Background Light-chain amyloidosis(AL)and multiple myeloma(MM)may coexist in some patients and,although they share some cytogenetic abnormalities,they usually present with different clinical phenotypes.Translocation(1...Background Light-chain amyloidosis(AL)and multiple myeloma(MM)may coexist in some patients and,although they share some cytogenetic abnormalities,they usually present with different clinical phenotypes.Translocation(11;14)is the most common cytogenetic abnormality in AL,but the prevalence and clinical implication of t(11;14)in patients with AL,with or without coexistent MM,remains unclear.Methods A total of 119 consecutive newly diagnosed AL patients with available fluorescence in situ hybridization(FISH)data were retrospectively included and classified as primary AL alone(pAL-alone)or AL with coexistent MM(AL-MM).Clinical characteristics,FISH profiles,and hematologic and survival outcomes were analyzed.Results There were 53 patients in the pAL-alone group and 66 in the AL-MM group.The prevalence of t(11;14)was significantly higher in the pAL-alone group than the AL-MM group(49.1%vs.26.2%,P=0.012).A significantly higher proportion of the pAL-alone group achieved hematologic response compared with the AL-MM group(60.4%vs.39.4%,P=0.023).Patients with AL-MM experienced significantly shorter hematologic event-free survival(hemEFS)than those with pAL-alone(median,4.8 months vs.44.3 months,P<0.001),as well as significantly shorter overall survival(OS;median,15.2 months vs.not reached,P<0.001).When stratified by the presence or absence of coexistent MM and t(11;14),AL-MM patients with t(11;14)had the worst hemEFS(median,3.8 months,P<0.001)and OS(median,5.4 months,P=0.001).Conclusions Patients with pAL-alone had a higher prevalence of t(11;14)than those with AL-MM.The AL-MM group had poorer outcomes,despite the availability of proteasome inhibitor treatment,with AL-MM patients with t(11;14)showing the worst outcomes.Better diagnostic and treatment approaches are warranted for this population.展开更多
Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex(MHC)-I ...Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex(MHC)-I molecules.Apart from this primary function in antigen presentation,immunoproteasome is also responsible for the degradation of proteins,both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor progression.The altered expression of immunoproteasome is frequently observed in cancers;however,its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor development.This review focuses on the dichotomous role of immunoproteasome in different cancer types,as well as summarizes the current progression in immunoproteasome activators and inhibitors.Specifically targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.展开更多
Since the middle of 1990 s autologous stem cell trans-plantation has been the cornerstone for the treatment of young patients with multiple myeloma(MM). In the last decade the introduction of novel agents such as immu...Since the middle of 1990 s autologous stem cell trans-plantation has been the cornerstone for the treatment of young patients with multiple myeloma(MM). In the last decade the introduction of novel agents such as immunomodulatory drugs(IMi Ds) and proteasome inhibitors(PI), has dramatically changed the therapeutic scenario of this yet incurable disease. Due to the impressive results achieved with IMi Ds and PI both in terms of response rates and in terms of progression free and overall survival, and to the toxicity linked to high dose therapy and autologous stem cell transplantation(ASCT), a burning question nowadays is whether all young patients should be offered autotransplanta-tion up front or if this should be reserved for the time of relapse. This article provides a review of the data available regarding ASCT in MM and of the current opinion of the scientific community regarding its optimal timing.展开更多
Background Forkhead box M1(FoxM1),a member of forkhead family,plays a key role in carcinogenesis,progression,invasion,metastasis and drug resistance.Based on the similarities between cancer and pulmonary arterial hype...Background Forkhead box M1(FoxM1),a member of forkhead family,plays a key role in carcinogenesis,progression,invasion,metastasis and drug resistance.Based on the similarities between cancer and pulmonary arterial hypertension,studies on the roles and mechanisms of FoxM1 in pulmonary arterial hypertension have been increasing.This article aims to review recent advances in the mechanisms of signal transduction associated with FoxM1 in pulmonary arterial hypertension.Data sources Articles were retrieved from PubMed and MEDLINE published after 1990,including-but not limited to FoxM1 and pulmonary arterial hypertension.Results FoxM 1 is overexpressed in pulmonary artery smooth muscle cells in both pulmonary arterial hypertension patients and animal models,and promotes pulmonary artery smooth muscle cell proliferation and inhibits cell apoptosis via regulating cell cycle progression.Multiple signaling molecules and pathways,including hypoxia-inducible factors,transforming growth factor-β/Smad,SET domain-containing 3/vascular endothelial growth factor,survivin,cell cycle regulatory genes and DNA damage response network,are reported to cross talk with FoxM1 in pulmonary arterial hypertension.Proteasome inhibitors are effective in the prevention and treatment of pulmonary arterial hypertension by inhibiting the expression and transcriptional activity of FoxM1.Conclusions FoxM1 has a crucial role in the pathogenesis of pulmonary arterial hypertension and may represent a novel therapeutic target.But more details of interaction between FoxM1 and other signaling pathways need to be clarified in the future.展开更多
Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Curre...Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.展开更多
Multiple myeloma(MM)is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains.Although incurable,a deeper understanding of MM pathobiology has fueled major t...Multiple myeloma(MM)is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains.Although incurable,a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades,significantly improving patient outcomes.Proteasome inhibitors,immunomodulatory drugs,and monoclonal antibodies are among the most effective anti-MM drugs,targeting not only the cancerous cells,but also the bone marrow microenvironment.However,de novo resistance has been reported,and acquired resistance is inevitable for most patients over time,leading to relapsed/refractory disease and poor outcomes.Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis,offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes.This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.展开更多
