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Cancer drugs often kill cells independent of their putative targets, suggesting the limitation of existing knowledge on the mechanisms of action. In this study, we explored whether the integration of loss-of-function genetic and drug sensitivity screening data can define a gene essentiality signature to better understand the drug target interactions. We showed that our gene essentiality signature can predict drug targets more accurately than chemical fingerprints and drug-perturbated gene expression signatures. We further showed how gene essentiality signature can help identify mechanisms of action of drugsde novo, including the EGFR inhibitor lapatinib, and drugs associated with DNA mismatch repair. Finally, we established gene essentiality signatures for noncancer drugs and used them to predict their anticancer targets. We have successfully validated the target predictions for multiple noncancer drugs, using cell-based drug target deconvolution by the proteome integral solubility alteration assay. Our study provides a novel signature of drugs that may facilitate the rational design of drug repurposing.

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods coupling cell states to future fates. However, transcriptional changes that drive pre-treatment cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance, and allows identification of asymmetric features that drive phenotypic heterogeneity. Applying ReSisTrace in ovarian cancer cells revealed that BRCAness transcriptional signatures are associated with pre-existing vulnerability not only to olaparib and carboplatin treatments, but also to natural killer cell-mediated cytotoxicity. This novel connection between DNA repair defect and susceptibility to natural killer cells was further validated both functionally and in a clinical cohort. The high-resolution analysis by ReSisTrace enables resolving pre-existing transcriptional features of treatment vulnerability, facilitating molecular patient stratification for personalised therapies.

Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease‐specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial–mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression., We have identified several prognostic markers and potential therapeutic targets in primary melanomas. One of them, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), proved critical for the invasion and survival of melanoma cells and the deposition of collagens (stained in blue) and CTHRC1 in the extracellular matrix and tumor blood vessel walls, maintaining their integrity.

Most patients treated in a hospital setting are fully or partially immobilised. The Activity Board (Träningstavlan® Phystec) is a useful tool to enhance mobilisation after major abdominal cancer surgery. Knowledge of patient experiences of the mobilisation tool is crucial in implementing the Activity Board in health care. This study aimed to describe patient experiences of using the Activity Board after surgery for abdominal cancer. Semi-structured face-to-face interviews were conducted in 15 patients who underwent abdominal surgery due to colorectal, ovarian or urinary bladder cancer. All 15 patients (mean age 67.7 years, range 40–86) used the Activity Board postoperatively. The interviews were transcribed verbatim and analysed according to inductive content analysis. The overarching theme that emerged from the interviews was that “enabling participation facilitates empowerment over rehabilitation”. Three categories supported the theme: prerequisites for using the Activity Board, the value of using supportive behavioural techniques, and the possibility to influence the patients’ care. These findings suggest that the Activity Board could be a viable tool that activates the person-centred postoperative rehabilitation process by cooperating with the medical team at the hospital ward.Implications for rehabilitationPatients who are in hospital due to cancer surgery are often immobilised, which increases the risk of complications.The Activity Board can stimulate the patients to participate in the rehabilitation process in a more active way.The Activity Board can be used to improve and clarify the person-centred approach in hospital settings. Patients who are in hospital due to cancer surgery are often immobilised, which increases the risk of complications. The Activity Board can stimulate the patients to participate in the rehabilitation process in a more active way. The Activity Board can be used to improve and clarify the person-centred approach in hospital settings.

From the drug discovery perspective, combination therapy is recommended for cancer treatment due to its efficiency and safety compared to the common cytotoxic and single-targeted monotherapies. However, identifying effective drug combinations is time-and cost-consuming. Here, we offer a novel strategy for predicting potential drug combinations and patient subclasses by constructing multipartite networks using drug-response data on patient samples. In this study, we used Beat AML and GDSC, two comprehensive datasets based on patient-derived and cell line-based samples, to show the potential of multipartite network modelling in combinatorial cancer therapy. We used the median values of cell viability to compare drug potency and reconstruct a weighted bipartite network that models the interaction of drugs and biological samples. Then, clusters of network communities were identified in two projected networks based on the topological structure of the networks. Chemical structures, drug-target networks, protein– protein interactions, and signalling networks were used to corroborate the intra-cluster homogeneity. We further leveraged the community structures within the drug-based multipartite networks to discover effective multi-targeted drug combinations and synergy levels, which were supported with more evidence using the DrugComb and ALMANAC databases. Furthermore, we confirmed the potency of selective combinations of drugs against monotherapy in in vitro experiments using three acute myeloid leukaemia (AML) cell lines. Taken together, this study presents an innovative data-driven strategy based on multipartite networks to suggest potential drug combinations to improve AML treatment.

