A novel PCDscore based on programmed cell death-related genes can effectively predict prognosis and therapy responses of colon adenocarcinoma.

Emerging evidence suggests a correlation between oncogenesis and programmed cell death (PCD). However, comprehensive studies that incorporate all identified PCD-related genes to guide colon adenocarcinoma (COAD) prognosis and precision treatment strategies are lacking. In this study, a series of bioinformatics analyses were comprehensively conducted using data from the TCGA-COAD, GSE17538, and GSE39582 cohorts. A total of 21 PCD-associated prognostic genes were identified through univariate Cox analysis. LASSO and multivariate Cox methods were employed to establish a prognostic gene signature (ALOX12, HSPA1A, IL13, MID2, RFFL, and SLC39A8) and the corresponding scoring system, termed PCDscore, which exhibited robust predictive ability. The ssGSEA and ESTIMATE algorithms were utilized to evaluate the tumor microenvironment of COAD. The high PCDscore group demonstrated a poorer prognosis, characterized by lower CD4+ T cell infiltration and a higher stromal score. In contrast, the low PCDscore group exhibited sensitivity to common chemotherapy drugs such as Cisplatin and 5-Fluorouracil. Single-cell sequencing analysis further revealed that the high-PCDscore group displayed a lower proportion of CD4+ T cells. Colorectal cancer samples from the years 2013-2017 were employed to validate the PCDscore, while those from 2018 to 2019 served as a temporal external validation set for the PCDscore. In vitro experimental results indicated that the overexpression of SLC39A8 inhibited the proliferation and invasion of colorectal cancer cells. The study developed a novel PCDscore system based on the analysis of genes related to all identified PCD types, providing valuable insights into clinical prognosis and drug sensitivity for patients with COAD.

Water-solubility croconic acid-bisindole dye with morpholine ring for tumor NIRF/PA imaging and photothermal therapy activated by lysosome pH-response.

A novel croconic acid-bisindole dye CR-630 with a morpholine ring showed good water-solubility and obvious lysosome-targeting. The protonation of the nitrogen atom in the indole and lysosome-targeting of morpholine ring let it exhibit stronger pH-responsive NIR/PA imaging and photothermal effect in the lysosome acidic microenvironment (pH 4.0-5.5) than in the tumor acidic microenvironment. In the animal study, compound CR-630 could NIRF/PA image in the tumor tissues in 1.5-2.0 h, effectively inhibit the growth of the tumor, and even ablate the tumor at the drug dose of 1 mg/kg. It also demonstrated good biosafety. This study gives a new idea to develop water-solubility organic dyes with lysosome targeting, stronger pH-responsive NIRF/PA imaging and PTT for breast cancer.

Chiral RuII -PtII Complexes Inducing Telomere Dysfunction against Cisplatin-Resistant Cancer Cells.

The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral RuII -PtII dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a RuII -PtII dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.

Supramolecular Assembly of An Organoplatinum(II) Complex with Ratiometric Dual Emission for Two-Photon Bioimaging.

The organoplatinum(II) complex [Pt(C^N^N)(Cl)] (C^N^N=5,6-diphenyl-2,2'-bipyridine, Pt1) can assemble into nanoaggregates via π-π stacking and complementary hydrogen bonds, rather than Pt-Pt interactions. Pt1 exhibits ratiometric dual emission, including rare blue emission (λem =445 nm) and assembly-induced yellow emission (λem =573 nm), under one- and two-photon excitation. Pt1 displays blue emission in cells with an intact membrane due to its low cellular uptake. In cells where the membrane is disrupted, uptake of the complex is increased and at higher concentrations yellow emission is observed. The ratio of yellow to blue emission shows a linear relationship to the loss of cell membrane integrity. Pt1 is, to our knowledge, the first example of an assembly-induced two-photon ratiometric dual emission organoplatinum complex. The excellent and unique characteristics of the complex enabled its use for the tracking of cell apoptosis, necrosis, and the inflammation process in zebrafish.

Correction: Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes.

Correction for 'Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes' by Ya Wen et al., Dalton Trans., 2020, DOI: .

Synthesis, characterization and anticancer mechanism studies of fluorinated cyclometalated ruthenium(ii) complexes.

