In vivo selective cancer-tracking gadolinium eradicator as new-generation photodynamic therapy agent.

In this work, we demonstrate a modality of photodynamic therapy (PDT) through the design of our truly dual-functional--PDT and imaging--gadolinium complex (Gd-N), which can target cancer cells specifically. In the light of our design, the PDT drug can specifically localize on the anionic cell membrane of cancer cells in which its laser-excited photoemission signal can be monitored without triggering the phototoxic generation of reactive oxygen species--singlet oxygen--before due excitation. Comprehensive in vitro and in vivo studies had been conducted for the substantiation of the effectiveness of Gd-N as such a tumor-selective PDT photosensitizer. This treatment modality does initiate a new direction in the development of "precision medicine" in line with stem cell and gene therapies as tools in cancer therapy.

[Hereditary renal tumors: More common than expected?]. / Hereditäre Nierentumoren: Häufiger als erwartet?

Renal cell carcinomas are associated with hereditary tumor syndromes in approximately 5 % of cases. In patients with a hereditary predisposition, tumors show an earlier age of onset, often with a multicentric and bilateral manifestation. While some patients with renal cell carcinoma can be classified into well-characterized kidney cancer syndromes others have a genetic background which is still poorly understood. Most of the specific tumor syndromes are associated with a histopathologically distinct renal cell tumor phenotype. The recognition of patients with hereditary renal cell carcinoma and the identification of individual family members with a higher risk of development of renal tumors is important for early tumor detection and treatment. This manuscript reviews the clinical pathological and molecular findings of hereditary renal cell carcinoma syndromes.

Injectable and Sprayable Fluorescent Nanoprobe for Rapid Real-Time Detection of Human Colorectal Tumors.

The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3 min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apcmin/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection.

Programming Affinity for Precise Tumor Recognition with Allosteric Nanosensing-Circles.

Although many smart probes for precise tumor recognition have been reported, the challenge of "on-target, off-tumor" remains. Therefore, we herein report the fabrication of a series of allosterically tunable DNA nanosensing-circles (NSCs). The recognition affinity of NSCs is programmed through sensitivity to tumor microenvironment (TME) hallmarks such as small molecules, acidity, or oncoproteins. Because of their special programming conditions and active targeting capabilities, NSCs can overcome the obstacles noted above, thus achieving precise tumor recognition. Results from in vitro analysis demonstrated that NSCs obtain their recognition ability through allosteric regulation after sensing TME hallmarks. Furthermore, in vivo imaging indicated that NSCs enable precise tumor imaging. These results demonstrate that our NSCs will be promising tools for precise tumor imaging and therapy.

Coal humus acid functionalized high stability fluorescent copper nanoclusters for tumor identification by sequential off-on-off monitoring tryptophan and Hg2.

The abnormalities of Tryptophan (Trp) and mercury ions (Hg2+) not only easily activate diseases, including mental illness and cancer, but also seriously affect human wellbeing. Fluorescent sensors are profoundly attractive options for identifying amino acids and ions; however, most sensors remain challenging due to the multipliable cost and deviation from the asynchronous quenching detection. In particular, fluorescent copper nanoclusters with high stability that quantitatively monitoring Trp and Hg2+ successively have seldom been reported. Herein, we employ coal humus acid (CHA) as a protective ligand and successfully construct weak cyan fluorescent copper nanoclusters (CHA-CuNCs) by a rapid, environmentally benign and cost-effective method. Significantly, the fluorescence of CHA-CuNCs is obviously improved by introducing Trp, because the indole group of Trp enhances the radiative recombination and aggregation-induced emissions. Interestingly, CHA-CuNCs not only realizes the highly selective and specific detection of Trp with a linear range of 25-200 µM and a detection limit of 0.043 µM based on the turn-on fluorescence strategy, but also quickly achieves the consecutive turn-off detection of Hg2+ due to the chelation interaction between Hg2+ and pyrrole heterocycle in Trp. Moreover, this method is successfully applied in the analysis of Trp and Hg2+ in real samples. Furthermore, the confocal fluorescent imaging of tumor cells demonstrates that CHA-CuNCs can be used for bioimaging and cancer cell recognition with Trp and Hg2+ abnormalities. These findings provide new guidance for the eco-friendly synthesis of CuNCs with eminent sequential off-on-off optical sensing property, indicating good prospects in biosensing and clinical medicine applications.

