A nanomicelle(denoted as TPGS/Ppa)was fabricated via the coassembly of the amphiphilic D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)and the hydrophobic photosensitizer pyropheophorbide a(Ppa)for photodynami...A nanomicelle(denoted as TPGS/Ppa)was fabricated via the coassembly of the amphiphilic D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)and the hydrophobic photosensitizer pyropheophorbide a(Ppa)for photodynamic therapy(PDT).The obtained nanomicelle possessed a spherical structure with a diameter of(18.0±2.2)nm and a zeta potential of approximately -18 mV.Besides,the nanomicelle exhibited excellent photostability,biocompatibility,and phototoxicity,and could effectively reach the tumor region via the enhanced permeability and retention effect.Additionally,it could be found that the TPGS/Ppa nanomicelle exhibited higher phototoxicity against 4T1 murine mammary cancer cells than free Ppa.In the 4T1 tumor-bearing mouse model,the nanomicelle showed an excellent antitumor therapeutic effect.This study develops a new type of photodynamic nanomicelle TPGS/Ppa,which can increase the accumulation of drugs and prolong their tumor retention time,providing a feasible strategy for realizing the delivery of small-molecule hydrophobic drugs and tumor PDT.展开更多
Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessi...Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity.Localized delivery of tumor-specific T-cells using biomaterials has shown promise,however,procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.Methods:Polyethylene glycol(PEG)-based three-dimensional(3D)scaffolds were developed and conjugated with positively charged poly-L-lysine(PLL)using carbamide chemistry for efficient loading of lentiviruses(LVs)carrying tumor antigen-specific T-cell receptors(TCRs).The physical and biological properties of the scaffold were extensively characterized.Further,the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin(B16-OVA)tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.Results:Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site.In B16-OVA melanoma tumor-bearing mice,the scaffolds efficiently transduce host T-cells with OVA-specific TCRs.These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs,resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines.Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.Conclusions:Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors.This approach offers a viable alternative to in vitro manipulation of T-cells,circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells.It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells,thereby,overcoming a major hurdle.展开更多
Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safet...Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.展开更多
Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune ...Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.展开更多
Objective To investigate the efficacy of raw corn starch(RCS)in clinical management of insulinoma-induced hypoglycemia.Methods We retrospectively collected clinical data of insulinoma patients who received RCS-supplem...Objective To investigate the efficacy of raw corn starch(RCS)in clinical management of insulinoma-induced hypoglycemia.Methods We retrospectively collected clinical data of insulinoma patients who received RCS-supplemented diet preoperatively,and analyzed the therapeutic effects of the RCS intervention on blood glucose control,weight change,and its adverse events.Results The study population consisted of 24 cases of insulinoma patients,7 males and 17 females,aged 46.08±14.15 years.Before RCS-supplemented diet,all patients had frequent hypoglycemic episodes(2.51±3.88 times/week),concurrent with neuroglycopenia(in 83.3% of patients)and autonomic manifestations(in 75.0% of patients),with the median fasting blood glucose(FBG)of 2.70(interquartile range[IQR]:2.50-2.90)mmol/L.The patients'weight increased by 0.38(IQR:0.05-0.65)kg per month,with 8(33.3%)cases developing overweight and 7(29.2%)cases developing obesity.All patients maintained the RCS-supplemented diet until they underwent tumor resection(23 cases)and transarterial chemoembolization for liver metastases(1 case).For 19 patients receiving RCS throughout the day,the median FBG within one week of nutritional management was 4.30(IQR:3.30-5.70)mmol/L,which was a significant increase compared to pre-nutritional level[2.25(IQR:1.60-2.90)mmol/L;P<0.001].Of them,10 patients receiving RCS throughout the day for over four weeks had sustained improvement in FBG compared to pre-treatment[3.20(IQR:2.60-3.95)mmol/L vs.2.15(IQR:1.83-2.33)mmol/L;P<0.001].Five patients who received RCS only at night also had a significant increase in FBG within one week of nutritional management[3.50(IQR:2.50-3.65)mmol/L vs.2.20(IQR:1.80-2.60)mmol/L;P<0.001],but only one patient who continued to receive RCS for over four weeks did not have a significant improvement in FBG.No improvement in weight gain was observed upon RCS supplementation.Mild diarrhea(2 cases)and flatulence(1 case)occurred,and were relieved by reduction of RCS dose.Conclusion The RCS-supplemented diet is effective in controlling insulinoma-induced hypoglycemia.展开更多
