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Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth, but very little has been known about its characteristics and origin. Recently, cancer-derived exosome has ...been suggested to transdifferentiate CAFs, by a new mechanism of endothelial to mesenchymal transition (EndMT), initiating angiogenic processes and triggering metastatic evolution. However, an enabling tool in vitro is yet to be developed to investigate complicated procedures of the EndMT and the transdifferentiation under reconstituted tumor microenvironment. Here we proposed an in vitro microfluidic model which enables to monitor a synergetic effect of complex tumor microenvironment in situ, including extracellular matrix (ECM), interstitial flow and environmental exosomes. The number of CAFs differentiated from human umbilical vein endothelial cells (HUVECs) increased with melanoma-derived exosomes, presenting apparent morphological and molecular changes with pronounced motility. Mesenchymal stem cell (MSC)-derived exosomes were found to suppress EndMT, induce angiogenesis and maintain vascular homeostasis, while cancer-derived exosomes promoted EndMT. Capabilities of the new microfluidic model exist in precise regulation of the complex tumor microenvironment and therefore successful reconstitution of 3D microvasculature niches, enabling in situ investigation of EndMT procedure between various cell types.
This study presents an in vitro 3D EndMT model to understand the progress of the CAF generation by recapitulating the 3D tumor microenvironment in a microfluidic device. Both cancer-derived exosomes and interstitial fluid flow synergetically played a pivotal role in the EndMT and consequent formation of CAFs through a collagen-based ECM. Our approach also enabled the demonstration of a homeostatic capability of MSC-derived exosomes, ultimately leading to the recovery of CAFs back to endothelial cells. The in vitro 3D EndMT model can serve as a powerful tool to validate exosomal components that could be further developed to anti-cancer drugs.
Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA ...accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.
Autophagy acts as a cytoprotective mechanism for malignant tumors, thus maintaining the survival and promoting proliferation and metastasis of malignant tumors. Recent studies have showed that ...autophagy inhibitors can enhance the chemotherapeutic efficacy of anti-tumor growth. However, the antimetastasis effects and the possible mechanisms of chemotherapeutics combined with autophagy inhibitors have not been thoroughly explored. Here, we prepared R8-dGR peptide modified paclitaxel (PTX) and hydroxychloroquine (HCQ) co-loaded liposomes (PTX/HCQ-R8-dGR-Lip) for enhanced delivery by recognizing integrin αvβ3 receptors and neuropilin-1 receptors on B16F10 melanoma cells. Our results showed that R8-dGR modified liposomes (R8-dGR-Lip) enhanced tumor-targeting delivery in vitro and in vivo. Besides, PTX/HCQ-R8-dGR-Lip exhibited the optimum inhibitory effects on migration, invasion and anoikis resistance of B16F10 cells in vitro, and showed enhanced efficiency on inhibiting primary tumor growth and reducing lung metastasis in vivo. Meanwhile, the antimetastasis mechanism studies confirmed that the combination of the chemotherapeutic PTX and the autophagy inhibitor HCQ further suppressed the degradation of paxillin, the expression of MMP9 and MMP2. Moreover, HCQ disturbed the CXCR4/CXCL12 axis which could induce invasion and metastasis of malignant melanoma in an autophagy-independent way.
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•Enhanced tumor-targeting delivery based on R8-dGR modification.•Enhanced anti-tumor and antimetastasis efficacy based on the combination of paclitaxel and hydroxychloroquine.•Regulation of paxillin and matrix metalloproteinases in an autophagy-dependent way.•Disturbance of CXCR4/CXCL12 axis in an autophagy-independent way.
