order to maximize performance. The dynamical complexity of turbulent aerodynamics makes this optimization problem unapproachable by conventional methods such as classical control theory, which rely on accurate and tractable analytical models of the dynamical system at hand. Here we propose to attack this problem through Reinforcement Learning, a technique that -- by repeated trial-and-error interactions with the environment -- learns to associate observations with profitable actions without requiring prior knowledge of the system. We show that in a simulated environment Reinforcement Learning finds an efficient way to control a kite so that it can tow a vehicle for long distances. The algorithm we use is based on a small set of intuitive observations and its physically transparent interpretation allows to describe the approximately optimal strategy as a simple list of manoeuvring instructions.

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