SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth

SMYD2 is a histone methyltransferase, which methylates both histone H3K4 as well as a number of non-histone proteins. Dysregulation of SMYD2 has been associated with several diseases including cancer. In the present study, we investigated whether and how SMYD2 might contribute to colorectal cancer. Increased expression levels of SMYD2 were detected in human and murine colon tumor tissues compared to tumor-free tissues. SMYD2 deficiency in colonic tumor cells strongly decreased tumor growth in two independent experimental cancer models. On a molecular level, SMYD2 deficiency sensitized colonic tumor cells to TNF-induced apoptosis and necroptosis without affecting cell proliferation. Moreover, we found that SMYD2 targeted RIPK1 and inhibited the phosphorylation of RIPK1. Finally, in a translational approach, pharmacological inhibition of SMYD2 attenuated colonic tumor growth. Collectively, our data show that SMYD2 is crucial for colon tumor growth and inhibits TNF-induced apoptosis and necroptosis.

Online patológiai vizsgálatkérő felület létrehozása a Semmelweis Egyetemen

Összefoglaló. Bevezetés: Az I. Patológiai és Kísérleti Rákkutató Intézet – a Semmelweis Egyetemen belüli diagnosztikai szolgáltatásnyújtás mellett – kiterjedt külső partneri hálózattal (vizsgálatmegrendelővel) bír. Az Intézet a napi működése során párhuzamosan használja az egyetem központi informatikai rendszerét, valamint belső, folyamattámogató alkalmazását (workflow management). A külsős partnerek hozzáférése vizsgálatfeladásra az egyetemi központi informatikai rendszerhez nincs biztosítva. A vizsgálatok rendelése papíralapú, a minta érkeztetésekor a klinikai adatok rögzítése manuális, kifejezetten humánerőforrás-igényes. Célkitűzés: Célunk volt a patológiai minták regisztrációjának egyszerűsítése és felgyorsítása, az adminisztratív folyamatok hatékonyságának javítása. Módszer: A kitűzött célt a minőségfejlesztésből ismert Plan-Do-Check-Act (Tervezés-Cselekvés-Ellenőrzés-Beavatkozás) ciklus módszereit alkalmazva kívántuk elérni, online, a mintavétel helyén elérhető, a meglévő belső folyamattámogató alkalmazáshoz kapcsolódó, szakterület-specifikus vizsgálatkérő felület kifejlesztésével. Eredmények: A vizsgálati minták regisztrációjának átlagos ideje 65%-kal csökkent az online vizsgálatkérő rendszerhez csatlakozott klinikai partnerek körében. Megbeszélés: Az elmúlt években tapasztalható volt, hogy kisebb, nem hatékonyan működtethető patológiai osztályok megszűntek, részben vagy egészben beolvadtak nagyobb diagnosztikai egységekbe. A humánerőforrás-problémák (elöregedő szakma a patológia) a fenti folyamatot minden bizonnyal tovább erősítik. Várható, hogy a nagyobb patológiai osztályokon a következő években a mintaszám tovább növekszik, a vizsgálatkérések egyre nagyobb hányada érkezik majd intézményen kívülről. Következtetés: A patológiai informatika fejlesztésekor figyelembe kell venni, hogy szükséges már a mintavétel helyén biztosítani az informatikai támogatást a minta nyomon követéséhez, nem elégséges csak a laboron belüli folyamatok kiszolgálása. Orv Hetil. 2021; 162(49): 1962–1967. Summary. Introduction: The 1st Department of Pathology and Experimental Cancer Research, Semmelweis University (Budapest, Hungary) has a broad network of clinical partners, many of which are non-university hospitals. A separate hospital information system and a local laboratory workflow management system is used at the Department. University clinics use the hospital information system for electronic requesting of tests. Non-university partners have no access to the systems, requesting tests is paper-based, registration of the requests at the pathology lab is manual and laborious. Objective: Our main objective was to improve the efficiency of the sample registration step of the pathology workflow. Method: Applying the Plan-Do-Check-Act procedure, a quality improvement project has been carried out and an online, subspecialty-based requesting application tool, interfaced with the current laboratory information system, was developed. Results: The average sample registration time improved with 65% among the early user partners. Discussion: The past years have shown smaller, inefficient pathology labs decreasing in number and integrated into larger regional diagnostic centers. Both issues of efficiency and quality assurance and problems rooted in human resources are drivers of further centralisation. The numbers of test requests and samples from non in-house partners are expected to be increased in the pathology labs in the future. Conclusion: Efficient and safe sample tracking has to start at the site of sample acquisition. State of the art laboratory information systems should support this expansion of competence. Orv Hetil. 2021; 162(49): 1962–1967.

