Abstract
Herein, an intelligent biodegradable hollow manganese dioxide (H-MnO
2
) nano-platform is developed for not only tumor microenvironment (TME)-specific imaging and on-demand drug release, but ...also modulation of hypoxic TME to enhance cancer therapy, resulting in comprehensive effects favoring anti-tumor immune responses. With hollow structures, H-MnO
2
nanoshells post modification with polyethylene glycol (PEG) could be co-loaded with a photodynamic agent chlorine e6 (Ce6), and a chemotherapy drug doxorubicin (DOX). The obtained H-MnO
2
-PEG/C&D would be dissociated under reduced pH within TME to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H
2
O
2
to relieve tumor hypoxia. As a result, a remarkable in vivo synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Its further combination with checkpoint-blockade therapy would lead to inhibition of tumors at distant sites, promising for tumor metastasis treatment.
Cancer metastases and recurrence after surgical resection remain an important cause of treatment failure. Here we demonstrate a general strategy to fabricate personalized nanovaccines based on a ...cationic fluoropolymer for post-surgical cancer immunotherapy. Nanoparticles formed by mixing the fluoropolymer with a model antigen ovalbumin, induce dendritic cell maturation via the Toll-like receptor 4 (TLR4)-mediated signalling pathway, and promote antigen transportation into the cytosol of dendritic cells, which leads to an effective antigen cross-presentation. Such a nanovaccine inhibits established ovalbumin-expressing B16-OVA melanoma. More importantly, a mix of the fluoropolymer with cell membranes from resected autologous primary tumours synergizes with checkpoint blockade therapy to inhibit post-surgical tumour recurrence and metastases in two subcutaneous tumour models and an orthotopic breast cancer tumour. Furthermore, in the orthotopic tumour model, we observed a strong immune memory against tumour rechallenge. Our work offers a simple and general strategy for the preparation of personalized cancer vaccines to prevent post-operative cancer recurrence and metastasis.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The first example of PdII‐catalyzed enantioselective C−H olefination with non‐chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized ...with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of PdII‐catalyzed enantioselective C(sp2)−H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers.
A PdII‐catalyzed enantioselective C−H olefination with non‐chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity through both desymmetrization and parallel kinetic resolution (PKR). This is the first reported PdII‐catalyzed enantioselective C(sp2)−H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
During January 26-February 10, 2020, an outbreak of 2019 novel coronavirus disease in an air-conditioned restaurant in Guangzhou, China, involved 3 family clusters. The airflow direction was ...consistent with droplet transmission. To prevent the spread of the virus in restaurants, we recommend increasing the distance between tables and improving ventilation.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Whole-brain mesoscale mapping in primates has been hindered by large brain sizes and the relatively low throughput of available microscopy methods. Here, we present an approach that combines ...primate-optimized tissue sectioning and clearing with ultrahigh-speed fluorescence microscopy implementing improved volumetric imaging with synchronized on-the-fly-scan and readout technique, and is capable of completing whole-brain imaging of a rhesus monkey at 1 × 1 × 2.5 µm
voxel resolution within 100 h. We also developed a highly efficient method for long-range tracing of sparse axonal fibers in datasets numbering hundreds of terabytes. This pipeline, which we call serial sectioning and clearing, three-dimensional microscopy with semiautomated reconstruction and tracing (SMART), enables effective connectome-scale mapping of large primate brains. With SMART, we were able to construct a cortical projection map of the mediodorsal nucleus of the thalamus and identify distinct turning and routing patterns of individual axons in the cortical folds while approaching their arborization destinations.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Near‐infrared (NIR)‐light‐triggered photothermal therapy (PTT) usually requires hyperthermia to >50 °C for effective tumor ablation, which can potentially induce inflammatory disease and heating ...damage of normal organs nearby, while tumor lesions without sufficient heating (e.g., the internal part) may survive after treatment. Achieving effective tumor killing under relatively low temperatures is thus critical toward successful clinical use of PTT. Herein, we design a simple strategy to fabricate poly(ethylene glycol) (PEG)‐modified one‐dimensional nanoscale coordination polymers (1D‐NCPs) with intrinsic biodegradability, large surface area, pH‐responsive behaviors, and versatile theranostic functions. With NCPs consisting of Mn2+/indocyanine green (ICG) as the example, Mn‐ICG@pHis‐PEG display efficient pH‐responsive tumor retention after systemic administration and then load Gambogic acid (GA), a natural inhibitor of heat‐shock protein 90 (Hsp90) that plays an essential role for cells to resist heating‐induced damage. Such Mn‐ICG@pHis‐PEG/GA under a mild NIR‐triggered heating is able to induce effective apoptosis of tumor cells, realizing low‐temperature PTT (~43 °C) with excellent tumor destruction efficacy. This work not only develops a facile approach to fabricate PEGylated 1D‐NCPs with tumor‐specific pH responsiveness and theranostic functionalities, but also presents a unique low‐temperature PTT strategy to kill cancer in a highly effective and minimally invasive manner.
