Reprogramming of mRNA translation has a key role in cancer development and drug resistance
. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ...modifications are required for specific codon decoding during translation
. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U
) tRNA (U
enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF
oncogene and by resistance to targeted therapy in melanoma. We show that BRAF
-expressing melanoma cells are dependent on U
enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U
enzymes. Mechanistically, U
enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U
enzymes and HIF1α. Together, these results demonstrate that U
enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Zusammenfassung
Der Einsatz von künstlicher Intelligenz (KI) setzt sich in den verschiedensten Bereichen der Medizin immer schneller durch. Dennoch fehlt vielen medizinischen Kollegen das technische ...Grundverständnis für die Funktionsweise dieser Technologie, was ihre Anwendung in Klinik und Forschung stark einschränkt. Daher möchten wir in dieser Übersichtsarbeit die Funktionsweise und Klassifizierung der KI am Beispiel des Melanoms erörtern, um ein Verständnis für die Technologie hinter der KI zu schaffen. Dazu werden ausführliche Illustrationen verwendet, die die Technologie schnell erklären. Bisherige Übersichten konzentrieren sich eher auf die potenziellen Anwendungen der KI und verpassen die Gelegenheit, ein tieferes Verständnis für die Materie herauszuarbeiten, das für die klinische Anwendung so wichtig ist. Das maligne Melanom ist zu einer erheblichen Belastung für die Gesundheitssysteme geworden. Bei frühzeitiger Entdeckung ist eine bessere Prognose zu erwarten, weshalb das Hautkrebs‐Screening immer populärer und von den Krankenkassen unterstützt wird. Die Zahl der Fachärzte ist jedoch begrenzt, was ihre Verfügbarkeit einschränkt und zu längeren Wartezeiten führt. Daher müssen innovative Ideen umgesetzt werden, um die notwendige Versorgung zu gewährleisten. Das maschinelle Lernen bietet die Möglichkeit, Melanome auf Bildern zu erkennen, und zwar auf einem Niveau, das mit dem von erfahrenen Dermatologen – unter optimierten Bedingungen – vergleichbar ist.
Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential ...therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.
In vivo detection of cellular senescence is accomplished by using mesoporous silica nanoparticles loaded with the NIR‐FDA approved Nile blue (NB) dye and capped with a galactohexasaccharide (S3). NB ...emission at 672 nm is highly quenched inside S3, yet a remarkable emission enhancement is observed upon cap hydrolysis in the presence of β‐galactosidase and dye release. The efficacy of the probe to detect cellular senescence is tested in vitro in melanoma SK‐Mel‐103 and breast cancer 4T1 cells and in vivo in palbociclib‐treated BALB/cByJ mice bearing breast cancer tumor.
I got the Nile blues: Mesoporous silica nanoparticles loaded with Nile blue and capped with a galacto‐hexasaccharide are used for in vivo imaging of cellular senescence. Fluorescence dye emission is quenched inside nanoparticles, yet a remarkable fluorescence is observed upon cap hydrolysis by β‐galactosidase. The probe detects cellular senescence in vitro and in vivo in palbociclib‐treated BALB/cByJ mice bearing breast tumors.
We report the first diselenide‐based probe for the selective detection of thioredoxin reductase (TrxR), an enzyme commonly overexpressed in melanomas. The probe design involves conjugation of a ...seminaphthorhodafluor dye with a diselenide moiety. TrxR reduces the diselenide bond, triggering a fluorescence turn‐on response of the probe. Kinetic studies reveal favorable binding of the probe with TrxR with a Michaelis–Menten constant (Km) of 15.89 μm. Computational docking simulations predict a greater binding affinity to the TrxR active site in comparison to its disulfide analogue. In vitro imaging studies further confirmed the diselenide probe exhibited improved signaling of TrxR activity compared to the disulfide analogue.
A reductive approach: A diselenide‐based probe for the detection of thioredoxin reductase 1 (TrxR1) was designed and synthesized. The non‐fluorescent probe switched on in the presence of TrxR1 and had minimal interference from other biological reducing species. The diselenide probe was successfully used in imaging TrxR1 in human lung cancer cells and showed greater fluorescence compared to a disulfide‐based analogue.
The American Association of Physicists in Medicine (AAPM) formed Task Group 221 (TG‐221) to discuss a generalized commissioning process, quality management considerations, and clinical physics ...practice standards for ocular plaque brachytherapy. The purpose of this report is also, in part, to aid the clinician to implement recommendations of the AAPM TG‐129 report, which placed emphasis on dosimetric considerations for ocular brachytherapy applicators used in the Collaborative Ocular Melanoma Study (COMS). This report is intended to assist medical physicists in establishing a new ocular brachytherapy program and, for existing programs, in reviewing and updating clinical practices. The report scope includes photon‐ and beta‐emitting sources and source:applicator combinations. Dosimetric studies for photon and beta sources are reviewed to summarize the salient issues and provide references for additional study. The components of an ocular plaque brachytherapy quality management program are discussed, including radiation safety considerations, source calibration methodology, applicator commissioning, imaging quality assurance tests for treatment planning, treatment planning strategies, and treatment planning system commissioning. Finally, specific guidelines for commissioning an ocular plaque brachytherapy program, clinical physics practice standards in ocular plaque brachytherapy, and other areas reflecting the need for specialized treatment planning systems, measurement phantoms, and detectors (among other topics) to support the clinical practice of ocular brachytherapy are presented. Expected future advances and developments for ocular brachytherapy are discussed.
