Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new l...Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymphangiogenesis is mandatory to pave the way for the development of new therapies for cancer.In the future,tailored treatments consisting of combinations of chemotherapy,other targeted therapies,and anti-lymphangiogenesis agents will hopefully improve patient outcomes.This progression to the clinic must be guided by new avenues of research,such as the identif ication of biomarkers that predict response to treatment.展开更多
It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by sys...It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responsesto chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.展开更多
In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA execu...In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA executive committee reported activities and programs and highlighted the partnership and collaboration between USCACA and other major organizations. The key initiatives and programs of USCACA included 1) USCACA-TIGM Esophageal Cancer Program that funds translational research of esophageal cancer prevention and treatment at the Xinxiang Medical University in Henan province, China; 2) the USCACA-NFCR-AFCR Scholarship Program, which has supported 10 young outstanding Chinese cancer researchers and will award 4 fellowships at the Guangzhou International Symposium on Oncology in November this year; 3) USCACA-Hengrui Training Program for Early Phase Clinical Research, which has supported the training of a Chinese scholar at two major cancer centers in the US; and 4) USCACA has continued its partnership with the Chinese Journal of Cancer, which has reached significant international impact.展开更多
Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti-inflammatory signaling events with protein and lipid m...Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti-inflammatory signaling events with protein and lipid mediators. Recent advances in lipid detection have revealed the importance of lipid mediators in inflammation. Omega three polyunsaturated fatty acids(ω-3 PUFA) are found naturally in fish oil and have been extensively studied in multiple inflammatory diseases with improved outcomes. Resolvins are thought to be the active metabolites of ω-3 PUFA, and are responsible for facilitating the resolving phase of acute inflammation. Clinically, resolvins have been associated with resolution of acute kidney injury and acute lung injury, micro and macro vascular response to injury, and inhibition of microglia-activated inflammation in neurodegenerative disorders. In addition to inflammatory diseases, ω-3 PUFA and resolvins appear to modulate cancer progression. ω-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and favorable phenotype in breast cancer. Resolvins offer promising therapeutic potential as they may modulate inflammation with minimal side-effects, in contrast to currently available anti-inflammatory medications. This review describes the roles of ω-3 PUFA and resolvins in the inflammatory cascade, various inflammatory diseases, and specific cancers. Additionally, it will discuss the clinical therapeutic potential of resolvins astargets in inflammatory diseases and cancers.展开更多
Malignant peritoneal mesothelioma(PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be sugg...Malignant peritoneal mesothelioma(PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction(CRS) with hyperthermic intraperitoneal chemotherapy(HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Ac-cordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1(SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.展开更多
The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors,which include epidermal growth factor receptor agonists and members of the transforming growth factor ...The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors,which include epidermal growth factor receptor agonists and members of the transforming growth factor β family.Furthermore,the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small,immunomodulatory proteins also play key roles in carcinogenesis and may,therefore,be potential targets for novel therapeutic approaches.In this review,we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.展开更多
The eye is a highly complex,yet readily accessible organ within the human body.As such,the eye is an appealing candidate target for a vast array of drug therapies.Despite advances in ocular drug therapy research,the f...The eye is a highly complex,yet readily accessible organ within the human body.As such,the eye is an appealing candidate target for a vast array of drug therapies.Despite advances in ocular drug therapy research,the focus on pediatric ocular drug delivery continues to be highly underrepresented due to the limited number of degenerative ocular diseases with childhood onset.In this review,we explore more deeply the reasons underlying the disparity between ocular therapies available for children and for adults by highlighting diseases that most commonly afflict children（with focus on the anterior eye） and existing prognoses,recent developments in ocular drug delivery systems and nanomedicines for children,and barriers to use for pediatric patients展开更多