New perspective of ceria nanodots for precise tumor therapy via oxidative stress pathway.

Ceria-based nanomaterials have aroused major attentions among the biomedical application research field in recent years. Most of the researches have mainly focused on promoting the functional healing therapies of normal cells/organs with cerium oxide compounds, while the applications of ceria-based materials employed on cancer curing processes have been merely mentioned. To explore the possible capabilities of cerium oxide nanomaterials exterminating tumor cells, innovatively, we synthesized the eco-friendly pure cerium oxide nanodots (CNDs), proving the prominent ability of CNDs used in tumor chemotherapy (CDT) via Fenton reaction with the highly presence of H2O2 (acidic pH) in tumor tissues. CNDs reacted with the self-produced H2O2 of tumor cells, which generated piled up toxic hydroxyl radical (·OH). The accumulated virulent ·OH restrained the growth of cancer cells intensively. This peroxidase-like activity, provided a distinguished paradigm for effective cancer curing treatment. We also verified the biosafety of CNDs applied on normal cells. Notably, not only did CNDs be harmless to normal cells, but also it protected them from the damages of reactive oxygen species (ROS). In normal cells/tissues, under the microenvironment of neutral pH and low level of H2O2, the CNDs could effectively function as an annihilator inhibiting ROS. They reduced the damages caused by ROS, exhibiting catalase-like activity. The research we studied, which estimated CNDs thoroughly, has provided a new perspective to the future researches of the cerium oxide biomaterial applications.

Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads.

For the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen prediction technologies provides opportunities for further development of personalized immunotherapies. In this study, we present a novel strategy to deliver in silico predicted neoantigens to autologous dendritic cells (DCs) using paramagnetic beads (EpiTCer beads). DCs pulsed with EpiTCer beads are superior in enriching for healthy donor and patient blood-derived tumor-specific CD8+ T cells compared to DC loaded with whole-tumor lysate or 9mer neoantigen peptides. A dose-dependent effect was observed, with higher EpiTCer bead per DC being favorable. We concluded that CD8+ T cells enriched by DC loaded with EpiTCer beads are tumor specific with limited tumor cross-reactivity and low recognition of autologous non-activated monocytes or CD8+ T cells. Furthermore, tumor specificity and recognition were improved and preserved after additional expansion using our Good Manufacturing Process (GMP)-compatible rapid expansion protocol. Phenotypic analysis of patient-derived EpiTCer DC expanded CD8+ T cells revealed efficient maturation, with high frequencies of central memory and effector memory T cells, similar to those observed in autologous expanded tumor-infiltrating lymphocytes. These results indicate that DC pulsed with EpiTCer beads enrich for a T-cell population with high capacity of tumor recognition and elimination, which are features needed for a T-cell product to be used for personalized adoptive cell therapy.

Palmitoylated antigens for the induction of anti-tumor CD8+ T cells and enhanced tumor recognition.

Induction of tumor-specific cytotoxic CD8+ T cells (CTLs) via immunization relies on the presentation of tumor-associated peptides in major histocompatibility complex (MHC) class I molecules by dendritic cells (DCs). To achieve presentation of exogenous peptides into MHC class I, cytosolic processing and cross-presentation are required. Vaccination strategies aiming to induce tumor-specific CD8+ T cells via this exogenous route therefore pose a challenge. In this study, we describe improved CD8+ T cell induction and in vivo tumor suppression of mono-palmitic acid-modified (C16:0) antigenic peptides, which can be attributed to their unique processing route, efficient receptor-independent integration within lipid bilayers, and continuous intracellular accumulation and presentation through MHC class I. We propose that this membrane-integrating feature of palmitoylated peptides can be exploited as a tool for quick and efficient antigen enrichment and MHC class I loading. Importantly, both DCs and non-professional antigen-presenting cells (APCs), similar to tumor cells, facilitate anti-tumor immunity by efficient CTL priming via DCs and effective recognition of tumors through enhanced presentation of antigens.