•Fucoidan LlF from L. longipes was α-L-fucan with unusual structure.•LlF consisted of 1,2-, 1,3- and 1,4-linked α-L-Fuc residues.•Fucans LlF and ScF had anticancer effect on melanoma and colon cancer ...cells.•Fucans LlF and ScF possessed comparable radiosensitizing activity.
The sulfated α-l-fucans ScF and LlF were obtained from brown algae of the Laminariaceae family (Saccharina cichorioides and Laminaria longipes). According to spectroscopy NMR, the LlF fucan predominantly contained the →3)-α-l-Fucp-(2SO3–)-(1→4)-α-l-Fucp-(1→2)-α-l-Fucp-(4SO3–)-(1→ repeating units, with small amounts of disaccharide 1,4-linked fragments and 3-sulfated fucose residues. Mass spectrometric analysis revealed the presence of the following fragments in the fucan structure: α-l-Fucp-(2SO3–)-(1→4)-α-l-Fucp-(2SO3–)-(1→3)-α-l-Fucp-(4SO3–); α-l-Fucp-(2,4SO3–)-(1→3)-α-l-Fucp-(1→3)-α-l-Fucp-(4SO3–); α-l-Fucp-(2SO3–)-(1→2)-α-l-Fucp; α-l-Fucp-(2SO3–)-(1→2)-α-l-Fucp-(4SO3–); α-l-Fucp-(2SO3–)-(1→3)-α-l-Fucp; α-l-Fucp-(2,4SO3–)-(1→3)-α-l-Fucp; α-l-Fucp-(4SO3–)-(1→4)-α-l-Fucp; and α-l-Fucp-(4SO3–)-(1→4)-α-l-Fucp-(2SO3–). Both ScF and LlF fucoidans inhibited colony formation and growth of melanoma and colon cancer cells and sensitize-tested cancer cells to X-ray radiation to a comparable degree.
A comparative study between two novel, highly water soluble, ruthenium(II) polypyridyl complexes, Ru(phen)2L′ and Ru(phen)2Cu(II)L′ (L and L‐CuII), containing the polyaazamacrocyclic unit ...4,4′‐(2,5,8,11,14‐pentaaza15)‐2,2′‐bipyridilophane (L′), is herein reported. L and L‐CuII interact with calf‐thymus DNA and efficiently cleave DNA plasmid when light‐activated. They also possess great penetration abilities and photo‐induced biological activities, evaluated on an A375 human melanoma cell line, with L‐CuII being the most effective. Our study highlights the key role of the Fenton active CuII center within the macrocycle framework, that would play a synergistic role with light activation in the formation of cytotoxic ROS species. Based on these results, an optimal design of RuII polypyridyl systems featuring specific CuII‐chelating polyamine units could represent a suitable strategy for the development of novel and effective photosensitizers in photodynamic therapy.
Charged for Therapy: Novel RuII and RuII/CuII mixed polypyridyl complexes featuring different light‐activated mechanisms, singlet oxygen generation, and Fenton‐like oxidative pathways were studied as possible photosensitizers for photodynamic therapy.
Simulated microgravity (SMG) was reported to affect tumor cell proliferation and metastasis. However, the underlying mechanism is elusive. In this study, we demonstrate that clinostat-modelled SMG ...reduces BL6-10 melanoma cell proliferation, adhesion and invasiveness in vitro and decreases tumor lung metastasis in vivo. It down-regulates metastasis-related integrin α6β4, MMP9 and Met72 molecules. SMG significantly reduces formation of focal adhesions and activation of focal adhesion kinase (FAK) and Rho family proteins (RhoA, Rac1 and Cdc42) and of mTORC1 kinase, but activates AMPK and ULK1 kinases. We demonstrate that SMG inhibits NADH induction and glycolysis, but induces mitochondrial biogenesis. Interestingly, administration of a RhoA activator, the cytotoxic necrotizing factor-1 (CNF1) effectively converts SMG-triggered alterations and effects on mitochondria biogenesis or glycolysis. CNF1 also converts the SMG-altered cell proliferation and tumor metastasis. In contrast, mTORC inhibitor, rapamycin, produces opposite responses and mimics SMG-induced effects in cells at normal gravity. Taken together, our observations indicate that SMG inhibits focal adhesions, leading to inhibition of signaling FAK and RhoA, and the mTORC1 pathway, which results in activation of the AMPK pathway and reduced melanoma cell proliferation and metastasis. Overall, our findings shed a new light on effects of microgravity on cell biology and human health.
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