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Using administrative data for West Germany, we study the relative importance of different determinants of the urban wage premium. More explicitly, we distinguish worker sorting, as well as portable and non-portable agglomeration effects. Our results indicate that worker sorting explains about two thirds of the urban-rural wage gap. We show that the estimated fraction of the urban wage premium attributed to worker sorting differs considerably depending on the selectivity of the sample used for identification and provide guidance how this selectivity can be reduced. Agglomeration effects explain about one third of the urban wage premium, with portable and non-portable agglomeration effects being of similar importance. Anhand administrativer Daten für Westdeutschland untersuchen wir die relative Bedeutung verschiedener Determinanten der städtischen Lohnprämie. Explizit unterscheiden wir zwischen Arbeitersortierung sowie portablen und nicht-portablen Agglomerationseffekten. Unsere Ergebnisse zeigen, dass die Arbeitersortierung etwa zwei Drittel des Lohnunterschieds zwischen Stadt und Land erklärt. Wir zeigen, dass der geschätzte Anteil der städtischen Lohnprämie, der auf die Arbeitersortierung zurückzuführen ist, je nach Selektivität der für die Identifikation verwendeten Stichprobe erheblich variiert und geben Hinweise, wie diese Selektivität reduziert werden kann. Agglomerationseffekte erklären etwa ein Drittel der städtischen Lohnprämie, wobei portable und nicht-portable Agglomerationseffekte von ähnlicher Bedeutung sind.

In many industrialised countries, the climate impact from long-distance travel is greater than that from short-distance travel. In this paper, we present five scenarios for long-distance travel in 2060, which are consistent with a 67% probability of limiting global warming to 1.8 degrees. The scenarios concern travel by the Swedish population, but per capita travel volume and fuel use could be generalised globally. A key result is that all scenarios require reductions in Swedish per capita air travel in the range of 38–59% compared to 2017. The direct effect on air travel of implementing a high-speed rail network in Sweden and Northern Europe was found to be modest. A higher emission reduction could be achieved if mixed mode trips comprising rail and air legs were more widely adopted. Finally, the pros and cons of future aviation fuels are discussed, the main candidates being biofuel, electrofuel, and liquid hydrogen.

Der technologische Wandel, die damit verbundene digitale Transformation verschiedener Gesellschaftsbereiche und zuletzt auch die COVID-19-Pandemie haben verdeutlicht, dass digitale Kompetenzen für Personen aller Altersgruppen unerlässlich sind. Mit den Daten des Nationalen Bildungspanels (NEPS) erarbeitet die vorliegende Studie eine umfangreiche Bestandsaufnahme zur Verteilung der sogenannten Digital Literacy in Deutschland. Die Ergebnisse weisen darauf hin, dass vor allem ältere und weniger gebildete Menschen, Frauen sowie Personen mit familiärer Einwanderungsgeschichte unterdurchschnittlich ausgeprägte digitale Kompetenzen vorweisen. Derartige geschlechts- und migrationsspezifische Unterschiede sind bei Kindern und Jugendlichen zunächst nur schwach ausgeprägt. Doch steigen sie bereits im Laufe der Schulzeit an und hängen stark vom sozio-ökonomischen Hintergrund des Elternhauses ab. Die aus dieser Studie abgeleiteten Handlungsempfehlungen richten sich folglich vor allem an den formalen Bildungssektor. Dieser sollte früh die digitalen Kompetenzen von Kindern und Jugendlichen fördern, um den im nicht-formalen Bereich geringen Kompetenzaufbau zu kompensieren. Auch sollten Bildungsangebote für Erwachsene gestärkt werden, um älteren Generationen eine weitere Partizipation in den sich ändernden Lebens-, Bildungs- und Arbeitsbereichen zu ermöglichen.

