Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to inc...Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.展开更多
AIM: To investigate the photodynamic effect of Cd Se/Zn S quantum dots(QDs) on pancreatic cancer cells and elucidate the probable mechanisms.METHODS: The pancreatic cancer cell line SW1990 was treated with different c...AIM: To investigate the photodynamic effect of Cd Se/Zn S quantum dots(QDs) on pancreatic cancer cells and elucidate the probable mechanisms.METHODS: The pancreatic cancer cell line SW1990 was treated with different concentrations of Cd Se/Zn S QDs(0, 0.5, 1.0, 1.5, 2.0, 2.5 μmol/L), with or without illumination. The viability of SW1990 cells was tested using the Cell Counting Kit-8(CCK-8) assay. The ultrastructural changes of SW1990 cells were observed by transmission electron microscopy. Apoptosis was detected by nuclear staining and flow cytometry(FCM). Reactive oxygen species(ROS) were measured by dichlorofluorescein diacetate via fluorescence microscopy. Expression of Bax, Bcl-2 and caspase-3 was measured by real-time polymerase chain reaction(PCR) and protein immunoblotting 24 h after SW1990 cells were treated with Cd Se/Zn S QDs and illuminated.RESULTS: The CCK-8 assay results showed that both Cd Se/Zn S QDs with and without illumination suppressed SW1990 cell proliferation. Cell viability was significantly lower when illuminated or with a longer incubation time and a higher light dose. Cd Se/Zn S QDs with illumination caused ultrastructural changes in SW1990 cells, such as organelle degeneration and chromatin condensation and aggregation at the periphery of the nucleus. Fluorescence microscopy and FCM showed that Cd Se/Zn S QDs(1.5 μmol/L) with illumination increased SW1990 cell apoptosis(53.2%) and ROS generation compared with no illumination. Real-time PCR showed that expression of Bax and caspase-3 was upregulated and Bcl-2 was downregulated. Immunoblotting results were consistent with real-time PCR results. Inhibition of ROS and apoptosis both attenuated QD-photodynamictherapy-induced cell death.CONCLUSION: Cd Se/Zn S QDs can be used as a photosensitizer to inhibit SW1990 cell proliferation through ROS generation and apoptotic protein expression regulation.展开更多
Spinal cord injury has long been a prominent challenge in the trauma repair process. Spinal cord injury is a research hotspot by virtue of its difficulty to treat and its escalating morbidity. Furthermore, spinal cord...Spinal cord injury has long been a prominent challenge in the trauma repair process. Spinal cord injury is a research hotspot by virtue of its difficulty to treat and its escalating morbidity. Furthermore, spinal cord injury has a long period of disease progression and leads to complications that exert a lot of mental and economic pressure on patients. There are currently a large number of therapeutic strategies for treating spinal cord injury, which range from pharmacological and surgical methods to cell therapy and rehabilitation training. All of these strategies have positive effects in the course of spinal cord injury treatment. This review mainly discusses the problems regarding stem cell therapy for spinal cord injury, including the characteristics and action modes of all relevant cell types. Induced pluripotent stem cells, which represent a special kind of stem cell population, have gained impetus in cell therapy development because of a range of advantages. Induced pluripotent stem cells can be developed into the precursor cells of each neural cell type at the site of spinal cord injury, and have great potential for application in spinal cord injury therapy.展开更多
Hydrogel capsules show attractive prospects in drug delivery recently because of high drug loading and sustained release behavior. In this study we reported a simple and convenient route to fabricate poly(acrylic acid...Hydrogel capsules show attractive prospects in drug delivery recently because of high drug loading and sustained release behavior. In this study we reported a simple and convenient route to fabricate poly(acrylic acid)-poly(N-isopropylacrylamide)(PAA-PNIPAm) hydrogel capsules by using hydroxypropylcellulose-poly(acrylic acid)(HPC-PAA) complexes as the templates. The capsules showed a high drug loading(～280% to the weight of capsules) for Doxorubicin hydrochloride. The release of drug from the capsules was responsive to the temperature and p H of the surroundings, showing a low-rate but sustained release behavior favorable for low-toxic and long-term therapy. Together with the convenient preparation, high drug loading, dual responsivity as well as the sustained release feature, it is implied that this polymeric hydrogel capsule might be a promising candidate for new drug carriers.展开更多
Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we...Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.展开更多
Gastric B-cell lymphoma of the mucosa associated lym-phoid tissue(MALT) lymphoma is one of the most com-mon forms of extranodal lymphoma.In addition to in-fection with Helicobacter pylori(H.pylori),the presence of an ...Gastric B-cell lymphoma of the mucosa associated lym-phoid tissue(MALT) lymphoma is one of the most com-mon forms of extranodal lymphoma.In addition to in-fection with Helicobacter pylori(H.pylori),the presence of an underlying autoimmune disease has also been associated with MALT lymphoma development.To date,no familial predisposition for MALT lymphomas has been reported as opposed to other types of lymphoma.A 65-year-old woman was admitted at our institution in 1998 with a diagnosis of H.pylori positive gastric MALT lymphoma and the presence of chronic autoim-mune thyroiditis was established on further work-up.H.pylori eradication did not result in regression of the lymphoma and RT-PCR showed the presence of the t(11;18)(q21;q21) translocation.About 1.5 years after H.pylori eradication,chemotherapy with cladribine resulted in complete remission.Due to lymphoma re-currence 13 mo later,radiotherapy to the stomach(46 Gy) resulted in minimal residual disease without further progression.The patient developed a second malig-nancy(Epstein-Bar virus-associated anaplastic large cell lymphoma in the mediastinum) in 2004 which initially responded to two courses of chemotherapy,but she re-fused further therapy and died of progressive lympho-ma in 2006.In 2008,her 55 years old daughter with a long standing Sj gren's syndrome was diagnosed with MALT lymphoma of the right parotid,but no evidence of gastric involvement or H.pylori infection was found.Currently,she is alive without therapy and undergoing regular check-ups.To our knowledge,this is the first report of MALT lymphoma in a f irst-degree relative of a patient with gastric MALT lymphoma in the context of two autoimmune diseases without a clearly established familial background.展开更多
C omprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and comple- mentary studies from...C omprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and comple- mentary studies from Barbieri et al. and Grasso et al.展开更多
Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional...Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional imaging mo-dalities,such as computed tomography(CT)and magnetic resonance imaging(MRI),primarily provide anatomical information,whereas 18F-fluorodeoxyglucose positron emission tomography/CT(18F-FDG PET/CT)integrates functional metabolic and anatomical imaging,serving as a critical complementary tool in the diagnosis and management of STS.This article reviews recent advances in the application of 18F-FDG PET/CT for STS.The advantages of 18F-FDG PET/CT in STS include:(1)Early detection of metabolic activity changes in tumors,partic-ularly when morphological alterations are insignificant;(2)Effective differen-tiation between benign and malignant soft tissue tumors,as well as aiding in distinguishing high-grade from low-grade sarcomas;(3)Identification of occult metastatic lesions,improving staging accuracy,and facilitating restaging in cases of recurrence or metastasis;(4)Utilization of parameters such as maximum stan-dardized uptake value and metabolic tumor volume to assist in tumor grading and prognostic evaluation;and(5)Monitoring treatment response to guide adjust-ments in personalized therapeutic strategies.However,18F-FDG PET/CT has limitations in diagnosis of certain STS subtypes(e.g.,myxoid liposarcoma),detection and biopsy of metastatic lymph nodes,necessitating integration with clinical evaluation and other imaging techniques.18F-FDG PET/CT is poised to play an increasingly vital role in the precision diagnosis and treatment of STS.展开更多
Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-E...Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.展开更多
Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target ...Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.展开更多
Triple-negative breast cancer(TNBC)is one type of the most aggressive breast can cers with poor prog no sis.It is of great urgency to develop new therapeutics for treati ng TNBC.Based on curre nt treatment guideline a...Triple-negative breast cancer(TNBC)is one type of the most aggressive breast can cers with poor prog no sis.It is of great urgency to develop new therapeutics for treati ng TNBC.Based on curre nt treatment guideline and genetic informatio n of TNBC,a combi nation al therapy platform in tegrati ng chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy.In this study,we developed paclitaxel amino lipid(PAL)derived nanoparticles(NPs)to incorporate both chemotherapy drugs and P53 mRNA.The PAL P53 mRNA NPs showed superior properties compared to Abraxane? and Lipusu? used in the clinic including high paclitaxel loading capacity(24 wt.%,calculated by paclitaxel in PAL),PAL encapsulation efficiency(94.7%±6.8%)and mRNA encapsulation efficiency(88.7%±0.7%).Meanwhile,these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells.More importantly,we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model.Overall,these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information,and therefore represent a promising approach for TNBC treatment.展开更多
Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficie...Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.展开更多
Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-pa...Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.展开更多
MicroRNAs （miRNAs） are small, non-coding RNAs that function as post-transcriptional regulators of gene expression. The deregulated expression of miRNAs is associated with a variety of diseases, including breast canc...MicroRNAs （miRNAs） are small, non-coding RNAs that function as post-transcriptional regulators of gene expression. The deregulated expression of miRNAs is associated with a variety of diseases, including breast cancer. In the present study, we found that miR-495 was markedly up-regulated in clinical breast cancer samples by quantitative real time-PCR （qRT-PCR）. Junctional adhesion molecule A （JAM-A） was predicted to be a potential target of miR-495 by bioinformatics analysis and was subsequently verified by luciferase assay and Western blotting. JAM-A was found to be negatively correlated with the migration of breast cancer cells through loss-of-function and gain-offunction assays, and the inhibition of JAM-A by miR- 495 promoted the migration of MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of JAM-A could restore miR-495-induced breast cancer cell migration. Taken together, our findings suggest that miR-4g5 could facilitate breast cancer progression through the repression of JAM-A, making this miRNA a potential therapeutic target.展开更多
Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be ...Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.展开更多
To the Editor:Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.GISTs mostly occur in the stomach or small intestine among patients around 40-60 years of age,an...To the Editor:Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.GISTs mostly occur in the stomach or small intestine among patients around 40-60 years of age,and are insensitive to chemotherapy or radiotherapy.展开更多
The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signa...The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.展开更多
Antibody drug conjugates(ADCs)normally compose of a humanized antibody and small molecular drug via a chemical linker.After decades of preclinical and clinical studies,a series of ADCs have been widely used for treati...Antibody drug conjugates(ADCs)normally compose of a humanized antibody and small molecular drug via a chemical linker.After decades of preclinical and clinical studies,a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin(Adcetris?)for relapsed Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma,gemtuzumab ozogamicin(Mylotarg?)for acute myeloid leukemia,ado-trastuzumab emtansine(Kadcyla?)for HER2-positive metastatic breast cancer,inotuzumab ozogamicin(Besponsa?)and most recently polatuzumab vedotin-piiq(Polivy?)for B cell malignancies.More than eighty ADCs have been investigated in different clinical stages from approximately six hundred clinical trials to date.This review summarizes the key elements of ADCs and highlights recent advances of ADCs,as well as important lessons learned from clinical data,and future directions.展开更多