AIM To examine the effect of high doses of vitamin C(VitC) on ex vivo human platelets(PLTs).METHODS Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to:(1) normal saline(contro...AIM To examine the effect of high doses of vitamin C(VitC) on ex vivo human platelets(PLTs).METHODS Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to:(1) normal saline(control);(2) 0.3 mmol/L VitC(Lo VitC); or(3) 3 mmol/L VitC(Hi VitC, final concentrations) and stored appropriately. The Vit C additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of Vit C used here correspond to plasma Vit C levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography(TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate(ATP) secretion in response to collagen or adenosine diphosphate(ADP); and flow cytometry, for changes in expression of CD-31, CD41 a, CD62 p and CD63. In addition, PLT intracellular Vit C content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time(PT), partial thrombplastin time(PTT), functional fibrinogen] and Lipidomics analysis(UPLC ESI-MS/MS).RESULTS VitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L(Lo VitC) and 15.7 mmol/L(Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period(P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle(P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups(P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups(P > 0.05). Finally, VitC at the higher dose(3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid(P < 0.05).CONCLUSION Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.展开更多
Background:Sodium iodate(SI)is a chemical widely applied to induce retina degeneration in animal models.SI treatment caused formation of rosettes/folds in the outer nuclear layer(ONL)of the rat retina,but it was previ...Background:Sodium iodate(SI)is a chemical widely applied to induce retina degeneration in animal models.SI treatment caused formation of rosettes/folds in the outer nuclear layer(ONL)of the rat retina,but it was previously unclear whether SI also forms rosettes in mice.In addition,SI induced retina degeneration was never addressed in non-separate sclerochoroid/retina pigment epithelium/retina whole mount.Here we displayed features of retina degeneration including rosette formation in mice and developed a morphological analytic assessment using sclerochoroid/retina pigment epithelium/retina whole mounts.Methods:SI was intraperitoneally injected in Sprague-Dawley(SD)rats and C57BL/6J mice using a single dose(50 mg/kg)or with a dose range(10 to 50 mg/kg)in BALB/C mice.Rat retinas were investigated up to 2-week post-injection by histology and whole mounts,and mouse retinas were investigated up to 3-week post-injection by histology,fluorescent staining of sections and/or sclerochoroid/retina pigment epithelium/retina whole mounts for the morphological evaluations of the SI-induced retina damage.Results:SI-induced retina damage caused photoreceptor(PR)degeneration and rosettes/folds formation,as well as retina pigment epithelium degeneration and inward migration.It displayed mixed nuclei from choroid to PRs,due to layer disorganization,as shown by single horizontal images in the sclerochoroid/retina pigment epithelium/retina whole mounts.Measurement of the PR rosette area induced by SI provided a quantitative,morphological evaluation of retina degeneration.Conclusions:The method of non-separate sclerochoroid/retina pigment epithelium/retina whole staining and mount allows us to observe the integral horizontal view of damage from sclera to PR layers,which cannot be addressed by using sectioned and separate whole mount methods.This method is applicable for morphological evaluation of retina damage,especially in the subretinal layer.展开更多
PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair p...PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair pathways.However,as the case with other chemotherapeutic agents,their effectiveness is often compromised by the development of resistance.PARP inhibitors have consistently been reported to promote autophagy,a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.Autophagy can exhibit different functional properties,the most prominent being cytoprotective.In addition,both cytotoxic and non-protective functions forms have also been identified.In this review,we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors,highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.展开更多
After surgical resection, patients with glioblastoma require many aspects of care to maximize function and quality of life. Patients face a multitude of hurdles that require the expertise of a variety of specialists. ...After surgical resection, patients with glioblastoma require many aspects of care to maximize function and quality of life. Patients face a multitude of hurdles that require the expertise of a variety of specialists. Here we will review the current literature on management of glioblastoma patients after surgical resection.展开更多