Dieser Schlussbericht präsentiert wissenschaftliche Erkenntnisse über Umsetzung, Inanspruchnahme, Wirkungen und Wirtschaftlichkeit der arbeitsmarktpolitischen Integrationsmaßnahmen für Geflüchtete. Es werden die Fragen beantwortet, wie effektiv und effizient die zentralen Maßnahmen der Arbeitsförderung in den Rechtskreisen SGB II und SGB III für Personen im Kontext von Fluchtmigration im Hinblick auf ihre Arbeitsmarktintegration und soziale Teilhabe sind, und welche Faktoren, wie etwa Sprachförderung und individuelle und lokale Kontextfaktoren, die Maßnahmenwirksamkeit verstärken oder hemmen. Die kausalanalytisch angelegte Auswertung administrativer Daten wird durch die Untersuchung von Befragungsdaten und eine umfassende Implementationsanalyse ergänzt. Aus den empirischen Erkenntnissen abgeleitete Handlungsempfehlungen geben schließlich Impulse, um die Organisation, Prozesse und Rahmenbedingungen der arbeitsmarktpolitischen Integrationsmaßnahmen für Geflüchtete so zu gestalten, dass ihre positiven Wirkungen weiter verstärkt werden können. This final report presents findings on the implementation, utilization, effects and economic efficiency of labor market integration measures for refugees. It answers the questions of how effective and efficient the central employment measures of SGB II and SGB III are for refugee migrants with regard to their labor market integration and social participation, and which factors, such as language support and individual and local context factors, strengthen or inhibit the effectiveness of the measures. The causal analysis of administrative data is complemented by the examination of survey data and a comprehensive implementation analysis. Finally, policy recommendations derived from the empirical findings provide impulses for designing the organization, processes and framework conditions of labor market integration measures for refugees in such a way that their positive effects can be further enhanced.

Emissions of greenhouse gases from tourism transport are rising globally, with air transport accounting for the largest share. Although travel is not likely to decrease drastically, people could travel differently, and still have similar experiences. This study aims to map the emissions from air travel and analyse the theoretical potential for emissions reduction by changing transport mode and destinations, and the readiness potential for emissions reduction based on tourists’ stated readiness to change their travel behaviour. The theoretical potential was assessed by analysing alternative trips to closer destinations and using transport modes with lower emissions or through virtual meetings. The readiness potential was assessed by a survey designed to capture people’s stated readiness to change their behaviour. The results show a theoretical potential for an emissions reduction of 67%, while the readiness potential is 26%. About half of the readiness potential for reductions is from changing destination, while only a small share is from changing transport mode. This shows that, when accounting for people’s readiness to change behaviour, destination choice has a greater potential to reduce emissions compared to transport mode choice. This finding has implications for policy makers in designing policy measures to reduce emissions.

Background Cell therapy, with all its promise as a powerful solid-tumor modality, is still hampered by the fundamental obstacle of cancer therapy: the acute shortage of truly tumor-specific targets. It is well known that an average tumor contains loss of heterozygosity (LOH) at an astonishing frequency: ~20% genome wide. These losses are irreversible and absolutely distinguish the cancer from normal cells. Methods We describe a novel approach to cancer immunotherapy that draws on LOH as a large, so far untapped source of cancer targets. To exploit such allelic losses, we focus on polymorphic loci and target the remaining allelic product of a locus that has LOH. We engineer T cells with a modular signal-integration circuit designed to be activated only by tumor cells that have lost expression of one specific allele on their surface. Results We use the HLA locus which undergoes LOH at a frequency of 13%, and the HLA-A*02 allele specifically, as proof of concept. We present a large body of quantitative in vitro data, along with in vivo data, that support the use of a synthetic signal-integration circuit called Tmod as a cancer therapy. We also describe Tmod’s mechanistic properties, including thorough structure/function analysis of its components. Conclusions LOH is a rich source of new targets, provided a system of sufficient power can be devised to exploit them. Our Tmod signal integration system confers on engineered T cells the capacity to discriminate effectively between normal and tumor cells that contain specific allelic losses. Ethics Approval The animal study was approved by Explora BioLabs’ Ethics Board, protocol number EB17-010-059