Lipid-like nanoparticles(LLNs)have been extensively explored for messenger RNA(mRNA)delivery in various biomedical applications.However,the long-term storage of these nanoparticles is still a challenge for their clini...Lipid-like nanoparticles(LLNs)have been extensively explored for messenger RNA(mRNA)delivery in various biomedical applications.However,the long-term storage of these nanoparticles is still a challenge for their clinical translation.In this study,we investigated a series of conditions for the long-term storage of LLNs with encapsulation of mRNA.We evaluated the stability of LLNs with different concentrations of cryoprotectants(sucrose,trehalose or mannitol)under the conditions of freezing or lyophilization processes.Through in vitro and in vivo mRNA delivery studies,we identified the optimal storage condition,and found that the addition with 5%(w/v)sucrose or trehalose to LLNs could remain their mRNA delivery efficiency for at least three months in the liquid nitrogen storage condition.展开更多
Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. ...Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. Herein, we enabled a co-delivery of mRNA molecules and superparamagnetic iron oxide nanoparticles （SPIONs） by using an amino-ester lipid-like nanomaterial. An orthogonal experimental design was used to identify the optimal formulation. The optimal formulation, MPA-Ab-8 LLNs, not only showed high encapsulation of both mRNA and SPIONs, but also increased the r2 relaxivity of SPIONs by more than 1.5-fold in vitro. MPA-Ab-8 LLNs effectively delivered mRNA and SPIONs into cells, and consequently induced high protein expression as well as strong MRI contrast. Consistent herewith, we observed both mRNA-mediated protein expression and an evident negative contrast enhancement of MRI signal in mice. In conclusion, amino-ester nanomaterials demonstrate great potential as delivery vehicles for theranostic applications.展开更多
基金Supported by Funding for Clinical Trials from the Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,No.2021-LCYJ-MS-11.
文摘Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.
基金Supported by the National Natural Science Foundation of China,No.81472844 and No.81301826Shanghai Municipal Education Commission,No.14ZZ114
文摘AIM: To investigate the photodynamic effect of Cd Se/Zn S quantum dots(QDs) on pancreatic cancer cells and elucidate the probable mechanisms.METHODS: The pancreatic cancer cell line SW1990 was treated with different concentrations of Cd Se/Zn S QDs(0, 0.5, 1.0, 1.5, 2.0, 2.5 μmol/L), with or without illumination. The viability of SW1990 cells was tested using the Cell Counting Kit-8(CCK-8) assay. The ultrastructural changes of SW1990 cells were observed by transmission electron microscopy. Apoptosis was detected by nuclear staining and flow cytometry(FCM). Reactive oxygen species(ROS) were measured by dichlorofluorescein diacetate via fluorescence microscopy. Expression of Bax, Bcl-2 and caspase-3 was measured by real-time polymerase chain reaction(PCR) and protein immunoblotting 24 h after SW1990 cells were treated with Cd Se/Zn S QDs and illuminated.RESULTS: The CCK-8 assay results showed that both Cd Se/Zn S QDs with and without illumination suppressed SW1990 cell proliferation. Cell viability was significantly lower when illuminated or with a longer incubation time and a higher light dose. Cd Se/Zn S QDs with illumination caused ultrastructural changes in SW1990 cells, such as organelle degeneration and chromatin condensation and aggregation at the periphery of the nucleus. Fluorescence microscopy and FCM showed that Cd Se/Zn S QDs(1.5 μmol/L) with illumination increased SW1990 cell apoptosis(53.2%) and ROS generation compared with no illumination. Real-time PCR showed that expression of Bax and caspase-3 was upregulated and Bcl-2 was downregulated. Immunoblotting results were consistent with real-time PCR results. Inhibition of ROS and apoptosis both attenuated QD-photodynamictherapy-induced cell death.CONCLUSION: Cd Se/Zn S QDs can be used as a photosensitizer to inhibit SW1990 cell proliferation through ROS generation and apoptotic protein expression regulation.