Objective:We review inflammatory drug targets in retinal and choroidal neovascularization(NV)in narrative manner.Background:Vascular remodeling and angiogenesis are processes typically associated with wound-healing me...Objective:We review inflammatory drug targets in retinal and choroidal neovascularization(NV)in narrative manner.Background:Vascular remodeling and angiogenesis are processes typically associated with wound-healing mechanisms intended to minimize ischemia and maintain tissue homeostasis.In the eye,however,these actions primarily deteriorate tissue homeostatic recovery,and could even contribute to the progress of severe conditions,e.g.,blindness.Angiogenesis in diabetic retinopathy(DR)and age-related macular degeneration(AMD)is the primary cause of vision loss in working-age and elderly populations.Current treatment of anti-vascular endothelial growth factor(VEGF)agents has limited action efficacy,working in less than 50%patients.Understanding cellular and molecular networks associated in retinal vascular remodeling may provide an insight to develop novel therapeutic strategies.Methods:Here,we highlight ocular cells-endothelial,mural,retinal pigment epithelium(RPE),glial and macrophages,as well as inflammatory molecules-such as the complement system,stromal derived factor-1,chemokine CXC receptor-4,inflammasome,interleukin-18,programed cell death ligand-1,insulin-like growth factor(IGF)and sphigosin-1-phosphate receptor,associated with retinal and choroidal NV,and discuss their recent and future therapeutic approaches.Conclusions:A deeper understanding on pathogenesis,pathobiology including ocular immunobiology of retinal and choroidal NV will pave the way to expand and overleap the current therapeutic approach.展开更多
Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a hetero...Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With the approval of immune checkpoint blockade(ICB)for TNBC,the addition of pembrolizumab to systemic chemotherapy has become standard of care(SOC)in neoadjuvant systemic therapy(NST)for high-risk early-stage TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated(ON),indicating an ineffective response to treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,the loss of SIAH expression(SIAH^(Low/OFF))in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation(OFF),indicating effective therapy and chemo-sensitive tumor cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.展开更多
The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g.,S63845,MIK665.However,their effectiveness in acute myeloid leukemia(AML)is limited by compensatory MCL-1 accumulation via th...The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g.,S63845,MIK665.However,their effectiveness in acute myeloid leukemia(AML)is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system.Here,we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g.,bosutinib(SKI-606)might circumvent this phenomenon.MCL-1 antagonist/SKI-606 co-administration synergistically induced apoptosis in diverse AML cell lines.Consistently,Src or MCL-1 knockdown with shRNA markedly sensitized cells to MCL-1 inhibitors or SKI-606 respectively,while ectopic MCL-1 expression significantly diminished apoptosis.Mechanistically,MCL-1 antagonist exposure induced MCL-1 up-regulation,an event blocked by Src inhibitors or Src shRNA knock-down.MCL-1 down-regulation was associated with diminished transcription and increased K48-linked degradative ubiquitination.Enhanced cell death depended functionally upon down-regulation of phosphorylated STAT3(Tyr705/Ser727)and cytoprotective downstream targets c-Myc and BCL-xL,as well as BAX/BAK activation,and NOXA induction.Importantly,the Src/MCL-1 inhibitor regimen robustly killed primary AML cells,including primitive progenitors,but spared normal hematopoietic CD34+cells and human cardiomyocytes.Notably,the regimen significantly improved survival in an MV4-11 cell xenograft model,while reducing tumor burden in two patient-derived xenograft(PDX)AML models and increased survival in a third.These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination,disrupting STAT-3-mediated transcription,and inducing NOXA-mediated MCL-1 degradation.They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies.展开更多
Epistaxis remains one of the most common otolaryngology emergencies. Severe epistaxis may be caused by internal carotid artery （ICA） pseudoaneurysm or cavernous fistula, which is clinically rare but life threatening...Epistaxis remains one of the most common otolaryngology emergencies. Severe epistaxis may be caused by internal carotid artery （ICA） pseudoaneurysm or cavernous fistula, which is clinically rare but life threatening if it is not diagnosed and treated timely. Most ICA pseudoaneurysms are mainly caused by trauma with few other causes. From January 1998 to December 2005, a total of 8 cases with non-traumatic carotid artery pseudoaneurysm were correctly diagnosed through digital subtraction angiography （DSA） in Ganzhou People＇s Hospital. The patients had suffered from serious nose bleeding repeatedly and had been resistant to routine treatments.展开更多