Cell therapy is poised to play a larger role in medicine, most notably for immuno-oncology. Despite the recent success of CAR-T therapeutics in the treatment of blood tumors and the rapid progress toward improved versions of both CAR- and TCR-Ts, important analytical aspects of preclinical development and manufacturing of engineered T cells remain immature. One limiting factor is the absence of robust multivariate assays to disentangle key parameters related to function of engineered effector cells, especially in the peptide-MHC (pMHC) target realm, the natural ligand for TCRs. Here we describe an imaging-based primary T cell assay that addresses several of these limitations. To our knowledge, this assay is the first quantitative, high-content assay that separates the key functional parameters of time- and antigen-dependent T cell proliferation from cytotoxicity. We show that the assay sheds light on relevant biology of CAR- and TCR-T cells, including response kinetics and the influence of effector:target ratio.

Background Recurrent cancer-specific targets are rare. Given the pace of genomic research over the past three decades, few are likely to lie yet undiscovered. In 2013 an innovative MAGE-A3-directed cancer therapeutic of great potential value was terminated in the clinic because of neurotoxicity.1 The safety problems were hypothesized to originate from off-target TCR activity against a closely related MAGE-A12 peptide. Methods A combination of published and new data led us to test this hypothesis with current technology, including RNA hybridization in situ and further analysis of the clinical TCR’s specificity to MAGE-A12 and other antigens. Results We find that a key prediction of the MAGE-A12 toxicity hypothesis, the existence of rare, high-MAGE-A12-expressing cells in the brain, is not supported by the data. Our results imply that an alternative related peptide from the EPS8L2 protein is more likely responsible for the toxicity. Therefore, it may be valuable to reconsider MAGE-A3 as a cancer target using HLA-A*02-restricted-TCRs or CARs. As a step in this direction, we isolated MAGE-A3 pMHC-directed CARs, targeting the same peptide as the clinical TCR. These CARs have high selectivity, and avoid cross-reaction with the EPS8L2 peptide that represents a significant risk for MAGE-A3-targeted therapeutics. Conclusions Given the qualities of MAGE-A3 as an onco-testis antigen widely expressed in tumors and largely absent from normal adult tissues, our findings suggest that MAGE-A3 may deserve further consideration as a cancer target. We have identified CARs with selectivity profiles consistent with a cell therapeutic directed against HLA-A*02-positive, MAGE-A3-expressing cancers. The relative merits of TCRs and CARs for this target will be discussed. Reference Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013;36:133–151, doi:10.1097/CJI.0b013e3182829903.

We describe an approach to cancer therapy based on exploitation of common losses of genetic material in tumor cells (loss of heterozygosity) (Basilion et al., 1999; Beroukhim et al., 2010). This therapeutic concept addresses the fundamental problem of discrimination between tumor and normal cells and can be applied in principle to the large majority of tumors. It utilizes modular activator/blocker elements that integrate signals related to the presence and absence of ligands displayed on the cell surface (Fedorov et al., 2013). We show that the targeting system works robustly in vitro and in a mouse cancer model where absence of the HLA-A*02 allele releases a brake on engineered T cells activated by the CD19 surface antigen. This therapeutic approach potentially opens a route toward a large, new source of cancer targets.

Chimeric antigen receptors (CARs) and their parent signaling molecule, the T cell receptor (TCR), are fascinating proteins of increasing relevance to disease therapy. Here we use a collection of 1221 pMHC-directed CAR constructs representing 10 pMHC targets to study aspects of CAR structure-activity relationships (SAR), with particular focus on the extracellular and transmembrane structural components. These experiments that involve pMHC targets whose number/cell can be manipulated by peptide dosing in vitro enable systematic analysis of the SAR of CARs in carefully controlled experimental situations (Harris and Kranz, 2016). We find that CARs tolerate a wide range of structural variation, with the ligand-binding domains (LBDs) dominating the SAR of CAR antigen sensitivity. Notwithstanding the critical role of the LBD, CAR antigen-binding on the cell surface, measured by pMHC tetramer staining, is not an effective predictor of functional sensitivity. These results have important implications for the design and testing of CARs aimed toward the clinic.