We have previously shown that proto-oncoprotein c-Jun is activated in ornithine decarboxylase (ODC)- and RAS-transformed mouse fibroblasts, and that the transformed morphology of these cells can be reversed by expressing the transactivation domain deletion mutant of c-Jun (TAM67). Here, we found that lysyl oxidase (Lox), encoding an extracellular matrix-modifying enzyme, is downregulated in a c-Jun-dependent manner in ODC-transformed fibroblasts (Odc cells). In addition to Lox, the Lox family members Lox-like 1 and 3 (Loxl1 and Loxl3) were found to be downregulated in Odc as well as in RAS-transformed fibroblasts (E4), whereas Lox-like 4 (Loxl4) was upregulated in Odc and downregulated in E4 cells compared to normal N1 fibroblasts. Tetracycline-regulatable LOX re-expression in Odc cells led to inhibition of cell growth and invasion in three-dimensional Matrigel in an activity-independent manner. On the contrary, LOX and especially LOXL2, LOXL3, and LOXL4 were found to be upregulated in several human melanoma cell lines, and LOX inhibitor B-aminopropionitrile inhibited the invasive growth of these cells particularly when co-cultured with fibroblasts in Matrigel. Knocking down the expression of LOX and especially LOXL2 in melanoma cells almost completely abrogated the invasive growth capability. Further, LOXL2 was significantly upregulated in clinical human primary melanomas compared to benign nevi, and high expression of LOXL2 in primary melanomas was associated with formation of metastases and shorter survival of patients. Thus, our studies reveal that inactive pro-LOX (together with Lox propeptide) functions as a tumor suppressor in ODC- and RAS-transformed murine fibroblasts by inhibiting cell growth and invasion, and active LOX and LOXL2 as tumor promoters in human melanoma cells by promoting their invasive growth. Copyright: Kielosto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

From the drug discovery perspective, combination therapy is recommended in cancer due to efficiency and safety compared to the common cytotoxic and single-targeted monotherapies. However, identifying effective drug combinations is time- and cost-consuming. Here, we offer a novel strategy of predicting potential drug combinations and patient subclasses by constructing multipartite networks using drug response data on patient samples. In the present study, we used Beat AML and GDSC, two comprehensive datasets based on patient-derived and cell line-based samples, to show the potential of multipartite network modeling in cancer combinatorial therapy. We used the median values of cell viability to compare drug potency and reconstruct a weighted bipartite network, which models the interaction of drugs and biological samples. Then, clusters of network communities were identified in two projected networks based on the topological structure of networks. Chemical structures, drug-target networks, protein-protein interactions, and signaling networks were used to corroborate the intra-cluster homogeneity. We further leveraged the community structures within the drug-based multipartite networks to discover effective multi-targeted drug combinations, and the synergy levels which were supported with more evidence using the DrugComb and the ALMANAC databases. Furthermore, we confirmed the potency of selective combinations of drugs against monotherapy in vitro experiment using three acute myeloid leukemia (AML) cell lines. Taken together, this study presents an innovative data-driven strategy based on multipartite networks to suggest potential drug combinations to improve treatment of AML.

The decentralisation of Swedish healthcare closer to citizens has been slow. Drawing from empirical material of the reform prior and amidst the COVID-19 pandemic, this paper argues that the pandemic has disrupted the healthcare ecosystem. Consequently, citizen-centred collaborations have accelerated integration of resources (such as knowledge and skills) across organisational, hierarchical and professional borders. However, collaborations have been delimited to traditional healthcare providers, neglecting the resources of citizens and other actors to be used to improve service delivery. The pandemic has revealed strengths and weaknesses with the prevailing healthcare ecosystem that post-COVID-19 public management must address, both theoretically and practically. Theoretically, the paper contributes to the development of a public service logic, addressing both strengths and difficulties with the logic in turbulent times. Practically, the empirical descriptions contribute to improved understanding of public service delivery reform and how it is impacted during the pandemic. © 2021 The Authors. Australian Journal of Public Administration published by John Wiley & Sons Australia, Ltd on behalf of Institute of Public Administration Australia.