The drug-resistance of cancer cells has become a major obstacle to the development of clinical drugs for chemotherapy. In order to overcome cisplatin-resistance, seven cyclometalated ruthenium(ii) complexes were synthesized with a varying degree of fluorine substitution, for use as anticancer agents. A cytotoxicity assay testified that the complexes possessed a more cytotoxic effect than cisplatin towards the cisplatin-resistant cell line A549R. The number of fluorine atoms regulated the lipophilicity of the complexes, but the relationship was not linear. Ru1 containing one fluorine atom had the highest lipophilicity and the best therapeutic effect. The complexes enter cells through an energy-dependent pathway and then localize in the nuclei and mitochondria. The complexes induced nuclear dysfunction by the inhibition of DNA replication as well as mitochondrial dysfunction by the loss of membrane potential. The damage to these vital organelles leads to cell apoptosis via the caspase 3/7 pathway. Our results indicated that the modulation of the number of fluorine atoms in therapeutic agents can have a profound effect and Ru1 is a complex with a high potential as a drug for the treatment of cisplatin-resistant cancer.

A mitochondria-targeting dinuclear Ir-Ru complex as a synergistic photoactivated chemotherapy and photodynamic therapy agent against cisplatin-resistant tumour cells.

A mitochondria-targeting hetero-binuclear Ir(iii)-Ru(ii) complex was developed as a photoactivated chemotherapy (PACT) and photodynamic therapy (PDT) bifunctional agent to achieve a synergistic effective therapeutic outcome for the therapy of cisplatin-resistant tumour cells.

The stepwise photodamage of organelles by two-photon luminescent ruthenium(ii) photosensitizers.

Ru(ii) polypyridyl complexes, containing a morpholine moiety, and possessing two-photon absorption properties and pH dependent singlet oxygen production were used for stepwise lysosomes-to-mitochondria photodamage of cancer cells.

Parallel beamlet dose calculation via beamlet contexts in a distributed multi-GPU framework.

PURPOSE: Dose calculation is one of the most computationally intensive, yet essential tasks in the treatment planning process. With the recent interest in automatic beam orientation and arc trajectory optimization techniques, there is a great need for more efficient model-based dose calculation algorithms that can accommodate hundreds to thousands of beam candidates at once. Foundational work has shown the translation of dose calculation algorithms to graphical processing units (GPUs), lending to remarkable gains in processing efficiency. But these methods provide parallelization of dose for only a single beamlet, serializing the calculation of multiple beamlets and under-utilizing the potential of modern GPUs. In this paper, the authors propose a framework enabling parallel computation of many beamlet doses using a novel beamlet context transformation and further embed this approach in a scalable network of multi-GPU computational nodes. METHODS: The proposed context-based transformation separates beamlet-local density and TERMA into distinct beamlet contexts that independently provide sufficient data for beamlet dose calculation. Beamlet contexts are arranged in a composite context array with dosimetric isolation, and the context array is subjected to a GPU collapsed-cone convolution superposition procedure, producing the set of beamlet-specific dose distributions in a single pass. Dose from each context is converted to a sparse representation for efficient storage and retrieval during treatment plan optimization. The context radius is a new parameter permitting flexibility between the speed and fidelity of the dose calculation process. A distributed manager-worker architecture is constructed around the context-based GPU dose calculation approach supporting an arbitrary number of worker nodes and resident GPUs. Phantom experiments were executed to verify the accuracy of the context-based approach compared to Monte Carlo and a reference CPU-CCCS implementation for single beamlets and broad beams composed by addition of beamlets. Dose for representative 4π beam sets was calculated in lung and prostate cases to compare its efficiency with that of an existing beamlet-sequential GPU-CCCS implementation. Code profiling was also performed to evaluate the scalability of the framework across many networked GPUs. RESULTS: The dosimetric accuracy of the context-based method displays <1.35% and 2.35% average error from the existing serialized CPU-CCCS algorithm and Monte Carlo simulation for beamlet-specific PDDs in water and slab phantoms, respectively. The context-based method demonstrates substantial speedup of up to two orders of magnitude over the beamlet-sequential GPU-CCCS method in the tested configurations. The context-based framework demonstrates near linear scaling in the number of distributed compute nodes and GPUs employed, indicating that it is flexible enough to meet the performance requirements of most users by simply increasing the hardware utilization. CONCLUSIONS: The context-based approach demonstrates a new expectation of performance for beamlet-based dose calculation methods. This approach has been successful in accelerating the dose calculation process for very large-scale treatment planning problems - such as automatic 4π IMRT beam orientation and VMAT arc trajectory selection, with hundreds of thousands of beamlets - in clinically feasible timeframes. The flexibility of this framework makes it as a strong candidate for use in a variety of other very large-scale treatment planning tasks and clinical workflows.