Cone-beam computed tomography(CBCT) is mostly used for position verification during the treatment process. However,severe image artifacts in CBCT hinder its direct use in dose calculation and adaptive radiation therap...Cone-beam computed tomography(CBCT) is mostly used for position verification during the treatment process. However,severe image artifacts in CBCT hinder its direct use in dose calculation and adaptive radiation therapy re-planning for proton therapy. In this study, an improved U-Net neural network named CBAM-U-Net was proposed for CBCT noise reduction in proton therapy, which is a CBCT denoised U-Net network with convolutional block attention modules. The datasets contained 20 groups of head and neck images. The CT images were registered to CBCT images as ground truth. The original CBCT denoised U-Net network, sCTU-Net, was trained for model performance comparison. The synthetic CT(SCT) images generated by CBAM-U-Net and the original sCTU-Net are called CBAM-SCT and U-Net-SCT images, respectively. The HU accuracies of the CT, CBCT, and SCT images were compared using four metrics: mean absolute error(MAE), root mean square error(RMSE), peak signal-to-noise ratio(PSNR), and structure similarity index measure(SSIM). The mean values of the MAE, RMSE, PSNR, and SSIM of CBAM-SCT images were 23.80 HU, 64.63 HU, 52.27 dB, and 0.9919, respectively,which were superior to those of the U-Net-SCT images. To evaluate dosimetric accuracy, the range accuracy was compared for a single-energy proton beam. The γ-index pass rates of a 4 cm × 4 cm scanned field and simple plan were calculated to compare the effects of the noise reduction capabilities of the original U-Net and CBAM-U-Net on the dose calculation results. CBAM-U-Net reduced noise more effectively than sCTU-Net, particularly in high-density tissues. We proposed a CBAM-U-Net model for CBCT noise reduction in proton therapy. Owing to the excellent noise reduction capabilities of CBAM-U-Net, the proposed model provided relatively explicit information regarding patient tissues. Moreover, it maybe be used in dose calculation and adaptive treatment planning in the future.展开更多
BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulinpotassium(GIK) therapy on clinical outcomes in acute coronary syndrome(ACS) patients receiving reperfusion therapy.METHODS:We sear...BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulinpotassium(GIK) therapy on clinical outcomes in acute coronary syndrome(ACS) patients receiving reperfusion therapy.METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs) that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs).RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio [RR] 0.57,95% confidence interval [95% CI]:0.35 to 0.94,P=0.03) and the risk of heart failure(RR 0.48,95% CI:0.25 to 0.95,P=0.04) and improved the left ventricular ejection fraction(LVEF)(mean difference [MD] 2.12,95% CI:0.40 to 3.92,P=0.02) at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95% CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95% CI:1.74 to 47.29,P=0.009) and hypoglycemia(RR 6.50,95% CI:1.28 to 33.01,P=0.02) but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD) activity but not glutathione peroxidase(GSH-Px) or catalase(CAT) activity.CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering eflcacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.展开更多
The development of supramolecular hosts which can efficiently encapsulate photosensitizers to improve the photodynamic efficacy holds great promise for cancer therapy.Here,we report two perylene diimide-based metallac...The development of supramolecular hosts which can efficiently encapsulate photosensitizers to improve the photodynamic efficacy holds great promise for cancer therapy.Here,we report two perylene diimide-based metallacages that can form stable host–guest complexes with planar conjugated molecules including polycyclic aromatic hydrocarbons and photosensitizers(hypocrellin A).Such host–guest complexation not only prevents the aggregation of photosensitizers in aqueous environments,but also offers fluorescence resonance energy transfer(FRET)from the metallacage to the photosensitizers to further improve the singlet oxygen generation(Φ_(Δ)=0.66).The complexes are further assembled with amphiphilic polymers,forming nanoparticles with improved stability for anticancer study.Both in vitro and in vivo studies indicate that the nanoparticles display excellent anticancer activities upon light irradiation,showing great potential for cancer photodynamic therapy.This study provides a straightforward and effective approach for enhancing the photosensitivity of conventional photosensitizers via host–guest complexation-based FRET,which will open a new avenue for host–guest chemistry-based supramolecular theranostics.展开更多
Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical b...Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.展开更多
Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),...Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),which is termed T cell exhaustion.This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment(TIME).Simultaneously,tumorigenesis entails robust reshaping of the epigenetic landscape,potentially instigating T cell exhaustion.In this review,we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion,and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies.Finally,we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.展开更多
The application of superconducting(SC)technology enables magnets to excite strong fields with small footprints,which has great potential for miniaturizing proton therapy gantries.However,the slow ramping rate of SC ma...The application of superconducting(SC)technology enables magnets to excite strong fields with small footprints,which has great potential for miniaturizing proton therapy gantries.However,the slow ramping rate of SC magnets results in a low treatment efficiency compared with normal-conducting(NC)gantries.To address this problem,this study proposes a compact proton therapy gantry design with a large momentum acceptance utilizing alternating-gradient canted-cosine-theta(AG-CCT)SC magnets.In our design,a high-transmission degrader is mounted in the middle of the gantry,and the upstream beamline employs NC magnets with small apertures.Downstream of the degrader,large-bore AG-CCT magnets with strong alternating focusing gradients are set symmetrically as a local achromat,which realizes a momentum acceptance of 20%(or 40%in the energy domain).Therefore,only three magnetic working points are required to cover a treatment energy of 70-230 Me V.Owing to the large momentum acceptance,the proton beam after the degrader can be directly delivered to the isocenter without truncating its energy spectrum,which can significantly increase the treatment efficiency but causes severe dispersion effects during pencil beam scanning.Therefore,a compensation method was introduced by tuning the normal and skewed quadrupoles during the scanning process.As a result,the new gantry not only presents a remarkable reduction in the size and weight of the facility but also shows good potential for fast treatment.展开更多
Objectives Renal replacement therapy(RRT)is increasingly adopted for critically ill patients diagnosed with acute kidney injury,but the optimal time for initiation remains unclear and prognosis is uncertain,leading to...Objectives Renal replacement therapy(RRT)is increasingly adopted for critically ill patients diagnosed with acute kidney injury,but the optimal time for initiation remains unclear and prognosis is uncertain,leading to medical complexity,ethical conflicts,and decision dilemmas in intensive care unit(ICU)settings.This study aimed to develop a decision aid(DA)for the family surrogate of critically ill patients to support their engagement in shared decision-making process with clinicians.Methods Development of DA employed a systematic process with user-centered design(UCD)principle,which included:(i)competitive analysis:searched,screened,and assessed the existing DAs to gather insights for design strategies,developmental techniques,and functionalities;(ii)user needs assessment:interviewed family surrogates in our hospital to explore target user group's decision-making experience and identify their unmet needs;(iii)evidence syntheses:integrate latest clinical evidence and pertinent information to inform the content development of DA.Results The competitive analysis included 16 relevant DAs,from which we derived valuable insights using existing resources.User decision needs were explored among a cohort of 15 family surrogates,revealing four thematic issues in decision-making,including stuck into dilemmas,sense of uncertainty,limited capacity,and delayed decision confirmation.A total of 27 articles were included for evidence syntheses.Relevant decision making knowledge on disease and treatment,as delineated in the literature sourced from decision support system or clinical guidelines,were formatted as the foundational knowledge base.Twenty-one items of evidence were extracted and integrated into the content panels of benefits and risks of RRT,possible outcomes,and reasons to choose.The DA was drafted into a web-based phototype using the elements of UCD.This platform could guide users in their preparation of decision-making through a sequential four-step process:identifying treatment options,weighing the benefits and risks,clarifying personal preferences and values,and formulating a schedule for formal shared decision-making with clinicians.Conclusions We developed a rapid prototype of DA tailored for family surrogate decision makers of critically ill patients in need of RRT in ICU setting.Future studies are needed to evaluate its usability,feasibility,and clinical effects of this intervention.展开更多