Background Countdown to 2030 (CD2030) tracks progress in the 81 countries that account for more than 90% of under-five child deaths and 95% of maternal deaths in the world. In 2017, CD2030 identified syphilis screening and treatment during antenatal care (ANC) as priority indicators for monitoring. Methods Country-reported data in the UNAIDS Global AIDS Monitoring System (GAM) system were used to evaluate four key syphilis indicators from CD2030 countries: (1) maternal syphilis screening and (2) treatment coverage during ANC, (3) syphilis seroprevalence among ANC attendees, and (4) national congenital syphilis (CS) case rates. A cascade analysis for CD2030 countries with coverage data for the number of women attending at least 4 antenatal care visits (ANC4), syphilis testing, seroprevalence and treatment was performed to estimate the number of CS cases that were attributable to missed opportunities for syphilis screening and treatment during antenatal care. Results Of 81 countries, 52 (64%) reported one or more values for CS indicators into the GAM system during 2016-2017; only 53 (65%) had maternal syphilis testing coverage, 41 (51%) had screening positivity, and 40 (49%) had treatment coverage. CS case rates were reported by 13 (16%) countries. During 2016-2017, four countries reported syphilis screening and treatment coverage of ≥95% consistent with World Health Organization (WHO) targets. Sufficient data were available for 40 (49%) of countries to construct a cascade for data years 2016 and 2017. Syphilis screening and treatment service gaps within ANC4 resulted in an estimated total of 103 648 adverse birth outcomes with 41 858 of these occurring as stillbirths among women attending ANC4 (n = 31 914 408). Women not in ANC4 (n = 25 619 784) contributed an additional 67 348 estimated adverse birth outcomes with 27 198 of these occurring as stillbirths for a total of 69 056 preventable stillbirths attributable to syphilis in these 40 countries. Conclusion These data and findings can serve as an initial baseline evaluation of antenatal syphilis surveillance and service coverage and can be used to guide improvement of delivery and monitoring of syphilis screening and treatment in ANC for these priority countries.

Data assembly in support of global data products, such as GLODAP, and submission of data to national data centers to support long-term preservation, demands significant effort. This is in addition to the effort required to perform quality control on the data prior to submission. Delays in data assembly can negatively affect the timely production of scientific indicators that are dependent upon these datasets, including products such as GLODAP. What if data submission, metadata assembly and quality control can all be rolled into a single application? To support more streamlined data management processes in the NOAA Ocean Acidification Program (OAP) we are developing such an application.This application has the potential for application towards a broader community.This application addresses the need that data contributing to analysis and synthesis products are high quality, well documented, and accessible from the applications scientists prefer to use. The Scientific Data Integration System (SDIS) application developed by the PMEL Science Data Integration Group, allows scientists to submit their data in a number of formats. Submitted data are checked for common errors. Metadata are extracted from the data that can then be complemented with a complete metadata record using the integrated metadata entry tool that collects rich metadata that meets the Carbon science community requirements. Still being developed, quality control for standard biogeochemical parameters will be integrated into the application. The quality control routines will be implemented in close collaboration with colleagues from the Bjerknes Climate Data Centre (BCDC) within the Bjerknes Centre for Climate Research (BCCR). This presentation will highlight the capabilities that are now available as well as the implementation of the archive automation workflow, and it’s potential use in support of GLODAP data assembly efforts.

Fertility challenges are a personal and important part of a woman's reproductive health and are associated with health and lifestyle factors. Limited data exist on infertility among women in Palau. We describe the lifetime prevalence of self-reported infertility in a nationally representative sample of women in Palau and investigate the association between tobacco and/or betel nut use and infertility. During May–December 2016, a population-based survey of noncommunicable diseases was conducted in Palau using a geographically stratified random sample of households (N=2409). Men and women ≥18 years of age were chosen randomly from each selected household. The prevalence of a self-reported lifetime episode of infertility (having tried unsuccessfully to become pregnant for ≥12 months) was evaluated among 874 women aged ≥18 years by key health and lifestyle factors. Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated. Of 315 women who ever tried to become pregnant, 39.7% (95% CI: 34.2%, 45.3%) reported a lifetime episode of infertility. Prevalence was higher in women of Palauan vs other ethnicity (PR=1.6, 95% CI: 1.1, 2.3), those who self-reported poor/not good vs. excellent/ very good health status (PR=2.1, 95% CI: 1.4, 3.3), and those with a body mass index (BMI) ≥30 vs

