Organotypic three-dimensional assays based on human leiomyoma-derived matrices

Alongside cancer cells, tumours exhibit a complex stroma containing a repertoire of cells, matrix molecules and soluble factors that actively crosstalk between each other. Recognition of this multifaceted concept of the tumour microenvironment (TME) calls for authentic TME mimetics to study cancer in vitro. Traditionally, tumourigenesis has been investigated in non-human, three-dimensional rat type I collagen containing organotypic discs or by means of mouse sarcoma-derived gel, such as Matrigel (R). However, the molecular compositions of these simplified assays do not properly simulate human TME. Here, we review the main properties and benefits of using human leiomyoma discs and their matrix Myogel for in vitro assays. Myoma discs are practical for investigating the invasion of cancer cells, as are cocultures of cancer and stromal cells in a stiff, hypoxic TME mimetic. Myoma discs contain soluble factors and matrix molecules commonly present in neoplastic stroma. In Transwell, IncuCyte, spheroid and sandwich assays, cancer cells move faster and form larger colonies in Myogel than in Matrigel (R). Additionally, Myogel can replace Matrigel (R) in hanging-drop and tube-formation assays. Myogel also suits three-dimensional drug testing and extracellular vesicle interactions. To conclude, we describe the application of our myoma-derived matrices in 3D in vitro cancer assays. This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.Peer reviewe

Bilberry (Vaccinium myrtillus L.) Powder Has Anticarcinogenic Effects on Oral Carcinoma In Vitro and In Vivo

Previous studies indicate that bilberry with high amounts of phenolic compounds can inhibit carcinogenic processes of colorectal cancer in vitro and in vivo. However, no studies have focused on the effects of bilberry on oral cancer. In this study, we aimed to examine the effects of bilberry powder on oral squamous cell carcinoma (OSCC) cells using both in vitro and in vivo assays. The effects of 0, 1, 10, and 25 mg/mL of whole bilberry powder on the viability, proliferation, migration, and invasion of OSCC (HSC-3) cells were examined and compared with 0.01 mg/mL of cetuximab. Two oral keratinocyte cell lines served as controls. Tumor area was analyzed in zebrafish microinjected with HSC-3 cells and treated with 2.5, 10, or 25 µg/mL of bilberry powder. Metastases in the head or tail areas were counted. Bilberry powder inhibited the viability, proliferation, migration, and invasion of HSC-3 cells (p < 0.05), which was more pronounced with higher concentrations. Cetuximab had no effect on HSC-3 cell migration or invasion. Compared to controls, the tumor area in zebrafish treated with bilberry powder (10 and 25 µg/mL) was reduced significantly (p = 0.038 and p = 0.021, respectively), but the number of fish with metastases did not differ between groups. Based on our in vitro and in vivo experiments, we conclude that whole bilberry powder has anti-tumor effects on OSCC cells

Hydrogen economy : Opportunities and limitations

Hydrogen economy aims to reduce CO2 emissions in sectors and processes where utilising other solutions is particularly challenging. Such processes can be found in industries, aviation, maritime transport, and heavy-duty road transport. The EU is currently preparing legislative changes to enable an increased implementation of hydrogen-based solutions. At the same time, countries in and outside Europe have been develoing their national hydrogen strategies. Thousands of projects are being established for the production and end-use of clean hydrogen in Europe alone. Hydrogen economy provides an opportunity for Finland, as Finnish power generation has a relatively low carbon intensity and there is a stable national transmission grid for electricity available. Furthermore, Finland has vast potential for additional wind power, which could be utilised to produce hydrogen and electrofuels to meet domestic demand as well as for exports. On the other hand, the future supply and demand still remain highly uncertain in the international market. Strong competition is anticipated between different technologies and alternative locations for production. Finland must ensure preconditions for industrial investments in the hydrogen economy, and create clear targets and an action plan for the hydrogen transition in different sectors. The development of the hydrogen economy can be supported, e.g., by easing the licensing of additional wind power construction, increasing hydrogen expertise, and supporting R&D activities in technologies, services, and collaboration. Electricity and hydrogen transmission infrastructures should be developed as a whole in preparation for the future needs while managing the related risks and costs. Alternative technologies and solutions must be considered along with the hydrogen-based solutions. In addition, conditions for fair competition must be ensured both domestically and internationally.This publication is part of the implementation of the Government Plan for Analysis, Assessment and Research. (tietokayttoon.fi) The content is the responsibility of the producers of the information and does not necessarily represent the view of the Government