Boron neutron capture therapy(BNCT)is recognized as a precise binary targeted radiotherapy technique that effectively eliminates tumors through the^(10)B(n,α)^(7)Li nuclear reaction.Among various neutron sources,acce...Boron neutron capture therapy(BNCT)is recognized as a precise binary targeted radiotherapy technique that effectively eliminates tumors through the^(10)B(n,α)^(7)Li nuclear reaction.Among various neutron sources,accelerator-based sources have emerged as particularly promising for BNCT applications.The^(7)Li(p,n)^(7)Be reaction is highly regarded as a potential neutron source for BNCT,owing to its low threshold energy for the reaction,significant neutron yield,appropriate average neutron energy,and additional benefits.This study utilized Monte Carlo simulations to model the physical interactions within a lithium target subjected to proton bombardment,including neutron moderation by an MgF_(2)moderator and subsequent BNCT dose analysis using a Snyder head phantom.The study focused on calculating the yields of epithermal neutrons for various incident proton energies,finding an optimal energy at 2.7 MeV.Furthermore,the Snyder head phantom was employed in dose simulations to validate the effectiveness of this specific incident energy when utilizing a^(7)Li(p,n)^(7)Be neutron source for BNCT purposes.展开更多
文摘A nanomicelle(denoted as TPGS/Ppa)was fabricated via the coassembly of the amphiphilic D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)and the hydrophobic photosensitizer pyropheophorbide a(Ppa)for photodynamic therapy(PDT).The obtained nanomicelle possessed a spherical structure with a diameter of(18.0±2.2)nm and a zeta potential of approximately -18 mV.Besides,the nanomicelle exhibited excellent photostability,biocompatibility,and phototoxicity,and could effectively reach the tumor region via the enhanced permeability and retention effect.Additionally,it could be found that the TPGS/Ppa nanomicelle exhibited higher phototoxicity against 4T1 murine mammary cancer cells than free Ppa.In the 4T1 tumor-bearing mouse model,the nanomicelle showed an excellent antitumor therapeutic effect.This study develops a new type of photodynamic nanomicelle TPGS/Ppa,which can increase the accumulation of drugs and prolong their tumor retention time,providing a feasible strategy for realizing the delivery of small-molecule hydrophobic drugs and tumor PDT.
基金Department of Biotechnology(DBT,Govt of India)(BT/PR31315/MED/32/667/2019)DBT along with Wadhwani Research Center for Bioengineering,IIT Bombay(BT/INF/22/SP23026/2017)Department of Biotechnology(DBT,Govt of India)(BT/INF/22/SP17358/2016).
文摘Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity.Localized delivery of tumor-specific T-cells using biomaterials has shown promise,however,procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.Methods:Polyethylene glycol(PEG)-based three-dimensional(3D)scaffolds were developed and conjugated with positively charged poly-L-lysine(PLL)using carbamide chemistry for efficient loading of lentiviruses(LVs)carrying tumor antigen-specific T-cell receptors(TCRs).The physical and biological properties of the scaffold were extensively characterized.Further,the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin(B16-OVA)tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.Results:Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site.In B16-OVA melanoma tumor-bearing mice,the scaffolds efficiently transduce host T-cells with OVA-specific TCRs.These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs,resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines.Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.Conclusions:Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors.This approach offers a viable alternative to in vitro manipulation of T-cells,circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells.It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells,thereby,overcoming a major hurdle.
基金The work was financially supported by the National Natural Science Foundation of China(No.52173135,22207024)Jiangsu Specially Appointed Professorship,Leading Talents of Innovation and Entrepreneurship of Gusu(ZXL2022496)the Suzhou Science and Technology Program(SKY2022039).