文摘Background Light-chain amyloidosis(AL)and multiple myeloma(MM)may coexist in some patients and,although they share some cytogenetic abnormalities,they usually present with different clinical phenotypes.Translocation(11;14)is the most common cytogenetic abnormality in AL,but the prevalence and clinical implication of t(11;14)in patients with AL,with or without coexistent MM,remains unclear.Methods A total of 119 consecutive newly diagnosed AL patients with available fluorescence in situ hybridization(FISH)data were retrospectively included and classified as primary AL alone(pAL-alone)or AL with coexistent MM(AL-MM).Clinical characteristics,FISH profiles,and hematologic and survival outcomes were analyzed.Results There were 53 patients in the pAL-alone group and 66 in the AL-MM group.The prevalence of t(11;14)was significantly higher in the pAL-alone group than the AL-MM group(49.1%vs.26.2%,P=0.012).A significantly higher proportion of the pAL-alone group achieved hematologic response compared with the AL-MM group(60.4%vs.39.4%,P=0.023).Patients with AL-MM experienced significantly shorter hematologic event-free survival(hemEFS)than those with pAL-alone(median,4.8 months vs.44.3 months,P<0.001),as well as significantly shorter overall survival(OS;median,15.2 months vs.not reached,P<0.001).When stratified by the presence or absence of coexistent MM and t(11;14),AL-MM patients with t(11;14)had the worst hemEFS(median,3.8 months,P<0.001)and OS(median,5.4 months,P=0.001).Conclusions Patients with pAL-alone had a higher prevalence of t(11;14)than those with AL-MM.The AL-MM group had poorer outcomes,despite the availability of proteasome inhibitor treatment,with AL-MM patients with t(11;14)showing the worst outcomes.Better diagnostic and treatment approaches are warranted for this population.
基金grants from National Natural Science Foundation of China(No.81930102 to Bo Yang)Zhejiang Provincial Natural Science Foundation(No.LR22H310002 to Ji Cao,China)Zhejiang University K.P.Chao's High Technology Development Foundation(China)。
文摘Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex(MHC)-I molecules.Apart from this primary function in antigen presentation,immunoproteasome is also responsible for the degradation of proteins,both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor progression.The altered expression of immunoproteasome is frequently observed in cancers;however,its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor development.This review focuses on the dichotomous role of immunoproteasome in different cancer types,as well as summarizes the current progression in immunoproteasome activators and inhibitors.Specifically targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.
文摘Since the middle of 1990 s autologous stem cell trans-plantation has been the cornerstone for the treatment of young patients with multiple myeloma(MM). In the last decade the introduction of novel agents such as immunomodulatory drugs(IMi Ds) and proteasome inhibitors(PI), has dramatically changed the therapeutic scenario of this yet incurable disease. Due to the impressive results achieved with IMi Ds and PI both in terms of response rates and in terms of progression free and overall survival, and to the toxicity linked to high dose therapy and autologous stem cell transplantation(ASCT), a burning question nowadays is whether all young patients should be offered autotransplanta-tion up front or if this should be reserved for the time of relapse. This article provides a review of the data available regarding ASCT in MM and of the current opinion of the scientific community regarding its optimal timing.
文摘Background Forkhead box M1(FoxM1),a member of forkhead family,plays a key role in carcinogenesis,progression,invasion,metastasis and drug resistance.Based on the similarities between cancer and pulmonary arterial hypertension,studies on the roles and mechanisms of FoxM1 in pulmonary arterial hypertension have been increasing.This article aims to review recent advances in the mechanisms of signal transduction associated with FoxM1 in pulmonary arterial hypertension.Data sources Articles were retrieved from PubMed and MEDLINE published after 1990,including-but not limited to FoxM1 and pulmonary arterial hypertension.Results FoxM 1 is overexpressed in pulmonary artery smooth muscle cells in both pulmonary arterial hypertension patients and animal models,and promotes pulmonary artery smooth muscle cell proliferation and inhibits cell apoptosis via regulating cell cycle progression.Multiple signaling molecules and pathways,including hypoxia-inducible factors,transforming growth factor-β/Smad,SET domain-containing 3/vascular endothelial growth factor,survivin,cell cycle regulatory genes and DNA damage response network,are reported to cross talk with FoxM1 in pulmonary arterial hypertension.Proteasome inhibitors are effective in the prevention and treatment of pulmonary arterial hypertension by inhibiting the expression and transcriptional activity of FoxM1.Conclusions FoxM1 has a crucial role in the pathogenesis of pulmonary arterial hypertension and may represent a novel therapeutic target.But more details of interaction between FoxM1 and other signaling pathways need to be clarified in the future.
基金supported by NIH R01(5R01AI139141 to JJD),University Hospitals Cleveland Medical Center/Seidman Cancer Center,and the Case Comprehensive Cancer Center.
文摘Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.
文摘Multiple myeloma(MM)is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains.Although incurable,a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades,significantly improving patient outcomes.Proteasome inhibitors,immunomodulatory drugs,and monoclonal antibodies are among the most effective anti-MM drugs,targeting not only the cancerous cells,but also the bone marrow microenvironment.However,de novo resistance has been reported,and acquired resistance is inevitable for most patients over time,leading to relapsed/refractory disease and poor outcomes.Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis,offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes.This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.