The aim of the study was to investigate the antimicrobial and antiproliferative activity of Citrus medica essential oil produced by hydrostillation and evaluate its commercial potential in the food ...industry. The main constituent of the C. medica peels and essential oil identified by SPME GC/MS or GC/MS analysis was limonene (≈88 and 64%, respectively). The antimicrobial properties were assayed and the minimum inhibitory and non-inhibitory concentration values were determined. Both C. medica essential oil and limonene were effective against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Listeria monocytogenes, Salmonella Enteritidis, Salmonella Typhimurium, Pseudomonas fragi, Saccharomyces cerevisiae and Aspergillus niger. MIC and MBC values for the oil ranged 845 ± 26–2008 ± 43 mg/l and 4184–8368 mg/l, respectively. C. medica essential oil was further assessed in different human cancer cell lines (HepG2, Caco2, MCF-7, and THP-1) and was found to have significant antiproliferative activity, being the most effective against the Caco2 cells. Citrus medica oil and limonene were shown to possess cancer-specific activity when tested against the skin melanoma A375 cells and normal skin cells (HaCat). The oil also appeared to inhibit LPS-induced nitric oxide (NO) production in RAW 264.7 cells.
•The biological properties of Citrus medica essential oil were studied.•The main constituent of C. medica peels and essential oil was limonene.•The essential oil was effective against spoilage and pathogenic microbes.•The essential oil was found to have significant antiproliferative activity.•The oil appeared to inhibit LPS-induced nitric oxide production in RAW 264.7 cells.
Biocompatible and bioresponsive microneedles (MNs) are emerging technology platforms for sustained drug release with a potential to be a key player in transdermal delivery of therapeutics. In this ...paper, an innovative biodegradable MNs patch for the sustained delivery of drugs using a polymer patch, which can adjust delivery rates based on its crosslinking degree, is reported. Gelatin methacryloyl (GelMA) is used as the base for engineering biodegradable MNs. The anticancer drug doxorubicin (DOX) is loaded into GelMA MNs using the one molding step. The GelMA MNs can efficiently penetrate the stratum corneum layer of a mouse cadaver skin. Mechanical properties and drug release behavior of the GelMA MNs can be adjusted by tuning the degree of crosslinking. The efficacy of the DOX released from the GelMA MNs is tested and the anticancer efficacy of the released drugs against melanoma cell line A375 is demonstrated. Since GelMA is a versatile material in engineering tissue scaffolds, it is expected that the GelMA MNs can be used as a platform for the delivery of various therapeutics.
A biocompatible and biodegradable microneedles patch based on gelatin methacryloyl are developed for transcutaneous delivery of drugs. The microneedles can efficiently penetrate the stratum corneum layer in a mouse cadaver skin model and the drug release profile can be controlled by tuning the crosslinking degrees. The model drug doxorubicin keeps its anticancer efficacy after enzyme‐mediated release from the patch.
Zusammenfassung
Hintergrund und Zielsetzung
Die Frage, wie oft Melanompatienten mit Mittel‐ bis Hochrisikomelanomen den Tumor bemerken und welche Eigenerkennungsmuster existieren ist bislang nicht ...beantwortet.
Patienten und Methoden
Wir haben eine retrospektive Studie an Melanompatienten durchgeführt, die sich zwischen 2004 und 2008 einer Sentinellymphknotenbiopsie unterzogen haben,. Der Fragebogen wurde von 127 der insgesamt 133 Patienten ausgefüllt.
Ergebnisse
25 % bemerkten den Tumor überhaupt nicht. Die restlichen 75 % zeigten verschiedene Eigenerkennungsmuster: 25 % holten nach 0–12 Wochen Rat ein, weitere 25 % innerhalb von 3–6 Monaten, und bei den restlichen 25 % wurde der Tumor mehr als sechs Monate lang beobachtet, bevor er entfernt wurde. Alter, Geschlecht und Lokalisation des Melanoms waren bei allen Eigenerkennungsgruppen vergleichbar. Die häufigsten Subtypen waren: SSM (59), NMM (31), ALM (9), UCM (9) und LMM (4). Seltene Subtypen (15) waren ebenfalls vorhanden. Patienten mit 3–6 Monate alten Läsionen zeigten die höchste durchschnittliche Tumordicke und die bei weitem höchste Anzahl von pT4‐Tumoren. 60 % der Patienten mit NMM hatten eine Krankengeschichte von <6 Monaten. Seltene Subtypen wie amelanotische, Spindelzell‐ und spitzoide Melanome wurden in nur 50 % der Fälle selbstständig erkannt.