基金supported by the National Key Research and Development Program of China,No. 2017YFA0104304 (to BW),2017YFA0205400 (to PPS),and 2017YFA0506000 (to PPS)the National Natural Science Foundation of China,No. 81571213 (to BW)+2 种基金the Nanjing Medical Science and Technique Development Foundation of China,No. QRX17006 (to BW)the Nanjing Medical Science and Innovation Platform,No. ZDX16005 (to BW)the Innovation and Entrepreneurship Plan of Jiangsu Province (2019)(to BW)。
文摘Spinal cord injury has long been a prominent challenge in the trauma repair process. Spinal cord injury is a research hotspot by virtue of its difficulty to treat and its escalating morbidity. Furthermore, spinal cord injury has a long period of disease progression and leads to complications that exert a lot of mental and economic pressure on patients. There are currently a large number of therapeutic strategies for treating spinal cord injury, which range from pharmacological and surgical methods to cell therapy and rehabilitation training. All of these strategies have positive effects in the course of spinal cord injury treatment. This review mainly discusses the problems regarding stem cell therapy for spinal cord injury, including the characteristics and action modes of all relevant cell types. Induced pluripotent stem cells, which represent a special kind of stem cell population, have gained impetus in cell therapy development because of a range of advantages. Induced pluripotent stem cells can be developed into the precursor cells of each neural cell type at the site of spinal cord injury, and have great potential for application in spinal cord injury therapy.
基金financially supported by the National Natural Science Foundation of China (Grant No. 31100427, No. 81101751)the Jiangsu Province Natural Science Foundation (BK20131071)
文摘Hydrogel capsules show attractive prospects in drug delivery recently because of high drug loading and sustained release behavior. In this study we reported a simple and convenient route to fabricate poly(acrylic acid)-poly(N-isopropylacrylamide)(PAA-PNIPAm) hydrogel capsules by using hydroxypropylcellulose-poly(acrylic acid)(HPC-PAA) complexes as the templates. The capsules showed a high drug loading(～280% to the weight of capsules) for Doxorubicin hydrochloride. The release of drug from the capsules was responsive to the temperature and p H of the surroundings, showing a low-rate but sustained release behavior favorable for low-toxic and long-term therapy. Together with the convenient preparation, high drug loading, dual responsivity as well as the sustained release feature, it is implied that this polymeric hydrogel capsule might be a promising candidate for new drug carriers.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.31471255,31771483,81171515,31670991,and 61721003)the National Key Research and Development Program(Grant Nos.2017YFC0908400 and 2017YFC0908401).
文摘Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.
文摘Gastric B-cell lymphoma of the mucosa associated lym-phoid tissue(MALT) lymphoma is one of the most com-mon forms of extranodal lymphoma.In addition to in-fection with Helicobacter pylori(H.pylori),the presence of an underlying autoimmune disease has also been associated with MALT lymphoma development.To date,no familial predisposition for MALT lymphomas has been reported as opposed to other types of lymphoma.A 65-year-old woman was admitted at our institution in 1998 with a diagnosis of H.pylori positive gastric MALT lymphoma and the presence of chronic autoim-mune thyroiditis was established on further work-up.H.pylori eradication did not result in regression of the lymphoma and RT-PCR showed the presence of the t(11;18)(q21;q21) translocation.About 1.5 years after H.pylori eradication,chemotherapy with cladribine resulted in complete remission.Due to lymphoma re-currence 13 mo later,radiotherapy to the stomach(46 Gy) resulted in minimal residual disease without further progression.The patient developed a second malig-nancy(Epstein-Bar virus-associated anaplastic large cell lymphoma in the mediastinum) in 2004 which initially responded to two courses of chemotherapy,but she re-fused further therapy and died of progressive lympho-ma in 2006.In 2008,her 55 years old daughter with a long standing Sj gren's syndrome was diagnosed with MALT lymphoma of the right parotid,but no evidence of gastric involvement or H.pylori infection was found.Currently,she is alive without therapy and undergoing regular check-ups.To our knowledge,this is the first report of MALT lymphoma in a f irst-degree relative of a patient with gastric MALT lymphoma in the context of two autoimmune diseases without a clearly established familial background.
文摘C omprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and comple- mentary studies from Barbieri et al. and Grasso et al.