Bakgrund: Patienters återhämtning påverkas av möte med sjuksköterskor, symtom, behandling, biverkningar och vårdrelation. Sjuksköterskors profession utgår ifrån att arbeta med individanpassad vård och det innebär att varje patient bör behandlas unikt och vårdas efter patientens omvårdnadsbehov. Syftet: Syftet var att beskriva kvinnliga patienters upplevelser av stöd från sjuksköterskor vid återhämning av bröstcancer. Metod: En systematisk litteraturstudie med tio vetenskapliga artiklar som analyserades utifrån Evans analysmetod. Resultat: Resultatet visade på två huvudteman och fyra subteman. Det första temat, uppmuntran till återhämtning och tillhörande subteman var: stödets betydelse och motivationens betydelse. Andra temat var: ge information om sjukdomen och tillhörande subteman var: förmedla muntlig information och förmedla skriftlig information. Slutsats: Patienters upplevelser av stöd från sjuksköterskor vid återhämtning av bröstcancer berodde på att patienter fick den vård som de var i behov av vilket innebar att ett vänligt förhållande mellan patienter och sjuksköterskor skapades. Det gjorde att patienter kunde lita på sjuksköterskor genom att patienterna sökte efter trygghet och säkerhet. Detta resulterade till att patienterna kunde uppnå återhämtning med hjälp av stöd från sjuksköterskorna. Background: Patients' recovery is affected by meeting with nurses, symptoms, treatment, side effects and relationship of care. The nursing profession is based on working with personalized care and this means that each patient should be treated uniquely and cared for according to the patient's nursing needs. Aim: The aim was to describe female patients' experiences of support from nurses in the recovery of breast cancer. Method: A systematic literature study with ten scientific articles that were analyzed based on Evans' analysis method. Results: The results showed two main themes and four subthemes. The first theme, recovery encouragement and associated sub-themes were: the importance of support and the importance of motivation. The second theme was to provide information about the disease and associated sub-themes were: convey oral information and convey written information. Conclusion: Patients' experiences of support from nurses in recovering from breast cancer were due to patients receiving the care they needed, which meant that a friendly relationship between patients and nurses was created. This allowed patients to trust nurses by seeking safety and security. This result led to patients being able to achieve recovery with the help of the support of the nurses.

Underlying drivers of species extinctions need to be better understood for effective conservation of biodiversity. Nearly half of all amphibian species are at risk of extinction, and pollution may be a significant threat as seasonal high-level agrochemical use overlaps with critical windows of larval development. The potential of environmental chemicals to reduce the fitness of future generations may have profound ecological and evolutionary implications. This study characterized effects of male developmental exposure to environmentally relevant concentrations of the anti-androgenic pesticide linuron over two generations of offspring in Xenopus tropicalis frogs. The adult male offspring of pesticide-exposed fathers (F1) showed reduced body size, decreased fertility, and signs of endocrine system disruption. Impacts were further propagated to the grand-offspring (F2), providing evidence of transgenerational effects in amphibians. The adult F2 males demonstrated increased weight and fat body palmitoleic-to-palmitic acid ratio, and decreased plasma glucose levels. The study provides important cross-species evidence of paternal epigenetic inheritance and pollutant-induced transgenerational toxicity, supporting a causal and complex role of environmental contamination in the ongoing species extinctions, particularly of amphibians.

Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance. In this study, systemic exposure was simulated by applying biopharmaceutics input parameters from isolated perfused rat lung (IPL) data to a lung model developed in MoBi® as an extension to the full physiologically-based pharmacokinetic (PBPK) model in PK-Sim®. These simulations were performed for a set of APIs with a variety of physicochemical properties and formulation types. Simulations based on rat IPL data were also compared to simulations based on in vitro data. The predictive performances of the simulations were evaluated by comparing simulated plasma concentration-time profiles to clinical observations after pulmonary administration. Simulations using IPL-based input parameters predicted systemic exposure well, with predicted AUCs within two-fold of the observed value for nine out of ten drug compounds/formulations, and predicted Cmax values within two-fold for eight out of ten drug compounds/formulations. Simulations using input parameters based on IPL data performed generally better than simulations based on in vitro input parameters. These results suggest that the developed model in combination with IPL data can be used to predict human lung absorption for compounds with different physicochemical properties and types of inhalation formulations.

Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silico model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1–6) was also established. This correlation (R2 = 0.76, p

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused rat lung (IPL) model. Two particle size distributions (d50 = 1.2 μm and d50 = 2.8 μm) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter ( kex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter ( kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 μM), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 μm). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between kex vivo and kin vitro. The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Excised rat intestinal tissue mounted in an Ussing chamber can be used for intestinal permeability assessments in drug development. The outer layer of the intestine, the serosa and part of the muscle layer, is traditionally removed since it is considered a barrier to the diffusion of nutrients and oxygen as well as to that of pharmaceutical substances. However, the procedure for removing the serosal-muscle layer, i.e. stripping, is a technically challenging process in the pre-experimental preparation of the tissue which may result in tissue damage and reduced viability of the segment. In this study, the viability of stripped and native (non-stripped) rat small intestine tissue segments mounted in Ussing chambers was monitored and the apparent permeability of the tissue to a set of test compounds across both tissue preparations was determined. Electrical measurements, in particular the potential difference (PD) across the intestinal membrane, were used to evaluate the viability. In this study, there were no differences in initial PD (health status of the tissue) or PD over time (viability throughout the experiment) between native and stripped rat jejunum segments. Overall, there were also no significant differences in permeability between stripped and native rat intestinal tissue for the compounds in this study. Based on these results, we propose that stripping can be excluded from the preparation procedures for rat jejunal tissue for permeability studies when using the Ussing chamber technique.