Schlussfolgerungen
Selbst fortgeschrittene Melanome blieben von den Patienten in 25 %, seltene Melanom‐Subtypen in 50 % der Fälle unerkannt. Daher sollte der Eigenerkennungshäufigkeit, dem erhöhten Bewusstsein für seltene Melanome und der schnellen Überweisung an einen Spezialisten in zukünftigen Aufklärungskampagnen besondere Aufmerksamkeit zukommen.
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•A redox prodrug co-loading camptothecin and curcumin was prepared.•The co-delivery system showed a synergetic inhibition effect to B16 melanoma cells.•The co-delivery system showed a ...good biocompatibility.
A redox prodrug consisting of camptothecin-conjugating PEG through the diselenide bond was synthesized, and the resultant amphiphilic prodrug was then used to load the curcumin to form the co-delivery system for the synergetic B16 melanoma cells inhibition. The co-delivery system showed a good response to glutataione, and the prodrug could be degraded and the two loaded drugs were then released. Both camptothecin and curcumin could induce the obvious cytotoxicity to B16 melanoma cells. Particularly, the co-delivery strategy showed a synergetic inhibition effect to B16 melanoma cells through an in vitro assay. In vivo assay also showed that the co-delivery system could inhibit B16 tumor growth and showed much better inhibition effect than that of only camptothecin or curcumin used. Moreover, as an injectable drug delivery system, the biocompatibility including the blood compatibility of the co-delivery system was confirmed, suggesting that the redox co-delivery system have a potential application in B16 tumor therapy.
Zusammenfassung
Lange Zeit wurde die Dermatochirurgie auch innerhalb der Dermatologie als isoliertes, nicht immer bedeutendes Teilgebiet betrachtet. Als therapeutische Option galt sie entweder als ...Goldstandard der Erstlinientherapie, beispielsweise bei der Operation des Basalzellkarzinoms und der Behandlung von Melanomen in frühen Stadien, oder als letzte Option, zum Beispiel bei der Behandlung von Warzen. Dass hier ein tiefgreifender Wandel stattgefunden hat und die Dermatochirurgie heute ein integraler, gleichberechtigter, manchmal führender, aber immer wichtiger Bestandteil der Dermatologie ist, zeigt diese Übersicht an drei Beispielen aus der geriatrischen Dermatologie, der Behandlung der Hidradenitis suppurativa (Acne inversa) und der Melanomtherapie. Ergänzt wird die Arbeit durch einen Abschnitt zur wichtigsten Therapieform innerhalb der Dermatochirurgie, der mikroskopisch (mikrographisch) kontrollierten Chirurgie.
Over the past decade, cold atmospheric plasmas have shown promising application in cancer therapy. The therapeutic use of plasma-activated media is a topic addressed in an emerging field known as ...plasma pharmacy. In oncology, plasma-activated media are used to harness the therapeutic effects of oxidant species when they come in contact with cancer cells. Among several factors that contribute to the anticancer effect of plasma-activated liquid media (PALM), H
O
and NO derivatives likely play a key role in the apoptotic pathway. Despite the significant amount of literature produced in recent years, a full understanding of the mechanisms by which PALM exert their activity against cancer cells is limited. In this paper, a sealed dielectric-barrier discharge was used to disentangle the effect of reactive nitrogen species (RNS) from that of reactive oxygen species (ROS) on cancer cells. Two cancers characterized by poor prognosis have been investigated: metastatic melanoma and pancreatic cancer. Both tumour models exposed to PALM rich in H
O
showed a reduction in proliferation and an increase in calreticulin exposure and ATP release, suggesting the potential use of activated media as an inducer of immunogenic cell death via activation of the innate immune system.
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