Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model

Combining different types of immune therapies might benefit certain patients. Here, the authors develop an autologous immune-humanized melanoma mouse model that allows the preclinical assessment of cancer cell–T cell interactions from each individual patient and the benefits of immunotherapies combinations

Target-driven sustainable product development

Figuring in sustainability in product development requires a profound understanding of the cause and effect of engineering decisions along the full spectrum of the product lifecycle and the triple bottomline of sustainability. Sustainability design targets can contribute to mitigating the complexity involved, by means of a formalised problem description. This article discusses how sustainability design targets can be defined and presents methods for systematically implementing these targets into the design process. To that end, different means of decision support mechanisms are presented. They comprise (a) use cases of target breakdowns in subsystems, (b) systematic reduction of solution space and (c) assistance in design activities to ensure achievement of sustainability design targets. This paper explains how interfaces to engineering tools such as Computer Aided Design/Engineering (CAD/CAE) or Product Data/Lifecycle Management (PDM/PLM) can be put in place to make the process of retrieving information and providing decision support more seamless

Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs

Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma

Ethnobotanical knowledge is vastly under-documented in northwestern South America

A main objective of ethnobotany is to document traditional knowledge about plants before it disappears. However, little is known about the coverage of past ethnobotanical studies and thus about how well the existing literature covers the overall traditional knowledge of different human groups. To bridge this gap, we investigated ethnobotanical data-collecting efforts across four countries (Colombia, Ecuador, Peru, Bolivia), three ecoregions (Amazon, Andes, Chocó), and several human groups (including Amerindians, mestizos, and Afro-Americans). We used palms (Arecaceae) as our model group because of their usefulness and pervasiveness in the ethnobotanical literature. We carried out a large number of field interviews (n = 2201) to determine the coverage and quality of palm ethnobotanical data in the existing ethnobotanical literature (n = 255) published over the past 60 years. In our fieldwork in 68 communities, we collected 87,886 use reports and documented 2262 different palm uses and 140 useful palm species. We demonstrate that traditional knowledge on palm uses is vastly under-documented across ecoregions, countries, and human groups. We suggest that the use of standardized data-collecting protocols in wide-ranging ethnobotanical fieldwork is a promising approach for filling critical information gaps. Our work contributes to the Aichi Biodiversity Targets and emphasizes the need for signatory nations to the Convention on Biological Diversity to respond to these information gaps. Given our findings, we hope to stimulate the formulation of clear plans to systematically document ethnobotanical knowledge in northwestern South America and elsewhere before it vanishesThis study was funded by the European Union, 7th Framework Programme (contract no. 212631), the Russel E. Train Education for Nature Program of the WWF (to NPZ), the Anne S. Chatham fellowship of the Garden Club of America (to NPZ), and the Universidad Autónoma de Madrid travel grants programme (to RCL

Prdm5 Regulates Collagen Gene Transcription by Association with RNA Polymerase II in Developing Bone

PRDM family members are transcriptional regulators involved in tissue specific differentiation. PRDM5 has been reported to predominantly repress transcription, but a characterization of its molecular functions in a relevant biological context is lacking. We demonstrate here that Prdm5 is highly expressed in developing bones; and, by genome-wide mapping of Prdm5 occupancy in pre-osteoblastic cells, we uncover a novel and unique role for Prdm5 in targeting all mouse collagen genes as well as several SLRP proteoglycan genes. In particular, we show that Prdm5 controls both Collagen I transcription and fibrillogenesis by binding inside the Col1a1 gene body and maintaining RNA polymerase II occupancy. In vivo, Prdm5 loss results in delayed ossification involving a pronounced impairment in the assembly of fibrillar collagens. Collectively, our results define a novel role for Prdm5 in sustaining the transcriptional program necessary to the proper assembly of osteoblastic extracellular matrix