QC 20210505

Since the start of the COVID-19 pandemic, the role of government in public health has come to the forefront of a national conversation. In the United States, social distancing measures such as mandatory stay-at-home orders and closures of schools and non-essential businesses have been implemented in nearly all 50 states. In response to the mandates, which have led to widespread unemployment and limitations on free movement, protests have been taking place in nearly half of the nation’s states. The protesters can be described as a coalition of social conservatives, fiscal conservatives, and civil libertarians unified by their desires “to get back to work and leave their homes.”[1] This paper argues that public health mandates that are kept to the least restrictive means necessary can work with certain civil liberties to ensure public health: the two should not be seen as mutually exclusive. Among social, economic, and political concerns, one objection to stay-at-home orders is ideological: nationwide, orders are seen as a state overreach and infringement on certain civil liberties. In the words of a Wisconsin Supreme Court justice, “Isn’t it the very definition of tyranny for one person to order people to be imprisoned for going to work among other ordinarily lawful activities?”[2] The shutdown of businesses has seriously affected the national economy, and with millions of Americans held back from work and laid off from their jobs, the US unemployment rate has soared to levels unseen since the Great Depression.[3] While the relationship between public health and economic activity is complex, these arguments in favor of civil liberties presume that freedom and public health cannot coexist during a crisis. The protests remain relatively small and spread out, and, according to a Pew Research Center survey, the majority of Americans on both sides of the political spectrum support the current social distancing restrictions.[4] Despite its current partisan amplification, the rhetorical strategy that positions public health and civil liberties against one another is not new. Many assume there are tradeoffs between public health and civil liberties and that to prioritize one is to sacrifice the other. Public health is acceptable, the protestors seem to say, only until it clashes with civil liberties - at which point it becomes an existential threat. To some, there is tension between protecting the health of a population and respecting the rights of the individual. The tension is between collectivism, or the prioritization of the wellbeing of the collective,[5] and individualism, or the right of an individual to freely determine his or her own life. Some of the core ethical challenges in public health arise when the two are at odds. In the influential 1905 court case Jacobson v. Massachusetts, the US Supreme Court upheld mandatory vaccination laws following an outbreak of smallpox. The ruling confirmed the police powers of the state to establish laws that guard the health and safety of the public like those that control the spread of deadly infectious disease.[6] The court concluded that it is sometimes acceptable for the state to infringe upon the rights of the individual in order to protect the health of the collective. Public health interventions that entail changes in civil liberties must be clearly shown to be both reasonable (given the situation) and necessary, and only implemented after less restrictive measures have failed. The AIDS epidemic in the 1980s added another dimension to the discussion around public health and civil liberties. Some public health officials called for measures such as shutting down bathhouses[7] and reporting the names of HIV-positive people to the government for surveillance purposes. However, others feared that coercive public health methods could backfire by driving people underground and eroding their trust in health systems. They recognized that privacy concerns, fear of discrimination, and laws prohibiting same-sex relations were hindering efforts to effectively combat the disease. In response, public health officials developed a new approach that better aligned civil liberties and public health through prioritizing HIV and AIDS education, building trust in marginalized communities, and encouraging voluntary condom usage. Consequently, “A simple dictum emerged: no public health policy that violated the rights of individuals could be effective in controlling the spread of HIV. There was, therefore, no tension between public health and civil liberties. Indeed, the protection of civil liberties was critical to the public health.”