Artificial intelligence in musculoskeletal oncological radiology.

BACKGROUND: Due to the rarity of primary bone tumors, precise radiologic diagnosis often requires an experienced musculoskeletal radiologist. In order to make the diagnosis more precise and to prevent the overlooking of potentially dangerous conditions, artificial intelligence has been continuously incorporated into medical practice in recent decades. This paper reviews some of the most promising systems developed, including those for diagnosis of primary and secondary bone tumors, breast, lung and colon neoplasms. CONCLUSIONS: Although there is still a shortage of long-term studies confirming its benefits, there is probably a considerable potential for further development of computer-based expert systems aiming at a more efficient diagnosis of bone and soft tissue tumors.

MR1-Restricted T Cells Are Unprecedented Cancer Fighters.

Non-polymorphic MHC class I-related molecule MR1 presents antigenic bacterial metabolites to mucosal-associated invariant T (MAIT) cells and self-antigens to MR1-restricted T (MR1T) cells. Both MR1-restricted T cell populations are readily identified in healthy individuals, with MAIT cells accounting for 1-10% of circulating T cells, while MR1T cells have frequencies comparable to peptide-specific T cells (<0.1%). Self-reactive MR1T cells display a heterogeneous phenotype, and are capable of releasing both TH1 and TH2 cytokines, supporting not only activation of inflammation but also contributing to its regulation. Importantly, MR1T cells recognize and kill a diverse range of MR1-expressing tumor cells. On the other hand, evidence suggests MAIT cells augment cancer growth and metastases. This review addresses the potential role of MR1-restricted T cells in controlling tumor cells, facilitating their elimination and regulating cancer immunity. We also discuss therapeutic opportunities surrounding MR1-restricted T cells in cancer.

Acidic pH and High-H2O2 Dual Tumor Microenvironment-Responsive Nanocatalytic Graphene Oxide for Cancer Selective Therapy and Recognition.

It is well known that tumors have an acidic pH microenvironment and contain a high content of hydrogen peroxide (H2O2). These features of the tumor microenvironment may provide physiochemical conditions that are suitable for selective tumor therapy and recognition. Here, for the first time, we demonstrate that a type of graphene oxide nanoparticle (N-GO) can exhibit peroxidase-like activities (i.e., can increase the levels of reactive oxygen species (ROS)) under acidic conditions and catalyze the conversion of H2O2 to ROS-hydroxyl radicals (HO·) in the acidic microenvironment in Hela tumors. The concentrated and highly toxic HO· can then trigger necrosis of tumor cells. In the microenvironment of normal tissues, which has a neutral pH and low levels of H2O2, N-GOs exhibit catalase-like activity (scavenge ROS) that splits H2O2 into O2 and water (H2O), leaving normal cells unharmed. In the recognition of tumors, an inherent redox characteristic of dopamine is that it oxidizes to form dopamine-quinine under neutral (pH 7.4) conditions, quenching the fluorescence of N-GOs; however, this characteristic has no effect on the fluorescence of N-GOs in an acidic (pH 6.0) medium. This pH-controlled response provides an active targeting strategy for the diagnostic recognition of tumor cells. Our current work demonstrates that nanocatalytic N-GOs in an acidic and high-H2O2 tumor microenvironment can provide novel benefits that can reduce drug resistance, minimize side effects on normal tissues, improve antitumor efficacy, and offer good biocompatibility for tumor selective therapeutics and specific recognition.

Tumor Targeting via Sialic Acid: [68Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET.

PURPOSE: The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia). PROCEDURES: The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [68Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [68Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent. RESULTS: The affinity of [68Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36 ± 2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [68Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection. CONCLUSIONS: Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.