American palm ethnomedicine: A meta-analysis

<p>Abstract</p> <p>Background</p> <p>Many recent papers have documented the phytochemical and pharmacological bases for the use of palms (<it>Arecaceae</it>) in ethnomedicine. Early publications were based almost entirely on interviews that solicited local knowledge. More recently, ethnobotanically guided searches for new medicinal plants have proven more successful than random sampling for identifying plants that contain biodynamic ingredients. However, limited laboratory time and the high cost of clinical trials make it difficult to test all potential medicinal plants in the search for new drug candidates. The purpose of this study was to summarize and analyze previous studies on the medicinal uses of American palms in order to narrow down the search for new palm-derived medicines.</p> <p>Methods</p> <p>Relevant literature was surveyed and data was extracted and organized into medicinal use categories. We focused on more recent literature than that considered in a review published 25 years ago. We included phytochemical and pharmacological research that explored the importance of American palms in ethnomedicine.</p> <p>Results</p> <p>Of 730 species of American palms, we found evidence that 106 species had known medicinal uses, ranging from treatments for diabetes and leishmaniasis to prostatic hyperplasia. Thus, the number of American palm species with known uses had increased from 48 to 106 over the last quarter of a century. Furthermore, the pharmacological bases for many of the effects are now understood.</p> <p>Conclusions</p> <p>Palms are important in American ethnomedicine. Some, like <it>Serenoa repens </it>and <it>Roystonea regia</it>, are the sources of drugs that have been approved for medicinal uses. In contrast, recent ethnopharmacological studies suggested that many of the reported uses of several other palms do not appear to have a strong physiological basis. This study has provided a useful assessment of the ethnobotanical and pharmacological data available on palms.</p

Strategic Life-Cycle Modeling and Simulation for Sustainable Product Innovation

Many specific methods and tools have been developed to deal with sustainability problems. However, without a unifying theory it is unclear how these relate to each other and how they can be used strategically. A Framework for Strategic Sustainable Development (FSSD) is being developed to cover this need for clarity and structure. It includes backcasting from a principled definition of sustainability as a key feature. The aim of this thesis is to study how this framework can guide the use and improvement of detailed methods and tools, in particular to support sustainable product innovation (SPI). First, a new strategic life-cycle management approach is presented, in which the selection of aspects to be considered are not based on typical down-stream impact categories, but on identified major violations of sustainability principles. Ideas of how this approach can inform various specific methods and tools are also presented, as a basis for an integrated “toolbox” for SPI. As part of such, a new “template” approach for sustainable product development (TSPD) is developed through a sustainability assessment case study of TVs. That study indicates that this approach can create a quick and strategically relevant overview of critical sustainability aspects of a product, as well as facilitate communication between top management, product developers and external stakeholders. Based on such an assessment, it is sometimes necessary to go deeper into details, including the use of specific engineering methods and tools. To facilitate a coordinated assessment of sustainability aspects and technical aspects, an introductory procedure for sustainability-driven design optimization is suggested trough a water jet cutting case study. Equally important, to get a breakthrough for SPI, it is essential to integrate sustainability aspects into the overall decision-making process at different levels in companies. An approach to assessing sustainability integration in strategic decision systems is therefore also developed through a case study involving several companies. Finally, the integration between the FSSD and general systems modeling and simulation (SMS) is discussed and tested in another water jet cutting case study. It is shown feasible to start with the FSSD to create lists of critical flows and practices, ideas of long term solutions and visions, and a first rough idea about prioritized early investments. After that, SMS can be applied to study the interrelationships between the listed items, in order to create more robust and refined analyses of the problems at hand, possible solutions and investment paths, while constantly coupling back to the sustainability principles and guidelines of the FSSD. This research shows that the combination of the FSSD with detailed methods and tools cohesively provides decision-makers with both a robust overview and, when needed, a more coordinated and effective detailed support. To utilize its full potential, this approach should now be integrated into decision processes, software and manuals for SPI

Snabba landtransporter för Sverige : En oberoende översikt för strategiska investeringsbeslut