Vetytalous – mahdollisuudet ja rajoitteet

Vetytaloudella tavoitellaan hiilidioksidipäästöjen vähentämistä aloilla, joilla muiden keinojen käyttö on erityisen haasteellista. Tällaisia kohteita löytyy mm. teollisuudesta, lento- ja meriliikenteestä sekä raskaasta tieliikenteestä. EU valmistelee yhteisiä vetyratkaisujen yleistymistä mahdollistavia lainsäädäntömuutoksia. Samaan aikaan eri maat Euroopassa ja sen ulkopuolella ovat laatineet kansallisia vetystrategioitaan. Vedyn tuotantoon ja loppukäyttöön suunnattuja projekteja on pelkästään Euroopassa kehitteillä tuhansittain. Suomelle vetytalous näyttäytyy mahdollisuutena, koska Suomessa on melko vähähiilinen sähköntuotantokapasiteetti ja vahva sähkön kantaverkko. Tämän lisäksi Suomessa on valtava tuulivoiman lisärakennuspotentiaali, jota voitaisiin hyödyntää vedyn ja sähköpolttoaineiden tuotantoon sekä kotimaan kysyntää että vientiä varten. Toisaalta kansainvälisen markkinan tulevaisuuden tarjontaan ja kysyntään liittyy suuria epävarmuuksia. Odotettavissa on tiukka kansainvälinen kilpailu eri teknologioiden ja tuotantopaikkavaihtoehtojen välillä. Suomessa on varmistettava edellytykset teollisuuden vetytalouteen suuntautuville investoinneille ja luotava selkeät tavoitteet ja toimenpidesuunnitelma vetyratkaisujen käyttöönotolle eri sektoreilla. Vetytalouden kehittymistä voidaan edistää mm. tuulivoiman lisärakentamisen luvitusta helpottamalla, vetyosaamista lisäämällä ja TKI-toimintaa tukemalla niin teknologioiden, palvelujen kuin yhteistyön osalta. Sähkönsiirto- ja vedynsiirtoinfrastruktuureja tulisi kehittää kokonaisuutena tulevaisuuden tarpeisiin varautuen, mutta halliten kustannuksia ja riskejä. Vetyratkaisujen edistämistoimissa tulee ottaa huomioon vaihtoehtoiset teknologiat ja ratkaisut. Samoin on huolehdittava tasapuolisten kilpailuedellytysten toteutumisesta niin kotimaassa kuin kansainvälisesti.Tämä julkaisu on toteutettu osana valtioneuvoston selvitys- ja tutkimussuunnitelman toimeenpanoa. (tietokayttoon.fi) Julkaisun sisällöstä vastaavat tiedon tuottajat, eikä tekstisisältö välttämättä edusta valtioneuvoston näkemystä

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC

Organotypic three-dimensional assays based on human leiomyoma–derived matrices

Abstract Alongside cancer cells, tumours exhibit a complex stroma containing a repertoire of cells, matrix molecules and soluble factors that actively crosstalk between each other. Recognition of this multifaceted concept of the tumour microenvironment (TME) calls for authentic TME mimetics to study cancer in vitro. Traditionally, tumourigenesis has been investigated in non-human, three-dimensional rat type I collagen containing organotypic discs or by means of mouse sarcoma-derived gel, such as Matrigel®. However, the molecular compositions of these simplified assays do not properly simulate human TME. Here, we review the main properties and benefits of using human leiomyoma discs and their matrix Myogel for in vitro assays. Myoma discs are practical for investigating the invasion of cancer cells, as are cocultures of cancer and stromal cells in a stiff, hypoxic TME mimetic. Myoma discs contain soluble factors and matrix molecules commonly present in neoplastic stroma. In Transwell, IncuCyte, spheroid and sandwich assays, cancer cells move faster and form larger colonies in Myogel than in Matrigel®. Additionally, Myogel can replace Matrigel® in hanging-drop and tubeformation assays. Myogel also suits three-dimensional drug testing and extracellular vesicle interactions. To conclude, we describe the application of our myoma-derived matrices in 3D in vitro cancer assays. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’

Sosiaalisesti kestävä hyvinvointiyhteiskunta kriiseissä

Non peer reviewe

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.

PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335)