Chitosan is a nature-based polymer with low toxicity,excellent biocompatibility and biodegradability.However,the intractable solubility of chitosan in water and most conventional solvents hampers its biomedical applic...Chitosan is a nature-based polymer with low toxicity,excellent biocompatibility and biodegradability.However,the intractable solubility of chitosan in water and most conventional solvents hampers its biomedical applications.Following the dissolution method for dissolving chitosan in plain water developed by us,chitosan was dissolved in ionic liquid followed by overnight freezing at−20℃ and subsequent solvent exchange with plain water at room temperature.In this study,we fabricated a drug-carrying chitosan film via solution casting and air-drying by using the plain water-based chitosan solution.Specifically,brimonidine tartrate(BT),an antiglaucoma drug,was dissolved in the plain-water based solution and used to prepare BT-loaded chitosan film,i.e.,chitosan-BT film.The resulting film is transparent,structurally stable,and mucoadhesive.Micro-sized antiglaucoma BT drug crystals form and are well dispersed in the chitosan film.The chitosan-BT film enables BT to have a high corneal permeability with fast drug release kinetics for potential ocular drug delivery.展开更多
Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in...Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.展开更多
The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different typ...The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different types of immune cells contribute to the progression of liver diseases,it is crucial to thoroughly characterize hepatic immune cells.Although direct digestion of liver tissue is a relatively simple method for isolating immune cells,it often induces excessive hepatocyte death,which causes a release of intracellular components that leads to the activation of stress responses and injury in the surrounding cells.This injury can lead to excessive death in the hepatic immune cells,making isolation and accurate characterization of the immune profile challenging,especially in diseased livers.The method described here addresses these challenges by utilizing Phosphate buffered saline(PBS)and digestion buffer perfusions to eliminate contaminating blood cells,ensure a pure hepatic immune population,and minimize hepatic immune cell death.Further ex vivo digestion of the liver enables the isolation of the immune cells from the hepatic tissues and the generation of a single-cell suspension that can be stained for spectral flow cytometry.To enhance intracellular cytokine detection and maintain signaling under different physiological and pathological conditions,this protocol uses an in vivo administration of Brefeldin A,a less toxic inhibitor of cytokine secretion.This in vivo administration of Brefeldin A allows for a more accurate representation of the immune cell function and cytokine expression compared to the traditionally used ex vivo Brefeldin A administration.A comprehensive spectral flow cytometry panel,comprising extracellular and intracellular staining,is used for deep immunophenotyping and immune cell effector function profiling.While this protocol is specifically designed for liver digestion of Mdr2 knockout mice(a model for primary sclerosing cholangitis)and flow cytometry staining,it can also be applied to other liver diseases and sensitive tissues.展开更多
Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(H...Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(HBV)and a drug cocktail is effective in bringing down blood hepatitis C virus(HCV)level to zero.With successful application of mRNA vaccine for COVID-19,it is a matter of time before an effective vaccine for HCV is generated.Despite these positive advancements,the incidence of HCC is continuing to rise because of HCC development as a direct consequence of non-alcoholic steatohepatitis(NASH)caused by obesity(1).While viral hepatitis is waning in the Western countries,obesity is now a global problem,requiring impactful treatment regimen for HCC that can provide meaningful survival benefit.展开更多
基金Supported by SUMITOMO Life Social Welfare Services Foundation (to Nagahashi M)Virginia Commonwealth University Grant BIRCWH K12HD055881,and Susan G Komen for the Cure Career Catalyst Research Grant KG090510 (to Takabe K)
文摘Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymphangiogenesis is mandatory to pave the way for the development of new therapies for cancer.In the future,tailored treatments consisting of combinations of chemotherapy,other targeted therapies,and anti-lymphangiogenesis agents will hopefully improve patient outcomes.This progression to the clinic must be guided by new avenues of research,such as the identif ication of biomarkers that predict response to treatment.
基金Supported by NIH,No.R01CA160688 and No.T32CA085159-10
文摘It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responsesto chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.
