Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which acc...Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.展开更多
The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consist...The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8（CDK8）modules （CKM） （Fig. 1A） （Yin and Wang, 2014; Allen and Taatjes, 2015）.展开更多
Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause o...Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.展开更多
Ferroptosis,a new form of non-apoptotic,regulated cell death characterized by iron dependency and lipid peroxidation,is involved in many pathological conditions such as neurodegenerative diseases,heart ischemia/reperf...Ferroptosis,a new form of non-apoptotic,regulated cell death characterized by iron dependency and lipid peroxidation,is involved in many pathological conditions such as neurodegenerative diseases,heart ischemia/reperfusion injury,acute renal failure,and cancer.While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death,glutathione peroxidase 4(GPX4)resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation,thereby suppressing ferroptosis.Indeed,RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice.Similarly,erastin and other system Xc−inhibitors can deplete intracellular glutathione required for GPX4 function,leading to lipid peroxidation and ferroptosis.As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens,the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy.This review will outline the molecular basis of ferroptosis,but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis.The potentials of these ferroptosis-inducing agents,which include system Xc−inhibitors,GPX4 inhibitors,and iron-based nanoparticles,in cancer therapy will be subsequently discussed.展开更多
We devoted this short interview piece with Dr Shou-Ching Tang at Augusta University to feature some promising results from a clinical phase II trial on a novel brain-penetrating peptide-paclitaxel-conjugate,ANG1005,in...We devoted this short interview piece with Dr Shou-Ching Tang at Augusta University to feature some promising results from a clinical phase II trial on a novel brain-penetrating peptide-paclitaxel-conjugate,ANG1005,in treating brain metastatic breast cancer.These results were presented by Dr.Tang at the recent annual meeting of the European Society for Medical Oncology(ESMO 2016 Congress).This development heralds an important step forward towards the development of effective chemotherapeutic agents,which can cross the bloodbrain-barrier and effectively treat and prevent the brain metastatic cancers.展开更多
The human epidermal growth factor receptor 2(HER2)is overexpressed in 25%e30%of breast cancer patients.Anti-HER2 therapies have changed the aggressive course of HER2t breast cancer.In spite of the therapeutic benefits...The human epidermal growth factor receptor 2(HER2)is overexpressed in 25%e30%of breast cancer patients.Anti-HER2 therapies have changed the aggressive course of HER2t breast cancer.In spite of the therapeutic benefits,their cardiotoxicities are major concerns,especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2t breast cancer.Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumabinduced severe cardiotoxicity while requiring additional anti-HER2 therapy.She received neoadjuvant anti-HER2 treatment for stage III breast caner.Due to severe reduction of cardiac ejection fraction(EF),she only received five doses of adjuvant transtuzumab.Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF.We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion.More importantly,the patient had one year of disease control without deterioration in her ejection fraction.We discussed the management of recurrent HER2t breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.展开更多
The majority of cancer-related deaths are caused by tumor recurrence,metastasis and therapeutic resistance.During the late stages of tumor progression,multiple factors are involved,including the downregulation and/or ...The majority of cancer-related deaths are caused by tumor recurrence,metastasis and therapeutic resistance.During the late stages of tumor progression,multiple factors are involved,including the downregulation and/or loss of function of metastasis suppressors.Epithelial protein lost in neoplasm(EPLIN),an actin-binding protein,was initially identified as a putative tumor suppressor that is frequently downregulated in epithelial tumors.Recent evidence indicates that EPLIN may negatively regulate epithelia-to-mesenchymal transition(EMT),a crucial process by which cancer cells acquire invasive capabilities and therapeutic resistance.Importantly,downregulation of EPLIN is associated with clinical metastasis in a variety of solid tumors,suggesting that EPLIN could be a suppressor of metastasis.In this review,I will discuss the regulation and function of EPLIN in human cancer cells and explore the clinical significance of EPLIN in metastatic disease.展开更多
Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements(MLN-eo FGFR1)disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder wi...Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements(MLN-eo FGFR1)disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder with or without eosinophilia and frequently presents with mixed lineage T-or B-lymphomas.The myeloproliferative disease frequently progresses to AML and lymphoid neoplasms can develop into acute lymphomas.No matter the cell type involved,or clinical presentation,chromosome translocations involving the FGFR1 kinase and various partner genes,which leads to constitutive activation of downstream oncogenic signaling cascades.These patients are not responsive to treatment regimens developed for other acute leukemias and survival is poor.Recent development of specific FGFR1 inhibitors has suggested an alternative therapeutic approach but resistance is likely to evolve over time.Mouse models of this disease syndrome have been developed and are being used for preclinical evaluation of FGFR1 inhibitors.Cell lines from these models have now been developed and have been used to investigate the mechanisms of resistance that might be expected in clinical cases.So far,a V561M mutation in the kinases domain and deletion of PTEN have been recognized as leading to resistance and both operate through the PI3K/AKT signaling axis.One of the important consequences is the suppression of PUMA,a potent enforcer of apoptosis,which operates through BCL2.Targeting BCL2 in the resistant cells leads to suppression of leukemia development in mouse models,which potentially provides an opportunity to treat patients that become resistant to FGFR1 inhibitors.In addition,elucidation of molecular mechanisms underlying FGFR1-driven leukemias and lymphomas also provides new targets for combined treatment as another option to bypass the FGFR1 inhibitor resistance and improve patient outcome.展开更多
Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previou...Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.展开更多
In a recent article published in Cell,Molgora et al.1 reported that a subset of tumor-infiltrating macrophages with TREM2 expression creates an immunosuppressive microenvironment that promotes tumor growth while suppr...In a recent article published in Cell,Molgora et al.1 reported that a subset of tumor-infiltrating macrophages with TREM2 expression creates an immunosuppressive microenvironment that promotes tumor growth while suppressing anti-tumor immune responses.Targeting these TREM2+macrophages via genetic ablation of the gene or specific antibodies against the protein reduces tumor growth in animal models;however,it further attenuates tumor growth when combined with immune checkpoint inhibitors(ICI)by promoting the expression of immunostimulatory molecules(Fig.1).展开更多
Cancer is a major disease threatening human health. The overall prognosis for hepatocellular carcinoma (HCC) patients is poor, with a dismal 5-year survival rate of approximately 5%-30%. The dysfunction of immune syst...Cancer is a major disease threatening human health. The overall prognosis for hepatocellular carcinoma (HCC) patients is poor, with a dismal 5-year survival rate of approximately 5%-30%. The dysfunction of immune system plays a pivotal role in the development of cancer, which has attracted attention of several researchers. Recent advances in immunotherapy have led to various inspired achievements and refreshed our concepts about cancer treatments. In this article, several types of immune-based therapies for treating HCC are reviewed. Their underlying mechanisms, preclinical and clinical study results, potential prospects, and deficiencies are discussed, and an outline for future research directions is proposed.展开更多
基金Supported by In part by Georgia Cancer Coalition Distinguished Cancer Scholar award,NIH-NCRR-RCMI,No.G-12-RR003034,No.U54 RR02613,and No.5P20RR11104NIHMD research endowment,No.2S21MD000101,and No.U54CA118638ING foundation grant to Rao VN
文摘Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.
基金partially supported by the National Institutes of Health(R21CA185833 and R01GM113242 to H.S.)the National Natural Science Foundation of China(Nos.81660041 and 81260021 to L.D.)the Education Department of Jiangxi Province(GJJ150219to X.T.)
文摘The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8（CDK8）modules （CKM） （Fig. 1A） （Yin and Wang, 2014; Allen and Taatjes, 2015）.
基金NIH/NCI grants(R01CA168912 and R01CA235159)Augusta University intramural grant。
文摘Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.
基金This work was supported by the National Institutes of Health grant(No.R01CA240966)the US Department of Defense award(No.W81XWH1910587 to CY).
文摘Ferroptosis,a new form of non-apoptotic,regulated cell death characterized by iron dependency and lipid peroxidation,is involved in many pathological conditions such as neurodegenerative diseases,heart ischemia/reperfusion injury,acute renal failure,and cancer.While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death,glutathione peroxidase 4(GPX4)resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation,thereby suppressing ferroptosis.Indeed,RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice.Similarly,erastin and other system Xc−inhibitors can deplete intracellular glutathione required for GPX4 function,leading to lipid peroxidation and ferroptosis.As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens,the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy.This review will outline the molecular basis of ferroptosis,but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis.The potentials of these ferroptosis-inducing agents,which include system Xc−inhibitors,GPX4 inhibitors,and iron-based nanoparticles,in cancer therapy will be subsequently discussed.
文摘We devoted this short interview piece with Dr Shou-Ching Tang at Augusta University to feature some promising results from a clinical phase II trial on a novel brain-penetrating peptide-paclitaxel-conjugate,ANG1005,in treating brain metastatic breast cancer.These results were presented by Dr.Tang at the recent annual meeting of the European Society for Medical Oncology(ESMO 2016 Congress).This development heralds an important step forward towards the development of effective chemotherapeutic agents,which can cross the bloodbrain-barrier and effectively treat and prevent the brain metastatic cancers.
基金This work was supported by grants from the NIH(K12HD085817)the Susan G.Komen Foundation(KG111460)to NJM.