文摘Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional imaging mo-dalities,such as computed tomography(CT)and magnetic resonance imaging(MRI),primarily provide anatomical information,whereas 18F-fluorodeoxyglucose positron emission tomography/CT(18F-FDG PET/CT)integrates functional metabolic and anatomical imaging,serving as a critical complementary tool in the diagnosis and management of STS.This article reviews recent advances in the application of 18F-FDG PET/CT for STS.The advantages of 18F-FDG PET/CT in STS include:(1)Early detection of metabolic activity changes in tumors,partic-ularly when morphological alterations are insignificant;(2)Effective differen-tiation between benign and malignant soft tissue tumors,as well as aiding in distinguishing high-grade from low-grade sarcomas;(3)Identification of occult metastatic lesions,improving staging accuracy,and facilitating restaging in cases of recurrence or metastasis;(4)Utilization of parameters such as maximum stan-dardized uptake value and metabolic tumor volume to assist in tumor grading and prognostic evaluation;and(5)Monitoring treatment response to guide adjust-ments in personalized therapeutic strategies.However,18F-FDG PET/CT has limitations in diagnosis of certain STS subtypes(e.g.,myxoid liposarcoma),detection and biopsy of metastatic lymph nodes,necessitating integration with clinical evaluation and other imaging techniques.18F-FDG PET/CT is poised to play an increasingly vital role in the precision diagnosis and treatment of STS.
文摘Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.
基金supported by grants from the Key International Cooperation of the National Natural Science Foundation of China(No.81920108029)the Key Foundation for Social Development Project of the Jiangsu Province,China(No.BE2021741)Youth Fund of the National Natural Science Foundation of China(No.82002783)
文摘Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.
文摘Triple-negative breast cancer(TNBC)is one type of the most aggressive breast can cers with poor prog no sis.It is of great urgency to develop new therapeutics for treati ng TNBC.Based on curre nt treatment guideline and genetic informatio n of TNBC,a combi nation al therapy platform in tegrati ng chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy.In this study,we developed paclitaxel amino lipid(PAL)derived nanoparticles(NPs)to incorporate both chemotherapy drugs and P53 mRNA.The PAL P53 mRNA NPs showed superior properties compared to Abraxane? and Lipusu? used in the clinic including high paclitaxel loading capacity(24 wt.%,calculated by paclitaxel in PAL),PAL encapsulation efficiency(94.7%±6.8%)and mRNA encapsulation efficiency(88.7%±0.7%).Meanwhile,these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells.More importantly,we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model.Overall,these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information,and therefore represent a promising approach for TNBC treatment.
基金supported by grants from the Natural Science Foundation of Huai'an Science and Technology Bureau(Grant No.HAB202312)the Science and Technology Development Fund of the Affiliated Hospital of Xuzhou Medical University(Grant No.XYFY2021018).
文摘Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.
基金National Key Research and Development Program of China(2020YFA0713804)the National Natural Science Foundation of China(82272811)+2 种基金Jiangsu Province Key Research and Development Program(BE2023654)Nanjing Jiangbei New Area Key Research and Development Program,Special Fund of Health Science and Technology Development of Nanjing(YKK20080)Fundings for Clinical Trials from the Affiliated Drum Tower Hospital,Medical School of Nanjing University(2023-LCYJ-PY-29).
文摘Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.
文摘MicroRNAs （miRNAs） are small, non-coding RNAs that function as post-transcriptional regulators of gene expression. The deregulated expression of miRNAs is associated with a variety of diseases, including breast cancer. In the present study, we found that miR-495 was markedly up-regulated in clinical breast cancer samples by quantitative real time-PCR （qRT-PCR）. Junctional adhesion molecule A （JAM-A） was predicted to be a potential target of miR-495 by bioinformatics analysis and was subsequently verified by luciferase assay and Western blotting. JAM-A was found to be negatively correlated with the migration of breast cancer cells through loss-of-function and gain-offunction assays, and the inhibition of JAM-A by miR- 495 promoted the migration of MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of JAM-A could restore miR-495-induced breast cancer cell migration. Taken together, our findings suggest that miR-4g5 could facilitate breast cancer progression through the repression of JAM-A, making this miRNA a potential therapeutic target.