文摘In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA executive committee reported activities and programs and highlighted the partnership and collaboration between USCACA and other major organizations. The key initiatives and programs of USCACA included 1) USCACA-TIGM Esophageal Cancer Program that funds translational research of esophageal cancer prevention and treatment at the Xinxiang Medical University in Henan province, China; 2) the USCACA-NFCR-AFCR Scholarship Program, which has supported 10 young outstanding Chinese cancer researchers and will award 4 fellowships at the Guangzhou International Symposium on Oncology in November this year; 3) USCACA-Hengrui Training Program for Early Phase Clinical Research, which has supported the training of a Chinese scholar at two major cancer centers in the US; and 4) USCACA has continued its partnership with the Chinese Journal of Cancer, which has reached significant international impact.
基金Supported by The Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,Nos.15H05676 and 15K15471 for Nagahashi M and No.15H04927 for Wakai Tsupported by the Uehara Memorial Foundation,Nakayama Cancer Research Institute,Takeda Science Foundation,Tsukada Medical Foundation+2 种基金supported by NIH/NCI,No.R01CA160688supported by Susan G.Komen Investigator Initiated Research,No.IIR12222224supported by Tohoku Cancer Professional Training Promotion Plan
文摘Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti-inflammatory signaling events with protein and lipid mediators. Recent advances in lipid detection have revealed the importance of lipid mediators in inflammation. Omega three polyunsaturated fatty acids(ω-3 PUFA) are found naturally in fish oil and have been extensively studied in multiple inflammatory diseases with improved outcomes. Resolvins are thought to be the active metabolites of ω-3 PUFA, and are responsible for facilitating the resolving phase of acute inflammation. Clinically, resolvins have been associated with resolution of acute kidney injury and acute lung injury, micro and macro vascular response to injury, and inhibition of microglia-activated inflammation in neurodegenerative disorders. In addition to inflammatory diseases, ω-3 PUFA and resolvins appear to modulate cancer progression. ω-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and favorable phenotype in breast cancer. Resolvins offer promising therapeutic potential as they may modulate inflammation with minimal side-effects, in contrast to currently available anti-inflammatory medications. This review describes the roles of ω-3 PUFA and resolvins in the inflammatory cascade, various inflammatory diseases, and specific cancers. Additionally, it will discuss the clinical therapeutic potential of resolvins astargets in inflammatory diseases and cancers.
基金Supported by United States National Institute of Health(to Kazuaki Takabe),No.R01CA160688Investigator Initiated Research Grant(to Susan G Komen),No.IIR12222224
文摘Malignant peritoneal mesothelioma(PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction(CRS) with hyperthermic intraperitoneal chemotherapy(HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Ac-cordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1(SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.
文摘The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors,which include epidermal growth factor receptor agonists and members of the transforming growth factor β family.Furthermore,the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small,immunomodulatory proteins also play key roles in carcinogenesis and may,therefore,be potential targets for novel therapeutic approaches.In this review,we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.
基金supported by the National Institutes of Health(No.R01EY024072)
文摘The eye is a highly complex,yet readily accessible organ within the human body.As such,the eye is an appealing candidate target for a vast array of drug therapies.Despite advances in ocular drug therapy research,the focus on pediatric ocular drug delivery continues to be highly underrepresented due to the limited number of degenerative ocular diseases with childhood onset.In this review,we explore more deeply the reasons underlying the disparity between ocular therapies available for children and for adults by highlighting diseases that most commonly afflict children（with focus on the anterior eye） and existing prognoses,recent developments in ocular drug delivery systems and nanomedicines for children,and barriers to use for pediatric patients
基金Supported by Virginia Blood Foundation,No.11(To KS and RN)Department of Veterans Affairs(Merit Review Award),No.5I01BX001792(To CEC)+3 种基金National Institutes of Health,No.1U01HD087198(To CEC)National Institutes of Health,No.1S10OD010641(To CEC)National Institutes of Health,No.5R01HL125353(To CEC)VCU Massey Cancer Center with funding from National Institutes of Health,No.P30CA016059
文摘AIM To examine the effect of high doses of vitamin C(VitC) on ex vivo human platelets(PLTs).METHODS Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to:(1) normal saline(control);(2) 0.3 mmol/L VitC(Lo VitC); or(3) 3 mmol/L VitC(Hi VitC, final concentrations) and stored appropriately. The Vit C additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of Vit C used here correspond to plasma Vit C levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography(TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate(ATP) secretion in response to collagen or adenosine diphosphate(ADP); and flow cytometry, for changes in expression of CD-31, CD41 a, CD62 p and CD63. In addition, PLT intracellular Vit C content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time(PT), partial thrombplastin time(PTT), functional fibrinogen] and Lipidomics analysis(UPLC ESI-MS/MS).RESULTS VitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L(Lo VitC) and 15.7 mmol/L(Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period(P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle(P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups(P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups(P > 0.05). Finally, VitC at the higher dose(3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid(P < 0.05).CONCLUSION Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.
