Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflamma...Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood.Ruxolitinib(RUX),a selective inhibitor of JAK1/2,was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung.However,its role in disrupting inflammation post-SCI has not been confirmed.In this study,microglia were treated with RUX for 24 hours and then activated with interferon-γfor 6 hours.The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited,and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,interleukin-6,and cell proliferation marker Ki67 were reduced.In further in vivo experiments,a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days,and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway.Moreover,microglia treated with RUX centripetally migrated toward injured foci,remaining limited and compacted within the glial scar,which resulted in axon preservation and less demyelination.Moreover,the protein expression levels of tumor necrosis factor-α,interleukin-1β,and interleukin-6 were reduced.The neuromotor function of SCI mice also recovered.These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway,thereby reducing secondary injury after SCI and producing neuroprotective effects.展开更多
The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arth...The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.展开更多
BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ru...BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD.METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation.Ruxolitinib was administered5-10 mg/d depending on disease severity,patient status,and the use of antifungal drugs.Overall response rate,time to best response,malignancy relapse rate,infection rate,and treatment-related adverse events were assessed.RESULTS The analysis included 10 patients with SR-aGVHD (gradeⅢ/Ⅳ,n=9) and 28patients with SR-cGVHD (moderate/severe,n=24).For the SR-aGVHD and SRcGVHD groups,respectively:Median number of previous GVHD therapies was 2(range:1-3) and 2 (1-4);median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo;median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo;and overall response rate was 100%(complete response:80%) and 82.1%(complete response:10.7%) with a response observed in all GVHD-affected organs.The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0%and 10.7%,respectively.Reactivation rates for cytomegalovirus,Epstein-Barr virus,and varicella-zoster virus,respectively,were 30.0%,10.0%,and 0%for the SR-aGVHD group and 0%,14.3%,and 7.1%for the SR-cGVHD group.CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.展开更多
Objective The aim of the study was to evaluate the clinical efficacy of decitabine(DEC)combined with ruxolitinib(RUX)in the treatment of chronic myelomonocytic leukemia(CMML).Methods The clinical characteristics of 12...Objective The aim of the study was to evaluate the clinical efficacy of decitabine(DEC)combined with ruxolitinib(RUX)in the treatment of chronic myelomonocytic leukemia(CMML).Methods The clinical characteristics of 12 patients with CMML were analyzed retrospectively and subsequent target sequencing was performed to investigate the efficacy of the combined treatment with DEC and RUX and the molecular signatures therein.Results Among the 12 cases,clinical improvement was observed in all patients(100%),spleen reduction was observed in six patients(67%),and hematologic improvement was observed in four patients(33%).In the CMML-1 group,the overall response was 50%(3/6),one case achieved complete response,one achieved bone marrow remission,and one achieved hematological improvement.In the CMML-2 group,the overall response was 17%(1/6),one case achieved complete response,four showed disease progression(PD),and one exhibited no response.As expected,ASXL1 mutation was predictive for the outcome of CMML(hazard ratio of 2.97,95%confidence interval of 1.21–7.06;P=0.02).Conclusion The use of DEC combined with RUX in the treatment of CMML effectively improved the clinical response and quality of life,especially for CMML-1 patients.Ongoing clinical trials will further evaluate the safety and efficacy of this novel therapeutic approach.展开更多
Classical Philadelphia-negative myeloproliferative neoplasms(MPNs),i.e.,polycythemia vera,essential thrombocythemia,and primary/secondary myelofibrosis,are clonal disorders of the hematopoietic stem cell in which an u...Classical Philadelphia-negative myeloproliferative neoplasms(MPNs),i.e.,polycythemia vera,essential thrombocythemia,and primary/secondary myelofibrosis,are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs.MPNs are characterized by mutations in driver genes,the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies.Thus,JAK inhibition has emerged as a potential therapeutic strategy in MPNs,with ruxolitinib being the first JAK inhibitor developed,approved,and prescribed in the management of these blood cancers.However,the use of ruxolitinib has been associated with a potential risk of infection,including opportunistic infections and reactivation of hepatitis B.Here,we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.展开更多
Polycythemia vera manifests as a myeloproliferative neoplasm associated with diverse symptoms, including aquagenic pruritis. This systematic review addresses the pressing need to enhance the understanding of the dise...Polycythemia vera manifests as a myeloproliferative neoplasm associated with diverse symptoms, including aquagenic pruritis. This systematic review addresses the pressing need to enhance the understanding of the disease’s symptomatology and optimize treatment strategies for improved patient outcomes. The rarity and low prevalence of polycythemia vera underscore the importance of this investigation, as existing standard of care involves a multifaceted approach and significant healthcare costs. Despite advancement in therapeutic options, persistent symptoms and resistance to first-line treatments pose challenges. Ruxolitinib has emerged as a promising intervention, demonstrating clinically significant improvement for patients. This systematic review appraises three randomized controlled trials, shedding light on the efficacy of ruxolitinib and its potential to ameliorate pruritis symptoms in symptomatic patients.展开更多
Objective To investigate the combined therapeutic role of the AKT inhibitor MK2206 and Ruxolitinib in treating Myeloproliferative Neoplasms(MPN)driven by a calreticulin(CALR)gene mutation.