文摘Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.
基金supported by the Natural Science Foundation of China(Nos.82203178,82272852,and 82103687)Jiangsu Provincial Key Research and Development Program(No.BE2020619)+1 种基金Natural Science Foundation of Jiangsu Province(No.BK20220191)Nanjing Medical Science and Technology Development Foundation(No.YKK22086).
文摘To the Editor:Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.GISTs mostly occur in the stomach or small intestine among patients around 40-60 years of age,and are insensitive to chemotherapy or radiotherapy.
基金supported by the Natural Science Foundation of China(grant number 82002456)China Postdoctoral Science Foundation(grant number 2022M723207)+10 种基金the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2023KY666)Zhejiang Traditional Chinese Medicine Science Fund Project(grant number 2024ZL372)Qiantang Cross Fund Project(grant number 2023-16)National Natural Science Foundation of China of Zhejiang Cancer Hospital Cultivation Project(grant number PY2023006)the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2024KY812)the Natural Science Foundation of Zhejiang Province(grant number LQ24H160036)Beijing Health Technologies Promotion Program[grant number BHTPP2022041]Peking University Clinical Scientist Training Program and the Fundamental Research Funds for the Central Universities[grant number BMU2024PYJH010]Science Foundation of Peking University Cancer Hospital[grant number PY202333]the Beijing Natural Science Foundation[grant number 7232248]Beijing Hospitals Authority Youth Programme[grant number QML20231902].
文摘The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.
基金supported by the start-up fund from the College of Pharmacy at The Ohio State University
文摘Antibody drug conjugates(ADCs)normally compose of a humanized antibody and small molecular drug via a chemical linker.After decades of preclinical and clinical studies,a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin(Adcetris?)for relapsed Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma,gemtuzumab ozogamicin(Mylotarg?)for acute myeloid leukemia,ado-trastuzumab emtansine(Kadcyla?)for HER2-positive metastatic breast cancer,inotuzumab ozogamicin(Besponsa?)and most recently polatuzumab vedotin-piiq(Polivy?)for B cell malignancies.More than eighty ADCs have been investigated in different clinical stages from approximately six hundred clinical trials to date.This review summarizes the key elements of ADCs and highlights recent advances of ADCs,as well as important lessons learned from clinical data,and future directions.
基金supported by the Bayer Hemophilia Awards Program as well as the start-up fund from the College of Pharmacy at The Ohio State University.
文摘Lipid-like nanoparticles(LLNs)have been extensively explored for messenger RNA(mRNA)delivery in various biomedical applications.However,the long-term storage of these nanoparticles is still a challenge for their clinical translation.In this study,we investigated a series of conditions for the long-term storage of LLNs with encapsulation of mRNA.We evaluated the stability of LLNs with different concentrations of cryoprotectants(sucrose,trehalose or mannitol)under the conditions of freezing or lyophilization processes.Through in vitro and in vivo mRNA delivery studies,we identified the optimal storage condition,and found that the addition with 5%(w/v)sucrose or trehalose to LLNs could remain their mRNA delivery efficiency for at least three months in the liquid nitrogen storage condition.
文摘Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. Herein, we enabled a co-delivery of mRNA molecules and superparamagnetic iron oxide nanoparticles （SPIONs） by using an amino-ester lipid-like nanomaterial. An orthogonal experimental design was used to identify the optimal formulation. The optimal formulation, MPA-Ab-8 LLNs, not only showed high encapsulation of both mRNA and SPIONs, but also increased the r2 relaxivity of SPIONs by more than 1.5-fold in vitro. MPA-Ab-8 LLNs effectively delivered mRNA and SPIONs into cells, and consequently induced high protein expression as well as strong MRI contrast. Consistent herewith, we observed both mRNA-mediated protein expression and an evident negative contrast enhancement of MRI signal in mice. In conclusion, amino-ester nanomaterials demonstrate great potential as delivery vehicles for theranostic applications.