Barnase-Barstar Pair: Contemporary Application in Cancer Research and Nanotechnology

Barnase is an extracellular ribonuclease secreted by Bacillus amyloliquefaciens that was originally studied as a small stable enzyme with robust folding. The identification of barnase intracellular inhibitor barstar led to the discovery of an incredibly strong protein-protein interaction. Together, barnase and barstar provide a fully genetically encoded toxin-antitoxin pair having an extremely low dissociation constant. Moreover, compared to other dimerization systems, the barnase-barstar module provides the exact one-to-one ratio of the complex components and possesses high stability of each component in a complex and high solubility in aqueous solutions without self-aggregation. The unique properties of barnase and barstar allow the application of this pair for the engineering of different variants of targeted anticancer compounds and cytotoxic supramolecular complexes. Using barnase in suicide gene therapy has also found its niche in anticancer therapy. The application of barnase and barstar in contemporary experimental cancer therapy is reflected in the review.

Targeted Chemotherapy Delivery via Gold Nanoparticles: A Scoping Review of In Vivo Studies

In the field of oncology, a lot of improvements in nanotechnology creates support for better diagnosis and therapeutic opportunities, and due to their physical and chemical properties, gold nanoparticles are highly applicable. We performed a literature review on the studies engaging the usage of gold nanoparticles on murine models with a focus on the type of the carrier, the chemotherapy drug, the target tumoral tissue and outcomes. We identified fifteen studies that fulfilled our search criteria, in which we analyzed the synthesis methods, the most used chemotherapy conjugates of gold nanoparticles in experimental cancer treatment, as well as the improved impact on tumor size and system toxicity. Due to their intrinsic traits, we conclude that chemotherapy conjugates of gold nanoparticles are promising in experimental cancer treatment and may prove to be a safer and improved therapy option than current alternatives.

Wnt/β-catenin signaling in cancers and targeted therapies

Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

Radiolabeling and PET–MRI microdosing of the experimental cancer therapeutic, MN-anti-miR10b, demonstrates delivery to metastatic lesions in a murine model of metastatic breast cancer

Background In our earlier work, we identified microRNA-10b (miR10b) as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR10b-targeted therapeutic consisting of an anti-miR10b antagomir conjugated to ultrasmall iron oxide nanoparticles (MN), termed MN-anti-miR10b. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b caused durable regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. Results In this study, we devised a method to efficiently radiolabel MN-anti-miR10b with Cu-64 (64Cu) and evaluated the pharmacokinetics and biodistribution of the radiolabeled product at two different doses: a therapeutic dose, referred to as macrodose, corresponding to 64Cu-MN-anti-miR10b co-injected with non-labeled MN-anti-miR10b, and a tracer-level dose of 64Cu-MN-anti-miR10b, referred to as microdose. In addition, we evaluated the uptake of 64Cu-MN-anti-miR10b by metastatic lesions using both in vivo and ex vivo positron emission tomography–magnetic resonance imaging (PET–MRI). A comparable distribution of the therapeutic was observed after administration of a microdose or macrodose. Uptake of the therapeutic by metastatic lymph nodes, lungs, and bone was also demonstrated by PET–MRI with a significantly higher PET signal than in the same organs devoid of metastatic lesions. Conclusion Our results demonstrate that PET–MRI following a microdose injection of the agent will accurately reflect the innate biodistribution of the therapeutic. The tools developed in the present study lay the groundwork for the clinical testing of MN-anti-miR10b and other similar therapeutics in patients with cancer.

Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers

Tweetable abstract US FDA-approved immune checkpoint inhibitors have limited efficacy for gastrointestinal cancers such as #colorectalcancer and #pancreaticcancer. Could combinations with experimental cancer ‘vaccines’ be the key?