文摘Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.
基金the financial support from the National Natural Science Foundation of China (No. 82372019, 82022034, 82173327)Jiangsu Province Natural Science Foundation of China (BK20200032)Double First Class Foundation of China Pharmaceutical University(CPUQNJC22_03)
文摘Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.
基金supported by the National High Level Hospital Clinical Research Fund(2022-PUMCH-A-146)the National Natural Science Foundation of China(72074222)the Na-tional Key Research and Development Program of China(2020YFC2005005).
文摘Objective To investigate the efficacy of raw corn starch(RCS)in clinical management of insulinoma-induced hypoglycemia.Methods We retrospectively collected clinical data of insulinoma patients who received RCS-supplemented diet preoperatively,and analyzed the therapeutic effects of the RCS intervention on blood glucose control,weight change,and its adverse events.Results The study population consisted of 24 cases of insulinoma patients,7 males and 17 females,aged 46.08±14.15 years.Before RCS-supplemented diet,all patients had frequent hypoglycemic episodes(2.51±3.88 times/week),concurrent with neuroglycopenia(in 83.3% of patients)and autonomic manifestations(in 75.0% of patients),with the median fasting blood glucose(FBG)of 2.70(interquartile range[IQR]:2.50-2.90)mmol/L.The patients'weight increased by 0.38(IQR:0.05-0.65)kg per month,with 8(33.3%)cases developing overweight and 7(29.2%)cases developing obesity.All patients maintained the RCS-supplemented diet until they underwent tumor resection(23 cases)and transarterial chemoembolization for liver metastases(1 case).For 19 patients receiving RCS throughout the day,the median FBG within one week of nutritional management was 4.30(IQR:3.30-5.70)mmol/L,which was a significant increase compared to pre-nutritional level[2.25(IQR:1.60-2.90)mmol/L;P<0.001].Of them,10 patients receiving RCS throughout the day for over four weeks had sustained improvement in FBG compared to pre-treatment[3.20(IQR:2.60-3.95)mmol/L vs.2.15(IQR:1.83-2.33)mmol/L;P<0.001].Five patients who received RCS only at night also had a significant increase in FBG within one week of nutritional management[3.50(IQR:2.50-3.65)mmol/L vs.2.20(IQR:1.80-2.60)mmol/L;P<0.001],but only one patient who continued to receive RCS for over four weeks did not have a significant improvement in FBG.No improvement in weight gain was observed upon RCS supplementation.Mild diarrhea(2 cases)and flatulence(1 case)occurred,and were relieved by reduction of RCS dose.Conclusion The RCS-supplemented diet is effective in controlling insulinoma-induced hypoglycemia.
基金Digital Medical Equipment Research and Development Project,Ministry of Science and Technology,China:The development of Synchrotron-based proton therapy system(2016YFC0105400).
文摘Cone-beam computed tomography(CBCT) is mostly used for position verification during the treatment process. However,severe image artifacts in CBCT hinder its direct use in dose calculation and adaptive radiation therapy re-planning for proton therapy. In this study, an improved U-Net neural network named CBAM-U-Net was proposed for CBCT noise reduction in proton therapy, which is a CBCT denoised U-Net network with convolutional block attention modules. The datasets contained 20 groups of head and neck images. The CT images were registered to CBCT images as ground truth. The original CBCT denoised U-Net network, sCTU-Net, was trained for model performance comparison. The synthetic CT(SCT) images generated by CBAM-U-Net and the original sCTU-Net are called CBAM-SCT and U-Net-SCT images, respectively. The HU accuracies of the CT, CBCT, and SCT images were compared using four metrics: mean absolute error(MAE), root mean square error(RMSE), peak signal-to-noise ratio(PSNR), and structure similarity index measure(SSIM). The mean values of the MAE, RMSE, PSNR, and SSIM of CBAM-SCT images were 23.80 HU, 64.63 HU, 52.27 dB, and 0.9919, respectively,which were superior to those of the U-Net-SCT images. To evaluate dosimetric accuracy, the range accuracy was compared for a single-energy proton beam. The γ-index pass rates of a 4 cm × 4 cm scanned field and simple plan were calculated to compare the effects of the noise reduction capabilities of the original U-Net and CBAM-U-Net on the dose calculation results. CBAM-U-Net reduced noise more effectively than sCTU-Net, particularly in high-density tissues. We proposed a CBAM-U-Net model for CBCT noise reduction in proton therapy. Owing to the excellent noise reduction capabilities of CBAM-U-Net, the proposed model provided relatively explicit information regarding patient tissues. Moreover, it maybe be used in dose calculation and adaptive treatment planning in the future.
