PathEX: Make good choice for whole slide image extraction.

BACKGROUND: The tile-based approach has been widely used for slide-level predictions in whole slide image (WSI) analysis. However, the irregular shapes and variable dimensions of tumor regions pose challenges for the process. To address this issue, we proposed PathEX, a framework that integrates intersection over tile (IoT) and background over tile (BoT) algorithms to extract tile images around boundaries of annotated regions while excluding the blank tile images within these regions. METHODS: We developed PathEX, which incorporated IoT and BoT into tile extraction, for training a classification model in CAM (239 WSIs) and PAIP (40 WSIs) datasets. By adjusting the IoT and BoT parameters, we generated eight training sets and corresponding models for each dataset. The performance of PathEX was assessed on the testing set comprising 13,076 tile images from 48 WSIs of CAM dataset and 6,391 tile images from 10 WSIs of PAIP dataset. RESULTS: PathEX could extract tile images around boundaries of annotated region differently by adjusting the IoT parameter, while exclusion of blank tile images within annotated regions achieved by setting the BoT parameter. As adjusting IoT from 0.1 to 1.0, and 1-BoT from 0.0 to 0.5, we got 8 train sets. Experimentation revealed that set C demonstrates potential as the most optimal candidate. Nevertheless, a combination of IoT values ranging from 0.2 to 0.5 and 1-BoT values ranging from 0.2 to 0.5 also yielded favorable outcomes. CONCLUSIONS: In this study, we proposed PathEX, a framework that integrates IoT and BoT algorithms for tile image extraction at the boundaries of annotated regions while excluding blank tiles within these regions. Researchers can conveniently set the thresholds for IoT and BoT to facilitate tile image extraction in their own studies. The insights gained from this research provide valuable guidance for tile image extraction in digital pathology applications.

Four cyclometalated Ir(iii) complexes and insights into their luminescence, cytotoxicity and DNA/BSA binding performance.

Four cyclometalated Ir(iii) complexes based on 4'-p-N,N-bis(2-hydroxyethyl)benzyl-2,2':6',2''-terpyridine (TPYOH) and 4'-p-N,N-bis(2-hydroxyethyl)benzyl-6'-benzyl-2,2'-bipyridine (PhbpyOH) were synthesized and characterized. All the Ir(iii) complexes exhibited strong MLCT absorption peaks at about 450 nm, broad emission bands in the range of 500-700 nm. Z-scan results revealed that only complex Ir1A could exhibit certain two-photon absorption with maximal cross section values of 215 GM at 890 nm. When excited by 700-850 nm femtosecond laser, complex Ir1A gave a TPEF peak around 567 nm. All four complexes exhibited enhanced cell growth inhibitory activity against MCF-7 tumour cells under light irradiation comparing to their dark toxicity, with Ir1B showing the highest PI value (>50). The pathways and efficiencies of ROS generation by Ir(iii) complexes varied, with Ir2A being more effective in producing 1O2 while Ir1A mainly generating O2˙-. The Ir(iii) complexes undergo hydrogen bonding with DNA bases/phosphodiester through two O-H bonds on the bis(hydroxyethyl)amino group. The free pyridine-N atom in Ir1A forms additional hydrogen bond with DNA base, while the ligand TPYOH in Ir2A has better molecular planarity due to adopting {N, N, N} coordination mode, thus these two complexes show better DNA affinity. The complexes demonstrated weak interactions with BSA, through hydrogen bonding with amino acid residues at different regions of BSA molecule.

A Dual Stimuli-Responsive Nanoplatform Loaded PtIV -Triptolide Prodrug for Achieving Synergistic Therapy toward Breast Cancer.