In 2020 and 2021 the Swedish debate about high speed ground transport intensified. Conflicting facts and opinions have been presented in a way that is quite inconsistent with a global sustainability perspective. It is important that all societal sectors can be sustainable together. This implies a need to model futures within sustainability constraints that take all essential sustainability related challenges into account. This study is an independent preliminary strategic decision support overview on fast ground transport - directed towards Swedish transport politicians and other high level decision makers within the transport sector. The study covered three steps: Step 1. Describing a Vision of the Desired Future. What societal goals and requirements does a future sustainable system for fast ground transport need to live up to? It should meet customer expectations for “value for money” (e.g. speed, punctuality, comfort) It should not contribute to systematic destruction of the environment (e.g. through emissions or physical destruction) or the social system (e.g. through health problems and discrimination). It should be prudent with the societal economy and resource reserves. Step 2. Assessing the Current Situation in Relation to the Vision. It was found that fuels and infrastructure for travel with trains are much better than private cars or domestic flights from a sustainability perspective. But it was also found that the Swedish train system has a maintenance debt and is operating near its maximum capacity with frequent disturbancies and delays. Step 3. Reviewing Strategic Investment Choices. What are some potential alternative investment choices to close the gap between the current situation and a desired future and what are their likely economic, ecological and social effects? Assumptions and variations around three main alternatives were reviewed with the following results: Scenario 1. Upgrade the Existing System. This may add some marginal benefits but may risk to not meet transport demands, to not protect the environment and to add societal costs. Scenario 2. Build a New High Speed Rail (HSR) System. This would likely be better for transport demands and the societal economy but also have some environmental impacts. Scenario 3. Build a New Magnetic Levitation (‘Maglev’) Train System. This could have the best potential to meet transport demands and to create benefits for the societal economy with the least environmental impacts. The main recommendation from this study is that Swedish transport politicans initiate a new independent investigation that compares at least the three future scenarios for high- speed ground transport suggested here and their potential effects for society at large and all modes of transport. If the initial findings of this study could be confirmed and acted upon then Sweden might become first in Europe to implement the new breakthrough Maglev technology in the transport sector. This could help Sweden to fulfil its goal to become one of the first fossil free welfare countries and also give the country great export opportunities.Under 2020 och 2021 intensifierades den svenska debatten om snabba landtransporter. Motstridiga fakta och åsikter har presenterats på ett sätt som är oförenligt med ett globalt hållbarhetsperspektiv. Samtidigt är det för att lösa den komplexa hållbarhetsutmaningen speciellt viktigt med ett helhetstänk och att samarbeta mellan alla samhällssektorer. Detta innebär ett behov av att kunna modellera framtider inom hållbarhetsbegränsningar som tar hänsyn till alla väsentliga hållbarhetsrelaterade utmaningar. Denna studie är en oberoende preliminär strategisk beslutsstödsöversikt om snabba landtransporter – riktad till svenska transportpolitiker och andra beslutsfattare på hög nivå inom transportsektorn. Studien delades upp i tre steg: Steg 1. Beskriv en vision om den önskade framtiden. Vilka samhälleliga mål och krav behöver ett framtida hållbart system för snabba marktransporter kunna leva upp till? Studien fann att ett sådant system: Ska uppfylla kundernas förväntningar på "valuta för pengarna" (inklusive hastighet, punktlighet och komfort) Inte ska bidra till systematisk förstörelse av miljön (t.ex. genom utsläpp eller fysisk förstörelse) eller det sociala systemet (t.ex. genom hälsoproblem och diskriminering). Bör vara sparsamt med samhällsekonomin och naturresurserna. Steg 2. Bedöm nuläget i relation till visionen. Studien fann att drivmedel och infrastruktur för resor med tåg är mycket bättre än privatbilar eller inrikesflyg ur ett hållbarhetsperspektiv. Men det konstaterades också att det svenska tågsystemet har en underhållsskuld och fungerar alltför nära sin maximala kapacitet vilket leder till frekventa störningar och förseningar. Steg 3. Granska strategiska investeringsval. Vilka potentiella alternativa investeringsscenarier kan identifieras för att minska gapet mellan nuläget och den önskade framtiden och vilka är deras troliga ekonomiska, ekologiska och sociala effekter? Antaganden och variationer kring tre huvudscenarier granskades med följande resultat: Scenario 1. Uppgradera befintligt system. Detta kan tillföra vissa marginella fördelar men riskerar att inte möta varken privatpersoners eller industrins transportbehov, att öka samhällskostnaderna samt att kräva kraftfulla styrmedel och tvingande regler för att kunna skydda miljön. Scenario 2. Bygg ett nytt höghastighetstågssystem (HSR). Detta skulle sannolikt kunna bli bättre för privatpersonernas och industrins transportbehov och för samhällsekonomin men det skulle också ha en kännbar miljöpåverkan. Scenario 3. Bygg ett nytt järnvägssystem med magnettåg ('Maglev'). Detta skulle kunna ha den bästa potentialen att möta privatpersoners och industrins transportbehov och samtidigt skapa fördelar för samhällsekonomin med minst miljöpåverkan. Huvudrekommendationen från denna studie är att svenska transportpolitiker inleder en ny oberoende utredning som gör en djupare jämförelse av åtminstone de tre framtidsscenarier för snabba landtransporter som föreslås här samt deras potentiella effekter för övriga transportslag och samhället i stort. Om den här inledande studiens slutsatser då kunde bekräftas och om politiker och andra högre beslutsfattare kunde agera därefter så kunde Sverige bli först i Europa med att bygga den nya genombrottsteknologin magnettåg. Detta skulle kunna hjälpa Sverige att nå sitt mål om att bli ett av världens första fossilfria välfärdsländer och samtidigt ge framtida exportmöjligheter genom att Sverige blir ett starkt alternativ för magnettågskunnande för hela den demokratiska världen