基金supported by the National Institutes of Health(R01EY027827,QX)and VCU(VETAR 2021,YO)grants.
文摘Background:Sodium iodate(SI)is a chemical widely applied to induce retina degeneration in animal models.SI treatment caused formation of rosettes/folds in the outer nuclear layer(ONL)of the rat retina,but it was previously unclear whether SI also forms rosettes in mice.In addition,SI induced retina degeneration was never addressed in non-separate sclerochoroid/retina pigment epithelium/retina whole mount.Here we displayed features of retina degeneration including rosette formation in mice and developed a morphological analytic assessment using sclerochoroid/retina pigment epithelium/retina whole mounts.Methods:SI was intraperitoneally injected in Sprague-Dawley(SD)rats and C57BL/6J mice using a single dose(50 mg/kg)or with a dose range(10 to 50 mg/kg)in BALB/C mice.Rat retinas were investigated up to 2-week post-injection by histology and whole mounts,and mouse retinas were investigated up to 3-week post-injection by histology,fluorescent staining of sections and/or sclerochoroid/retina pigment epithelium/retina whole mounts for the morphological evaluations of the SI-induced retina damage.Results:SI-induced retina damage caused photoreceptor(PR)degeneration and rosettes/folds formation,as well as retina pigment epithelium degeneration and inward migration.It displayed mixed nuclei from choroid to PRs,due to layer disorganization,as shown by single horizontal images in the sclerochoroid/retina pigment epithelium/retina whole mounts.Measurement of the PR rosette area induced by SI provided a quantitative,morphological evaluation of retina degeneration.Conclusions:The method of non-separate sclerochoroid/retina pigment epithelium/retina whole staining and mount allows us to observe the integral horizontal view of damage from sclera to PR layers,which cannot be addressed by using sectioned and separate whole mount methods.This method is applicable for morphological evaluation of retina damage,especially in the subretinal layer.
基金Research in Dr.Gewirtz’s laboratory is supported by Grants#CA268819 and CA239706 from the National Cancer InstituteNational Institutes of Health and Grant#W81XWH 19-1-0490 from the Department of Defense Congressionally Directed Breast Cancer Research Program.
文摘PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair pathways.However,as the case with other chemotherapeutic agents,their effectiveness is often compromised by the development of resistance.PARP inhibitors have consistently been reported to promote autophagy,a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.Autophagy can exhibit different functional properties,the most prominent being cytoprotective.In addition,both cytotoxic and non-protective functions forms have also been identified.In this review,we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors,highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.
文摘After surgical resection, patients with glioblastoma require many aspects of care to maximize function and quality of life. Patients face a multitude of hurdles that require the expertise of a variety of specialists. Here we will review the current literature on management of glioblastoma patients after surgical resection.
基金supported,in part,by VCU Quest for Innovation Commercialization Fund and Intellectual Property Foundation Support Fund(YO).