[8] Rather than presupposing that the health of the public and the rights of the individual conflict, the AIDS crisis revealed another possibility: to view public health and civil liberties not as antagonists, but as partners in protecting health. In the midst of the current COVID-19 pandemic, it is possible that, like in the AIDS crisis, the debate presents a false choice between either public health or civil liberties. While there is a tension between the two, their opposition is not a foregone conclusion. Failures in early detection and prevention, the disbandment of the White House pandemic preparedness team in 2018, and a lack of reliable testing kits contributed to the need for widespread stay-at-home orders that exacerbated the tension. A compromise solution could focus on educating the public on how COVID-19 is transmitted, implementing voluntary public health interventions such as mask-wearing and social distancing that allow people to be in public safely, and providing sufficient safety net programs so that those who follow stay-at-home orders are not at risk of losing their paycheck. Mischaracterizing public health as an enemy of civil liberties erodes confidence in the public health institutions that are themselves dependent on the trust of the public. In order to move forward, public health policies must use the least restrictive means necessary and support civil liberties. While the government may order mandatory measures if voluntary recommendations fail, the decision should be made transparently, with clear scientific evidence and public accountability to ensure that any trade-offs are made openly with a process for appeal.[9] Protests could be avoided if less restrictive means (such as social distancing and mask requirements) were implemented early, which would allow businesses to remain open and workers to remain employed. This would align the goals of both public health and those dedicated to civil liberties. By thinking proactively about solutions that can simultaneously protect both public health and civil liberties, we will be better prepared the next time the country faces a crisis. Photo by Sandie Clarke on Unsplash [1] Vogel, Kenneth P., Jim Rutenberg, and Lisa Lerer. “The Quiet Hand of Conservative Groups in the Anti-Lockdown Protests.” New York Times, April 21, 2020. https://www.nytimes.com/2020/04/21/us/politics/coronavirus-protests-trump.html. [2] Stern, Mark Joseph. “Wisconsin’s Supreme Court Is Going to Use Fox News Arguments to Undo the State’s COVID-19 Restrictions.” Slate, May 5, 2020. https://slate.com/news-and-politics/2020/05/wisconsin-supreme-court-lift-covid-restrictions-fox-news.html [3] Long, Heather and Andrew Van Dam. “U.S. unemployment rate soars to 14.7 percent, the worst since the Depression era.” Washington Post, May 8, 2020. https://www.washingtonpost.com/business/2020/05/08/april-2020-jobs-report/. [4] Pew Research Center. “Most Americans Say Trump Was Too Slow in Initial Response to Coronavirus Threat.” Pew Research Center, April 16, 2020. https://www.people-press.org/2020/04/16/covid-19-and-the-countrys-trajectory/. [5] Nuffield Council on Bioethics. “Public Health: Ethical Issues.” November 2007. http://nuffieldbioethics.org/project/public-health/. [6] Jacobson v. Massachusetts, 197 U.S. 11 (1905). [7] Culhane, John G. “Sex, Fear, and Public Health Policy.” Review of Gay Bathhouses and Public Health Policy, edited by William J. Woods and Diane Binson, Yale Journal of Health Policy, Law, and Ethics 5, no. 1 (2005): 327-340. [8] Bayer, Ronald and Amy L. Fairchild. “The Genesis of Public Health Ethics.” Bioethics 18, no. 6 (2004): 473-492. [9] Childress, James F. et al. “Public Health Ethics: Mapping the Terrain.” Journal of Law, Medicine & Ethics 30 (2002): 170-178., Voices in Bioethics, Vol 6 (2020)