Strategisk livscykelmodellering för hållbar produktutveckling

Decision makers are challenged by complex sustainability problems within the socio-ecological system. In response, a vast range of sustainability-related methods/tools have been developed, each focusing on certain aspects of this challenge. Without a unifying theory it is, however, unclear how these methods/tools can support strategic progress towards sustainability and how they relate to each other. This need for clarity and structure urged some sustainability pioneers to start develop an overarching framework for strategic sustainable development (SSD), often called “The Natural Step (TNS) framework”, from the NGO that has facilitated its development and application, or the “backcasting from sustainability principles (BSP) framework” from its main operational philosophy. The aim of this thesis is to study if, and in that case how, this framework can aid coordination and further development of various sustainability-related methods/tools, specifically to increase their capacity to support sustainable product development (SPD). Life-cycle assessment (LCA), “templates” for SPD and systems modeling and simulation (SMS) are the methods/tools in focus. A new strategic life-cycle management approach is presented, in which the main sustainability aspects, LCA “impacts”, are identified through socioecological sustainability principles. This creates new opportunities to avoid the reductionism that often follows from traditional system boundaries or from a focus on specific impacts. Ideas of how this approach can inform the studied tools are given. This may eventually lead to a whole integrated toolbox for SPD (a “Design Space”). As part of such a Design Space, a new “template” approach for SPD is developed. A case study of a sustainability assessment of TVs at the Matsushita Electric Group indicates that this approach can create a quick overview of critical sustainability aspects in the early part of the product development process and facilitate communication of this overview between top management, product developers, and other stakeholders. A potential integration between BSP and SMS is also discussed. It is suggested that this should start with BSP to create lists of critical presentday flows and practices, ideas of long term solutions and visions, and a first rough idea about prioritized early investments. After that, SMS should be applied to study the interrelationships between the listed items, in order to create more robust and refined analyses of the problems at hand, possible solutions and investment paths, while constantly coupling back to the sustainability principles and guidelines of the BSP framework. v Decision makers seem to need more of an overview and of simplicity around sustainability issues. A general conclusion is, however, that it is important that this is achieved without a loss of relevant aspects and their interrelations. Over-simplifications might lead to sub-optimized designs and investments paths. Combining the BSP framework with more detailed methods/tools seems to be a promising approach to finding the right balance and to get synergies between various methods/tools