文摘Objective:We review inflammatory drug targets in retinal and choroidal neovascularization(NV)in narrative manner.Background:Vascular remodeling and angiogenesis are processes typically associated with wound-healing mechanisms intended to minimize ischemia and maintain tissue homeostasis.In the eye,however,these actions primarily deteriorate tissue homeostatic recovery,and could even contribute to the progress of severe conditions,e.g.,blindness.Angiogenesis in diabetic retinopathy(DR)and age-related macular degeneration(AMD)is the primary cause of vision loss in working-age and elderly populations.Current treatment of anti-vascular endothelial growth factor(VEGF)agents has limited action efficacy,working in less than 50%patients.Understanding cellular and molecular networks associated in retinal vascular remodeling may provide an insight to develop novel therapeutic strategies.Methods:Here,we highlight ocular cells-endothelial,mural,retinal pigment epithelium(RPE),glial and macrophages,as well as inflammatory molecules-such as the complement system,stromal derived factor-1,chemokine CXC receptor-4,inflammasome,interleukin-18,programed cell death ligand-1,insulin-like growth factor(IGF)and sphigosin-1-phosphate receptor,associated with retinal and choroidal NV,and discuss their recent and future therapeutic approaches.Conclusions:A deeper understanding on pathogenesis,pathobiology including ocular immunobiology of retinal and choroidal NV will pave the way to expand and overleap the current therapeutic approach.
基金supported by DOD-BCRP Level II Breakthrough Award(BC180907 to A.H.T.)National Institutes of Health National Cancer Institute(R01 CA140550 to A.H.T.)+1 种基金the Center for Innovative Technology(CIT)-Commonwealth Research Commercialization Fund(CRCF)(MF14S-009-LS to A.H.T.)Dorothy G.Hoefer Foundation(Breast Cancer Grant to A.H.T.).
文摘Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With the approval of immune checkpoint blockade(ICB)for TNBC,the addition of pembrolizumab to systemic chemotherapy has become standard of care(SOC)in neoadjuvant systemic therapy(NST)for high-risk early-stage TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated(ON),indicating an ineffective response to treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,the loss of SIAH expression(SIAH^(Low/OFF))in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation(OFF),indicating effective therapy and chemo-sensitive tumor cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.
基金funding from NIH-NCI Cancer Center Support Grant P30 CA016059supported by P30 CA16059,5UM1CA186644,CA205607.
文摘The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g.,S63845,MIK665.However,their effectiveness in acute myeloid leukemia(AML)is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system.Here,we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g.,bosutinib(SKI-606)might circumvent this phenomenon.MCL-1 antagonist/SKI-606 co-administration synergistically induced apoptosis in diverse AML cell lines.Consistently,Src or MCL-1 knockdown with shRNA markedly sensitized cells to MCL-1 inhibitors or SKI-606 respectively,while ectopic MCL-1 expression significantly diminished apoptosis.Mechanistically,MCL-1 antagonist exposure induced MCL-1 up-regulation,an event blocked by Src inhibitors or Src shRNA knock-down.MCL-1 down-regulation was associated with diminished transcription and increased K48-linked degradative ubiquitination.Enhanced cell death depended functionally upon down-regulation of phosphorylated STAT3(Tyr705/Ser727)and cytoprotective downstream targets c-Myc and BCL-xL,as well as BAX/BAK activation,and NOXA induction.Importantly,the Src/MCL-1 inhibitor regimen robustly killed primary AML cells,including primitive progenitors,but spared normal hematopoietic CD34+cells and human cardiomyocytes.Notably,the regimen significantly improved survival in an MV4-11 cell xenograft model,while reducing tumor burden in two patient-derived xenograft(PDX)AML models and increased survival in a third.These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination,disrupting STAT-3-mediated transcription,and inducing NOXA-mediated MCL-1 degradation.They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies.
文摘Epistaxis remains one of the most common otolaryngology emergencies. Severe epistaxis may be caused by internal carotid artery （ICA） pseudoaneurysm or cavernous fistula, which is clinically rare but life threatening if it is not diagnosed and treated timely. Most ICA pseudoaneurysms are mainly caused by trauma with few other causes. From January 1998 to December 2005, a total of 8 cases with non-traumatic carotid artery pseudoaneurysm were correctly diagnosed through digital subtraction angiography （DSA） in Ganzhou People＇s Hospital. The patients had suffered from serious nose bleeding repeatedly and had been resistant to routine treatments.