To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide, herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy of both "1+1" apoptosis and "1+1" ferroptosis is designed. Remarkably, ZIF8 in response to tumor microenvironment enhances drug targeting and protects drugs from premature degradation. Meanwhile, the PtIV  center can be easily reduced to cisplatin because of the large amount of GSH, thus liberating the triptolide as the coordinated ligand. The released cisplatin and hemin in turn boost the tumor cell "1+1" apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction through PtIV  weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus "1+1" ferroptosis can be achieved. Both in vitro and in vivo results demonstrate that the nanosystem can not only perform superior specificity and therapeutic outcomes but also reduce the toxicity to normal cells/tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provides an efficient therapeutic strategy for cancer treatment by virtue of the effect of enhanced "1+1" apoptosis and "1+1" ferroptosis therapies.

Immunomodulator-Mediated Suppressive Tumor Immune Microenvironment Remodeling Nanoplatform for Enhanced Immuno/Chemo/Photothermal Combination Therapy of Triple Negative Breast Cancer.

Despite immunotherapy having revolutionized cancer therapy, the efficacy of immunotherapy in triple-negative breast cancer (TNBC) is seriously restricted due to the insufficient infiltration of mature dendritic cells (DCs) and the highly diffusion of immunosuppressive cells in the tumor microenvironment. Herein, an immunomodulatory nanoplatform (HA/Lipo@MTO@IMQ), in which the DCs could be maximally activated, was engineered to remarkably eradicate the tumor via the combination of suppressive tumor immune microenvironment reversal immunotherapy, chemotherapy, and photothermal therapy. It was noticed that the immunotherapy efficacy could be significantly facilitated by this triple-assistance therapy: First, a robust immunogenic cell death (ICD) effect was induced by mitoxantrone hydrochloride (MTO) to boost DCs maturation and cytotoxic T lymphocytes infiltration. Second, the powerful promaturation property of the toll-like receptor 7/8 (TLR7/8) agonist on DCs simultaneously strengthened the ICD effect and restricted antitumor immunity to the tumor bed and lymph nodes. On this basis, tumor-associated macrophages were also dramatically repolarized toward the antitumor M1 phenotype in response to TLR7/8 agonist to intensify the phagocytosis and reverse the immunosuppressive microenvironment. Furthermore, the recruitment of immunocompetent cells and tumor growth inhibition were further promoted by the photothermal characteristic. The nanoplatform with no conspicuous untoward effects exhibited a splendid ability to activate the systemic immune system so as to increase the immunogenicity of the tumor microenvironment, thus enhancing the tumor killing effect. Taken together, HA/Lipo@MTO@IMQ might highlight an efficient combination of therapeutic modality for TNBC.

A mitochondrion-targeting Mn(ii)-terpyridine complex for two-photon photodynamic therapy.

We developed a mitochondrion-targeting MnII-terpyridine complex (MTP) for two-photon photodynamic therapy. MTP was subjected to two-photon excitation in the NIR region to generate 1O2 and hence produce a PDT effect. This use of MTP overcame the drawbacks of traditional PDT agents. The MnII center of MTP apparently catalyzed the H2O2-mediated production of ROS and oxygen, which subsequently promoted the 1O2 generation, furthering the PDT effect. Additionally, the mitochondrion targeting of MTP provided a good spatial condition for the generation of 1O2, which further promoted the PDT effect.

Enhancement of Acid Protease Activity of Aspergillus oryzae Using Atmospheric and Room Temperature Plasma.

Atmospheric and room temperature plasma (ARTP) system is a novel and efficient mutagenesis protocol for microbial breeding. In this study, ARTP was employed to treat spores of Aspergillus oryzae strain 3.042 for selection of high acid protease producers. With an irradiation time of 150 s at the lethal rate of 90%, 19 mutants with higher acid protease activity were initially selected based on different mutant colony morphology and ratio of the clarification halo of protease activity to the colony diameter. Measurements of the acid protease activity revealed that mutant strain B-2 is characterized by a steady hereditary stability with increased acid protease, neutral protease and total protease activities of 54.7, 17.3, and 8.5%, respectively, and decreased alkaline protease activity of 8.1%. In summary, the identified mutant strain B-2 exhibits great potential for the enhancement of the insufficient acid protease activity during the middle and later stages of soy sauce fermentation.