基金supported by grants from the National Natural Science Foundation of China (82370378 and 82070388)Taishan Scholar Program of Shandong Province (tsqn202211310)National Natural Science Foundation of Shandong Province (ZR2020MH035)。
文摘BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulinpotassium(GIK) therapy on clinical outcomes in acute coronary syndrome(ACS) patients receiving reperfusion therapy.METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs) that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs).RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio [RR] 0.57,95% confidence interval [95% CI]:0.35 to 0.94,P=0.03) and the risk of heart failure(RR 0.48,95% CI:0.25 to 0.95,P=0.04) and improved the left ventricular ejection fraction(LVEF)(mean difference [MD] 2.12,95% CI:0.40 to 3.92,P=0.02) at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95% CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95% CI:1.74 to 47.29,P=0.009) and hypoglycemia(RR 6.50,95% CI:1.28 to 33.01,P=0.02) but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD) activity but not glutathione peroxidase(GSH-Px) or catalase(CAT) activity.CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering eflcacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.
基金supported by the National Natural Science Foundation of China(22171219 and 22222112)Innovation Talent Promotion Plan of Shaanxi Province for Science and Technology Innovation Team(2023-CX-TD-51)+2 种基金Key Laboratory Fund for Plasma Physics(6142A04210108)the Interdisciplinary Training Program for Doctoral Candidate of Xi’an Jiaotong University(IDT2105)National Natural Science Foundation NSAF Joint Fund(U2230112).
文摘The development of supramolecular hosts which can efficiently encapsulate photosensitizers to improve the photodynamic efficacy holds great promise for cancer therapy.Here,we report two perylene diimide-based metallacages that can form stable host–guest complexes with planar conjugated molecules including polycyclic aromatic hydrocarbons and photosensitizers(hypocrellin A).Such host–guest complexation not only prevents the aggregation of photosensitizers in aqueous environments,but also offers fluorescence resonance energy transfer(FRET)from the metallacage to the photosensitizers to further improve the singlet oxygen generation(Φ_(Δ)=0.66).The complexes are further assembled with amphiphilic polymers,forming nanoparticles with improved stability for anticancer study.Both in vitro and in vivo studies indicate that the nanoparticles display excellent anticancer activities upon light irradiation,showing great potential for cancer photodynamic therapy.This study provides a straightforward and effective approach for enhancing the photosensitivity of conventional photosensitizers via host–guest complexation-based FRET,which will open a new avenue for host–guest chemistry-based supramolecular theranostics.
基金National Key Research and Development Program of China(2022YFC2502700)National Natural Science Foundation of China(81873434,82100190).
文摘Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.
基金supported by the National Natural Science Foundation of China(82273202,82370948,82072996,82170941)the Fundamental Research Funds for the Central Universities(2042022dx0003)+1 种基金the Hubei Province International Science and Technology Cooperation Project(2021EHB027)the National Key Research and Development Program(2022YFC2504200).