基金supported,in part,by the National Institutes of Health(R01EY024072)(HY)the Fundamental Research Funds for the Central Universities(Grant No.3332019100,2019PT320028)(BL).
文摘Chitosan is a nature-based polymer with low toxicity,excellent biocompatibility and biodegradability.However,the intractable solubility of chitosan in water and most conventional solvents hampers its biomedical applications.Following the dissolution method for dissolving chitosan in plain water developed by us,chitosan was dissolved in ionic liquid followed by overnight freezing at−20℃ and subsequent solvent exchange with plain water at room temperature.In this study,we fabricated a drug-carrying chitosan film via solution casting and air-drying by using the plain water-based chitosan solution.Specifically,brimonidine tartrate(BT),an antiglaucoma drug,was dissolved in the plain-water based solution and used to prepare BT-loaded chitosan film,i.e.,chitosan-BT film.The resulting film is transparent,structurally stable,and mucoadhesive.Micro-sized antiglaucoma BT drug crystals form and are well dispersed in the chitosan film.The chitosan-BT film enables BT to have a high corneal permeability with fast drug release kinetics for potential ocular drug delivery.
基金G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455)DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1)+3 种基金NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649)American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD)METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203)Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).
文摘Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.
基金supported by VA Merit Award 5 I01 BX005730VA Research Career Scientist(IK6BX004477)+1 种基金National Institutes of Health Grant R01 DK104893,R01DK-057543 and 1R01AA030180funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
文摘The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different types of immune cells contribute to the progression of liver diseases,it is crucial to thoroughly characterize hepatic immune cells.Although direct digestion of liver tissue is a relatively simple method for isolating immune cells,it often induces excessive hepatocyte death,which causes a release of intracellular components that leads to the activation of stress responses and injury in the surrounding cells.This injury can lead to excessive death in the hepatic immune cells,making isolation and accurate characterization of the immune profile challenging,especially in diseased livers.The method described here addresses these challenges by utilizing Phosphate buffered saline(PBS)and digestion buffer perfusions to eliminate contaminating blood cells,ensure a pure hepatic immune population,and minimize hepatic immune cell death.Further ex vivo digestion of the liver enables the isolation of the immune cells from the hepatic tissues and the generation of a single-cell suspension that can be stained for spectral flow cytometry.To enhance intracellular cytokine detection and maintain signaling under different physiological and pathological conditions,this protocol uses an in vivo administration of Brefeldin A,a less toxic inhibitor of cytokine secretion.This in vivo administration of Brefeldin A allows for a more accurate representation of the immune cell function and cytokine expression compared to the traditionally used ex vivo Brefeldin A administration.A comprehensive spectral flow cytometry panel,comprising extracellular and intracellular staining,is used for deep immunophenotyping and immune cell effector function profiling.While this protocol is specifically designed for liver digestion of Mdr2 knockout mice(a model for primary sclerosing cholangitis)and flow cytometry staining,it can also be applied to other liver diseases and sensitive tissues.
基金supported in part by The National Cancer Institute(NCI)Grants(Nos.1R01CA230561-01A1,1R01CA240004-01 and 1R01CA244993-01)The National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)Grant(No.2R01DK107451-05).
文摘Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(HBV)and a drug cocktail is effective in bringing down blood hepatitis C virus(HCV)level to zero.With successful application of mRNA vaccine for COVID-19,it is a matter of time before an effective vaccine for HCV is generated.Despite these positive advancements,the incidence of HCC is continuing to rise because of HCC development as a direct consequence of non-alcoholic steatohepatitis(NASH)caused by obesity(1).While viral hepatitis is waning in the Western countries,obesity is now a global problem,requiring impactful treatment regimen for HCC that can provide meaningful survival benefit.