基金supported by the National Natural Science Foundation of China,Nos.81871773(to XJC),81672152(to XJC),81802149(to LY)Primary Research and Development Plan of Jiangsu Province of China,No.BE2018132(to XJC)Scientific Research Project of Health Commission of Jiangsu Province of China,No.LGY2020068(to HJL).
文摘Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood.Ruxolitinib(RUX),a selective inhibitor of JAK1/2,was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung.However,its role in disrupting inflammation post-SCI has not been confirmed.In this study,microglia were treated with RUX for 24 hours and then activated with interferon-γfor 6 hours.The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited,and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,interleukin-6,and cell proliferation marker Ki67 were reduced.In further in vivo experiments,a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days,and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway.Moreover,microglia treated with RUX centripetally migrated toward injured foci,remaining limited and compacted within the glial scar,which resulted in axon preservation and less demyelination.Moreover,the protein expression levels of tumor necrosis factor-α,interleukin-1β,and interleukin-6 were reduced.The neuromotor function of SCI mice also recovered.These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway,thereby reducing secondary injury after SCI and producing neuroprotective effects.
基金supported by the National Natural Science Foundation of China,No.82272484(to XC).
文摘The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.
文摘BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD.METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation.Ruxolitinib was administered5-10 mg/d depending on disease severity,patient status,and the use of antifungal drugs.Overall response rate,time to best response,malignancy relapse rate,infection rate,and treatment-related adverse events were assessed.RESULTS The analysis included 10 patients with SR-aGVHD (gradeⅢ/Ⅳ,n=9) and 28patients with SR-cGVHD (moderate/severe,n=24).For the SR-aGVHD and SRcGVHD groups,respectively:Median number of previous GVHD therapies was 2(range:1-3) and 2 (1-4);median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo;median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo;and overall response rate was 100%(complete response:80%) and 82.1%(complete response:10.7%) with a response observed in all GVHD-affected organs.The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0%and 10.7%,respectively.Reactivation rates for cytomegalovirus,Epstein-Barr virus,and varicella-zoster virus,respectively,were 30.0%,10.0%,and 0%for the SR-aGVHD group and 0%,14.3%,and 7.1%for the SR-cGVHD group.CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.
基金Supported by a grant from the Fund of Ruijin Hospital North affiliated to Shanghai Jiao Tong University School of Medicine(No:2018ZY03)
文摘Objective The aim of the study was to evaluate the clinical efficacy of decitabine(DEC)combined with ruxolitinib(RUX)in the treatment of chronic myelomonocytic leukemia(CMML).Methods The clinical characteristics of 12 patients with CMML were analyzed retrospectively and subsequent target sequencing was performed to investigate the efficacy of the combined treatment with DEC and RUX and the molecular signatures therein.Results Among the 12 cases,clinical improvement was observed in all patients(100%),spleen reduction was observed in six patients(67%),and hematologic improvement was observed in four patients(33%).In the CMML-1 group,the overall response was 50%(3/6),one case achieved complete response,one achieved bone marrow remission,and one achieved hematological improvement.In the CMML-2 group,the overall response was 17%(1/6),one case achieved complete response,four showed disease progression(PD),and one exhibited no response.As expected,ASXL1 mutation was predictive for the outcome of CMML(hazard ratio of 2.97,95%confidence interval of 1.21–7.06;P=0.02).Conclusion The use of DEC combined with RUX in the treatment of CMML effectively improved the clinical response and quality of life,especially for CMML-1 patients.Ongoing clinical trials will further evaluate the safety and efficacy of this novel therapeutic approach.
文摘Classical Philadelphia-negative myeloproliferative neoplasms(MPNs),i.e.,polycythemia vera,essential thrombocythemia,and primary/secondary myelofibrosis,are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs.MPNs are characterized by mutations in driver genes,the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies.Thus,JAK inhibition has emerged as a potential therapeutic strategy in MPNs,with ruxolitinib being the first JAK inhibitor developed,approved,and prescribed in the management of these blood cancers.However,the use of ruxolitinib has been associated with a potential risk of infection,including opportunistic infections and reactivation of hepatitis B.Here,we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.
文摘Polycythemia vera manifests as a myeloproliferative neoplasm associated with diverse symptoms, including aquagenic pruritis. This systematic review addresses the pressing need to enhance the understanding of the disease’s symptomatology and optimize treatment strategies for improved patient outcomes. The rarity and low prevalence of polycythemia vera underscore the importance of this investigation, as existing standard of care involves a multifaceted approach and significant healthcare costs. Despite advancement in therapeutic options, persistent symptoms and resistance to first-line treatments pose challenges. Ruxolitinib has emerged as a promising intervention, demonstrating clinically significant improvement for patients. This systematic review appraises three randomized controlled trials, shedding light on the efficacy of ruxolitinib and its potential to ameliorate pruritis symptoms in symptomatic patients.
文摘Objective To investigate the combined therapeutic role of the AKT inhibitor MK2206 and Ruxolitinib in treating Myeloproliferative Neoplasms(MPN)driven by a calreticulin(CALR)gene mutation.