文摘The human epidermal growth factor receptor 2(HER2)is overexpressed in 25%e30%of breast cancer patients.Anti-HER2 therapies have changed the aggressive course of HER2t breast cancer.In spite of the therapeutic benefits,their cardiotoxicities are major concerns,especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2t breast cancer.Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumabinduced severe cardiotoxicity while requiring additional anti-HER2 therapy.She received neoadjuvant anti-HER2 treatment for stage III breast caner.Due to severe reduction of cardiac ejection fraction(EF),she only received five doses of adjuvant transtuzumab.Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF.We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion.More importantly,the patient had one year of disease control without deterioration in her ejection fraction.We discussed the management of recurrent HER2t breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.
基金This work was supported by National Cancer Institute grants 1R21CA164612-01A1,1R41CA186498-01A1 and 1R41CA206725-01A1Georgia Research Alliance Ventures grant+1 种基金University of Georgia/Augusta University Cancer Research Initiative AwardGeorgia Cancer Center Startup Fund(D.Wu).
文摘The majority of cancer-related deaths are caused by tumor recurrence,metastasis and therapeutic resistance.During the late stages of tumor progression,multiple factors are involved,including the downregulation and/or loss of function of metastasis suppressors.Epithelial protein lost in neoplasm(EPLIN),an actin-binding protein,was initially identified as a putative tumor suppressor that is frequently downregulated in epithelial tumors.Recent evidence indicates that EPLIN may negatively regulate epithelia-to-mesenchymal transition(EMT),a crucial process by which cancer cells acquire invasive capabilities and therapeutic resistance.Importantly,downregulation of EPLIN is associated with clinical metastasis in a variety of solid tumors,suggesting that EPLIN could be a suppressor of metastasis.In this review,I will discuss the regulation and function of EPLIN in human cancer cells and explore the clinical significance of EPLIN in metastatic disease.
基金This work was supported by a grant from the National Institutes of Health,CA076167。
文摘Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements(MLN-eo FGFR1)disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder with or without eosinophilia and frequently presents with mixed lineage T-or B-lymphomas.The myeloproliferative disease frequently progresses to AML and lymphoid neoplasms can develop into acute lymphomas.No matter the cell type involved,or clinical presentation,chromosome translocations involving the FGFR1 kinase and various partner genes,which leads to constitutive activation of downstream oncogenic signaling cascades.These patients are not responsive to treatment regimens developed for other acute leukemias and survival is poor.Recent development of specific FGFR1 inhibitors has suggested an alternative therapeutic approach but resistance is likely to evolve over time.Mouse models of this disease syndrome have been developed and are being used for preclinical evaluation of FGFR1 inhibitors.Cell lines from these models have now been developed and have been used to investigate the mechanisms of resistance that might be expected in clinical cases.So far,a V561M mutation in the kinases domain and deletion of PTEN have been recognized as leading to resistance and both operate through the PI3K/AKT signaling axis.One of the important consequences is the suppression of PUMA,a potent enforcer of apoptosis,which operates through BCL2.Targeting BCL2 in the resistant cells leads to suppression of leukemia development in mouse models,which potentially provides an opportunity to treat patients that become resistant to FGFR1 inhibitors.In addition,elucidation of molecular mechanisms underlying FGFR1-driven leukemias and lymphomas also provides new targets for combined treatment as another option to bypass the FGFR1 inhibitor resistance and improve patient outcome.
基金This work was supported by grants from the National Institutes of Health,National Institute of Allergy and Infectious Diseases P01 AI056299,R37 AI034495(BRB),and R01 AI091627(IM)and the National Heart,Lung,and Blood Institute R01 HL56067(BRB)This work was supported in part using the resources of the Center for Innovative Technology at Vanderbilt University.GT was supported by a Canadian Institutes of Health Research(CIHR)fellowship.
文摘Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.
基金Funding provided to HK by Georgia Cancer Center startup fund,American Cancer Society Intitutional pilot research fund,Bridge Fund by Augusta University Research Inc.,Evans County CARES fund and Forbes Institute fund.
文摘In a recent article published in Cell,Molgora et al.1 reported that a subset of tumor-infiltrating macrophages with TREM2 expression creates an immunosuppressive microenvironment that promotes tumor growth while suppressing anti-tumor immune responses.Targeting these TREM2+macrophages via genetic ablation of the gene or specific antibodies against the protein reduces tumor growth in animal models;however,it further attenuates tumor growth when combined with immune checkpoint inhibitors(ICI)by promoting the expression of immunostimulatory molecules(Fig.1).
文摘Cancer is a major disease threatening human health. The overall prognosis for hepatocellular carcinoma (HCC) patients is poor, with a dismal 5-year survival rate of approximately 5%-30%. The dysfunction of immune system plays a pivotal role in the development of cancer, which has attracted attention of several researchers. Recent advances in immunotherapy have led to various inspired achievements and refreshed our concepts about cancer treatments. In this article, several types of immune-based therapies for treating HCC are reviewed. Their underlying mechanisms, preclinical and clinical study results, potential prospects, and deficiencies are discussed, and an outline for future research directions is proposed.