Cell therapy is an emerging therapeutic modality with the power to exploit new cancer targets and potentially achieve positive outcomes for patients with few other options. Like all synthetic treatments, cell therapy has the risk of toxicity via unpredicted off-target behavior. We describe an empirical method to model off-tumor, off-target reactivity of receptors used for investigational T cell therapies. This approach utilizes an optimal panel of diverse human cell-lines to capture the large majority of protein-coding gene expression in adult human tissues. We apply this cell-line set to test Jurkat and primary T cells engineered with a dual-signal integrator, called Tmod

Global civil aviation accounts for 4–5% of total greenhouse gas emissions and these emissions are increasing. In the absence of sufficiently effective global climate instruments, national instruments might be considered as a complement, in which case some way of allocating emissions from international air travel between countries is needed. The purpose of this paper is to develop an accounting method that reflects one country's greenhouse gas emissions from international air travel, and to apply this methodology to Sweden. The new methodology consists of three parts: the number of international air trips made by the country's residents; the average distance of these trips; and the greenhouse gas emissions per passenger km. For Sweden, data for 1990 to 2014 show an increase in the number of trips by Sweden's population of 3.6% per year, resulting in, on average, one international journey (round trip 5800 km) per capita in 2014. The average distance to the final destination has increased only marginally due to simultaneous growth in both long and short trips. However, global average greenhouse gas emissions per passenger km have decreased by 1.9% per year between 1990 and 2014. Because the increase in the number of their trips has outweighed the decrease in emissions per km, the total emissions from Swedish residents' international air travel have increased by 61% between 1990 and 2014. The total emissions from Swedish residents' air travel, including both CO2 and non-CO2-effects, were 11 Mt CO2 equivalents in 2014, which is the same level as the emissions from Swedish car traffic. This type of reliable data is important when designing policies and for getting public support for new policies.

Some diseases are accompanied with a change in biological parameters of which the dosage is possible in urine or blood. Previous studies have shown changes in parameters in kidney failure. The latter causes an impairment of the heart function later on. We have carried out a study of changes in biological parameters in people suffering exclusively from heart failure without any associated diseases or complications. The present research has been an analytic and case control one. It has been focused on urine, creatinine and on the total proteins found in the blood of heart failure patients diagnosed and hospitalized in the cardiologic Centre of Lubumbashi (D R Congo). Out of a population of 60 patients, our research has revealed a high level of urea and creatinine in the blood during heart failure, whereas the rate of total proteins has remained in the acceptable threshold.

BackgroundMesothelin (MSLN) and carcinoembryonic antigen (CEA) are classic tumor-associated antigens that are expressed in many solid tumors including the majority of lung, colorectal and pancreatic cancers. However, both MSLN and CEA are also expressed in vital normal organs. This normal expression creates risk of serious inflammation for CEA- or MSLN-directed therapeutics. To date all active CEA- or MSLN-targeted investigational therapeutics have been toxic when administered systemically.MethodsWe have developed a safety mechanism to protect normal tissues without abrogating sensitivity of cytotoxic T cells directed at MLSN(+) or CEA(+) tumors in a subset of patients with defined loss of heterozygosity (LOH) in their tumors (figure 1). This dual-receptor (Tmod< sup >TM) system exploits common LOH at the HLA locus in cancer cells, allowing T cells to recognize the difference between tumor and normal tissue.1 2 T cells engineered with specific Tmod constructs contain: (i) a MSLN- or CEA-activated CAR; and, (ii) an inhibitory receptor gated by HLA-A*02. HLA-A*02 binding blocks T cell cytotoxicity, even in the presence of MSLN or CEA. The Tmod system is designed to treat heterozygous HLA class I patients, selected for HLA LOH. When HLA-A*02 is absent from tumors selected for LOH, the CARs are predicted to mediate potent killing of the A*02(-) malignant cells.ResultsThe Tmod system robustly protects surrogate normal cells even in mixed-cell populations in vitro while mediating robust cytotoxicity of tumor cells in xenograft models (see example in figure 2). The MSLN CAR can also be paired with other blockers, supporting scalability of the approach to patients beyond HLA-A*02 heterozygotes.Abstract 122 Figure 1Illustration of the Tmod T cell engaging with tumor cells with somatic loss of HLA-A*02 and with normal cells.Abstract 122 Figure 2Bioluminescence measurements show the average difference between the size of the MSLN(+)A*02(+) ‘normal’ graft compared to the MSLN(+)A*02(-) tumor graft on the two flanks of mice after T cell infusion. Both tumor and normal grafts are destroyed by CAR-Ts (CAR-3 and M5 benchmark) while the MSLN Tmod cells kill the tumor but not the normal graft.ConclusionsThe Tmod mechanism may provide an alternative route to leverage solid-tumor antigens such as MSLN and CEA in safer, more effective ways than previously possible.ReferencesHamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol 2020;128:298–310.Hwang MS, Mog BJ, Douglass J, et al. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A 2021;118(12):e2022410118.