A mitochondria-targeting hetero-binuclear Ir(iii)-Pt(ii) complex induces necrosis in cisplatin-resistant tumor cells.

A hetero-binuclear Ir(iii)-Pt(ii) complex was developed as an antitumor agent. In vitro cytotoxicity results indicated that this complex was effective against cisplatin-resistant tumor cells. Mechanism experiments showed that it can overcome cisplatin resistance by increasing cellular uptake, targeting mitochondria, and inducing cell necrosis.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer agents.

Four cyclometalated iridium(III) complexes [Ir(dfppy)2(L)](+) (dfppy = 2-(2,4-difluorophenyl)pyridine, L = 6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine, Ir1; 6-(isoquinolin-1-yl)-1,3,5-triazine-2,4-diamine, Ir2; 6-(quinolin-2-yl)-1,3,5-triazine-2,4-diamine, Ir3; 6-(isoquinolin-3-yl)-1,3,5-triazine-2,4-diamine, Ir4) have been synthesized and characterized. Distinct from cisplatin, Ir1-Ir4 could specifically target mitochondria and induced apoptosis against various cancer cell lines, especially for cisplatin resistant cells. ICP-MS results indicated that Ir1-Ir4 were taken up via different mechanism for cancer cells and normal cells, which resulted in their high selectivity. The structure-activity relationship and signaling pathways were also discussed.

Chemical Exchange Saturation Transfer MR Imaging: Preliminary Results for Differentiation of Malignant and Benign Thoracic Lesions.

PURPOSE: To prospectively evaluate the capability of amide proton transfer-weighted chemical exchange saturation transfer magnetic resonance (MR) imaging for characterization of thoracic lesions. MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from 21 patients (13 men and eight women; mean age, 72 years) prior to enrollment. Each patient underwent chemical exchange saturation transfer MR imaging by using respiratory-synchronized half-Fourier fast spin-echo imaging after a series of magnetization transfer pulses. Next, a magnetization transfer ratio asymmetry at 3.5 ppm map was computationally generated. Pathology examinations resulted in a diagnosis of 13 malignant and eight benign thoracic lesions. The malignant lesions were further diagnosed as being nine lung cancers, comprising six adenocarcinomas, three squamous cell carcinomas, and four other thoracic malignancies. The Student t test was used to evaluate the capability of magnetization transfer ratio asymmetry (at 3.5 ppm), as assessed by means of region of interest measurements, for differentiating benign and malignant lesions, lung cancers and other thoracic lesions, and adenocarcinomas and squamous cell carcinomas. RESULTS: Magnetization transfer ratio asymmetry (at 3.5 ppm) was significantly higher for malignant tumors (mean ± standard deviation, 3.56% ± 3.01) than for benign lesions (0.33% ± 0.38, P = .008). It was also significantly higher for other thoracic malignancies (6.71% ± 3.46) than for lung cancer (2.16% ± 1.41, P = .005) and for adenocarcinoma (2.88% ± 1.13) than for squamous cell carcinoma (0.71% ± 0.17, P = .02). CONCLUSION: Amide proton transfer-weighted chemical exchange saturation transfer MR imaging allows characterization of thoracic lesions.

Z-Spectrum analysis provides proton environment data (ZAPPED): a new two-pool technique for human gray and white matter.

A new technique - Z-spectrum Analysis Provides Proton Environment Data (ZAPPED) - was used to map cross-relaxing free and restricted protons in nine healthy subjects plus two brain tumor patients at 3T. First, MT data were acquired over a wide symmetric range of frequency offsets, and then a trio of quantitative biomarkers, i.e., the apparent spin-spin relaxation times (T2,f, T2,r) in both free and restricted proton pools as well as the restricted pool fraction Fr, were mapped by fitting the measured Z-spectra to a simple two-Lorentzian compartment model on a voxel-by-voxel basis. The mean restricted exchangeable proton fraction, Fr, was found to be 0.17 in gray matter (GM) and 0.28 in white matter (WM) in healthy subjects. Corresponding mean values for apparent spin-spin relaxation times were 785 µs (T2,f) and 17.7 µs (T2,r) in GM, 672 µs (T2,f) and 23.4 µs (T2,r) in WM. The percentages of Ff and Fr in GM are similar for all ages, whereas Fr shows a tendency to decrease with age in WM among healthy subjects. The patient ZAPPED images show higher contrast between tumor and normal tissues than traditional T2-weighted and T1-weighted images. The ZAPPED method provides a simple phenomenological approach to estimating fractions and apparent T2 values of free and restricted MT-active protons, and it may offer clinical useful information.