文摘Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),which is termed T cell exhaustion.This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment(TIME).Simultaneously,tumorigenesis entails robust reshaping of the epigenetic landscape,potentially instigating T cell exhaustion.In this review,we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion,and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies.Finally,we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
基金supported by the National Natural Science Foundation of China(No.11975107,12205111)。
文摘The application of superconducting(SC)technology enables magnets to excite strong fields with small footprints,which has great potential for miniaturizing proton therapy gantries.However,the slow ramping rate of SC magnets results in a low treatment efficiency compared with normal-conducting(NC)gantries.To address this problem,this study proposes a compact proton therapy gantry design with a large momentum acceptance utilizing alternating-gradient canted-cosine-theta(AG-CCT)SC magnets.In our design,a high-transmission degrader is mounted in the middle of the gantry,and the upstream beamline employs NC magnets with small apertures.Downstream of the degrader,large-bore AG-CCT magnets with strong alternating focusing gradients are set symmetrically as a local achromat,which realizes a momentum acceptance of 20%(or 40%in the energy domain).Therefore,only three magnetic working points are required to cover a treatment energy of 70-230 Me V.Owing to the large momentum acceptance,the proton beam after the degrader can be directly delivered to the isocenter without truncating its energy spectrum,which can significantly increase the treatment efficiency but causes severe dispersion effects during pencil beam scanning.Therefore,a compensation method was introduced by tuning the normal and skewed quadrupoles during the scanning process.As a result,the new gantry not only presents a remarkable reduction in the size and weight of the facility but also shows good potential for fast treatment.
文摘Objectives Renal replacement therapy(RRT)is increasingly adopted for critically ill patients diagnosed with acute kidney injury,but the optimal time for initiation remains unclear and prognosis is uncertain,leading to medical complexity,ethical conflicts,and decision dilemmas in intensive care unit(ICU)settings.This study aimed to develop a decision aid(DA)for the family surrogate of critically ill patients to support their engagement in shared decision-making process with clinicians.Methods Development of DA employed a systematic process with user-centered design(UCD)principle,which included:(i)competitive analysis:searched,screened,and assessed the existing DAs to gather insights for design strategies,developmental techniques,and functionalities;(ii)user needs assessment:interviewed family surrogates in our hospital to explore target user group's decision-making experience and identify their unmet needs;(iii)evidence syntheses:integrate latest clinical evidence and pertinent information to inform the content development of DA.Results The competitive analysis included 16 relevant DAs,from which we derived valuable insights using existing resources.User decision needs were explored among a cohort of 15 family surrogates,revealing four thematic issues in decision-making,including stuck into dilemmas,sense of uncertainty,limited capacity,and delayed decision confirmation.A total of 27 articles were included for evidence syntheses.Relevant decision making knowledge on disease and treatment,as delineated in the literature sourced from decision support system or clinical guidelines,were formatted as the foundational knowledge base.Twenty-one items of evidence were extracted and integrated into the content panels of benefits and risks of RRT,possible outcomes,and reasons to choose.The DA was drafted into a web-based phototype using the elements of UCD.This platform could guide users in their preparation of decision-making through a sequential four-step process:identifying treatment options,weighing the benefits and risks,clarifying personal preferences and values,and formulating a schedule for formal shared decision-making with clinicians.Conclusions We developed a rapid prototype of DA tailored for family surrogate decision makers of critically ill patients in need of RRT in ICU setting.Future studies are needed to evaluate its usability,feasibility,and clinical effects of this intervention.
文摘Boron neutron capture therapy(BNCT)is recognized as a precise binary targeted radiotherapy technique that effectively eliminates tumors through the^(10)B(n,α)^(7)Li nuclear reaction.Among various neutron sources,accelerator-based sources have emerged as particularly promising for BNCT applications.The^(7)Li(p,n)^(7)Be reaction is highly regarded as a potential neutron source for BNCT,owing to its low threshold energy for the reaction,significant neutron yield,appropriate average neutron energy,and additional benefits.This study utilized Monte Carlo simulations to model the physical interactions within a lithium target subjected to proton bombardment,including neutron moderation by an MgF_(2)moderator and subsequent BNCT dose analysis using a Snyder head phantom.The study focused on calculating the yields of epithermal neutrons for various incident proton energies,finding an optimal energy at 2.7 MeV.Furthermore,the Snyder head phantom was employed in dose simulations to validate the effectiveness of this specific incident energy when utilizing a^(7)Li(p,n)^(7)Be neutron source for BNCT purposes.