A one‐dimensional (1D) PEGylated nanoscale coordination polymer (NCP) is fabricated via a one‐step method. After loading gambogic acid (GA), such Mn‐ICG@pHis‐PEG/GA displays efficient pH‐responsive tumor retention after systemic administration. Owing to the GA‐induced down‐regulation of Hsp90 to overcome the thermal‐resistance of tumor cells, highly effective in vivo destruction of tumors is relized with Mn‐ICG@pHis‐PEG/GA under low‐temperature photothermal therapy at 43 °C.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The recent years have witnessed the blooming of cancer immunotherapy, as well as their combinational use together with other existing cancer treatment techniques including radiotherapy. However, ...hypoxia is one of several causes of the immunosuppressive tumor microenvironment (TME). Herein, we develop an innovative strategy to relieve tumor hypoxia by delivering exogenous H2O2 into tumors and the subsequent catalase-triggered H2O2 decomposition. In our experiment, H2O2 and catalase are separately loaded within stealthy liposomes. After intravenous (iv) preinjection of CAT@liposome, another dose of H2O2@liposome is injected 4 h later. The sustainably released H2O2 could be decomposed by CAT@liposome, resulting in a long lasting effect in tumor oxygenation enhancement. As the result, the combination treatment by CAT@liposome plus H2O2@liposome offers remarkably enhanced therapeutic effects in cancer radiotherapy as observed in a mouse tumor model as well as a more clinically relevant patient-derived xenograft tumor model. Moreover, the relieved tumor hypoxia would reverse the immunosuppressive TME to favor antitumor immunities, further enhancing the combined radio-immunotherapy with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. This work presents a simple yet effective strategy to promote tumor oxygenation via sequential delivering catalase and exogenous H2O2 into tumors using well-established liposomal carriers, showing great potential for clinical translation in radio-immunotherapy of cancer.
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IJS, KILJ, NUK, PNG, UL, UM
A method was proposed to couple the heat source with ORCs (Organic Rankine Cycles). The integrated-average temperature difference, ΔTave, quantifies the thermal match in the evaporator. ΔTave ...decreases with increase in critical temperatures (Tc). The fluid with Tc approaching Tgas,in (flue gas inlet temperature) can have ΔTave → 0.5 × (Tgas,out − T5), which is called the optimal temperature difference, at which the thermal efficiency is maximum. The ORC performance with fluids of Tc > Tgas,in has less deviation from the optimal condition. Thermal efficiencies are well correlated with critical temperatures. The ORC thermal efficiencies are randomly distributed against other fluid physical properties except Tc. Thus, the critical temperature can be the sole criterion for the fluid selection, as far as the thermal efficiency is concerned. The organic fluids with Tc in the range of (Tgas,in − 20–30 K, Tgas,in + 100 K) are recommended. Specific fluids are recommended for heat source temperature in the range of (100–300 °C) by screening 57 fluids. More fluids are available for ORCs with low heat source temperatures. Limited fluids are available for high temperature heat source applications. Due to the expanded fluids in region II, some fluids such as R245fa can be used over a wide heat source temperature range.
•The integrated-average temperature difference quantifies the thermal match for the evaporator.•An optimal temperature difference was identified at which the thermal efficiency is maximum.•Critical temperature can be the sole criterion for selection of working fluids for subcritical ORCs.•Working fluids were recommended for flue gas driving ORCs in the range of 100–300 °C.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against hypoxic solid tumours and distant metastases. Here, we show that intratumoral injection, in mouse and ...rabbit xenografts and in patient-derived mouse xenografts, of a sodium alginate formulation containing catalase (Cat) labelled with the therapeutic
I radioisotope enables long-term relief of tumour hypoxia and complete tumour elimination at low radioactivity doses. On injection, the soluble polysaccharide rapidly transforms into a hydrogel in the presence of endogenous Ca
, fixing
I-Cat within the tumours. We also show that local radiotherapy with a formulation that includes the immunostimulatory CpG oligonucleotide combined with systemic checkpoint-blockade therapy using an anti-CTLA-4 antibody leads to metastasis inhibition and protection against tumour rechallenge. The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments that can be combined with systemic therapeutic responses, for the inhibition of tumour metastasis and the prevention of tumour recurrence in patients with advanced-stage cancer.
Abstract
Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 ...single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
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