// Johanna Eriksson 1 , Vadim Le Joncour 2 , Pirjo Nummela 1 , Tiina Jahkola 3 , Susanna Virolainen 1 , Pirjo Laakkonen 2 , Olli Saksela 4 , Erkki Holtta 1 1 Department of Pathology, University of Helsinki, FI-00014 Helsinki, Finland 2 University of Helsinki, Research Programs Unit, Translational Cancer Biology, Biomedicum Helsinki, FI-00014 Helsinki, Finland 3 Department of Plastic Surgery, Helsinki University Central Hospital, FI-00029 Helsinki, Finland 4 Department of Dermatology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland Correspondence to: Erkki Holtta, e-mail: erkki.holtta@helsinki.fi Keywords: melanoma, invasion/metastasis, CTHRC1, NFATC2, TGFβ Received: June 11, 2015 Accepted: January 31, 2016 Published: February 23, 2016 ABSTRACT Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 ( CTHRC1 ), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators—NFATC2, TGFβ, and BRAF—attractive therapeutic targets against metastatic melanomas.

Letter volumes in Denmark dropped with 75 percent between 2000 and 2016, whereas Sweden’s declined with 34 percent. We make a comparative analysis of Denmark and Sweden by analyzing the effects of digitalization and the strategies from the common USO-provider Postnord. Denmark had a national digitalization strategy already from 2001 and a law in 2012 required everybody to have a digital mailbox. In response to falling demand, prices were increased sharply and service reduced. Sweden has a fragmented market for digital messages and with large postal volumes, competitive prices, a well-functioning market for second class mail and better ability to adjust costs, digital substitution was limited.

One factor influencing quality in the building industry is the ability of users, such as residents, to identify and express their requirements for the product, i.e. the residential building. However, the handling of communication with users in building projects has been insufficiently specified and studied. Drawing on a study of user involvement in building project design, production, and management, this paper examines user involvement in Swedish residential projects. To map current perceptions and approaches, building industry actors met in four focus groups. Group participants were asked to reflect on the definition of users, communication handling, how information from users is used, and challenges and opportunities in user involvement. Our initial emphasis was front-end activities, but focus group results revealed that user involvement was a continuous process extending from project initiation to evaluating the finished project as a basis for future projects. Discussions indicated confusion about who constituted users in various situations but, regardless of level of experience, focus group participants agreed on the importance and potential of user involvement and on the need for specific methods to acquire useful input.

Are you interested in designing new ways of networking at the Nordes conference with fellow researchers?Do you want to explore and discuss the so called “workspacelab” as a platform for user involvement?This workshop invites participants to explore a particular version of the design:lab called the workspace:lab. With a focus on methods like probekits, design games and experience prototyping the participants will experience what it is like being part of the design:lab as “users” and they will be exposed to the different equipment and tools used in the “laboratory of change”. Though the main focus of the workshop is to explore the workspace:lab, the actual output of the workshop is also relevant. The participants will be encouraged to codesign examples of new ways of networking at conferences, which could benifit the Nordes community in the future.

Day surgery is an expanding service, yet in many cases the current built environment is based on the general surgical department, with access to day bed wards and has changed very little since 1950s in the UK. In Dec 2019 a one-day workshop was organised to investigate the future concept for day surgery services and to explore the spatial provi-sions. The event consisted of a range of stakeholders from government, practice and aca-demia involved in healthcare environments. A design dialogue methodology was imple-mented, exploring the ‘ideal model of care’ through a series of activities using word, image and free association from user experiences. A design game, using tangible materials, let the participants develop and build visual proposals of new surgical environments. The workshop outcome was further processed through identification, sorting and coding of key themes for improvement, such as; user experience, logistics, adaptable design, after-care and recovery. By defining high and low parameters of patient experiences, a number of topics were discussed, including social community systems, information awareness, safety and wellbeing, continuity of patient pathways as well as efficiency and effectiveness of staff. The final design game combined the themes and topics and further deepened the in-sights. The use of a variety of design dialogue methods combined perspectives and knowledge and the workshop clearly identified the value and impact of interdisciplinary collabora-tion to deliberate and explore ideas for future healthcare facilities.