Global Cancer Statistics 2022 reported the prevalence and high mortality rate of lung cancer.Notably,non-small cell lung cancer(NSCLC)accounts for the majority of the histologic types1.Precision therapy for lung cance...Global Cancer Statistics 2022 reported the prevalence and high mortality rate of lung cancer.Notably,non-small cell lung cancer(NSCLC)accounts for the majority of the histologic types1.Precision therapy for lung cancer has progressed rapidly and immune checkpoint inhibitors(ICIs)have become a leading research topic.Indeed,ICI therapy has been shown to improve the prognosis of lung cancer patients.展开更多
Background and objective Anlotinib is a newly developed small molecule multiple receptor tyrosine kinase(RTK) inhibitor that was approved for the treatment of patients with lung cancer in China. We aim to report 3 cas...Background and objective Anlotinib is a newly developed small molecule multiple receptor tyrosine kinase(RTK) inhibitor that was approved for the treatment of patients with lung cancer in China. We aim to report 3 cases of rare complication of anlotinib-bronchial fistula(BF) during the treatment of lung cancer patients and summarize the possible causes.Methods We collected three patients who developed BF due to anlotinib treatment, and conducted a search of Medline and Pub Med for medical literature published between 2018 and 2020 using the following search terms: "anlotinib," "lung cancer," and "fistula."Results Our literature search produced two case reports(three patients) which, in addition to our three patients. We collated the patients’ clinical characteristics including demographic information, cancer type, imaging features, treatment received, risk factors for anlotinib related BF, and treatment-related outcomes. The six patients shared some common characteristics: advanced age, male, concurrent infection symptoms, diabetes mellitus(DM), advanced squamous cell and small cell lung cancers, centrally located tumors, tumor measuring ≥5 cm in longest diameter, and newly formed tumor cavitation after multi-line treatment especially after receiving radiotherapy. Fistula types included broncho-pericardial fistula, broncho-pleural fistula, and esophagotracheobronchial fistula. Six patients all died within 6 months.Conclusion Although anlotinib is relatively safe, it is still necessary to pay attention to the occurrence of BF, a rare treatment side effect that threatens the quality of life and overall survival of patients. Anlotinib, therefore, requires selective use and close observation of high-risk patients.展开更多
BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untr...BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untreated non-small cell lung cancer to date.CASE SUMMARY A 44-year-old nonsmoking woman presented to the hospital due to fever,palpitation,nausea,and cough for 1 mo and was diagnosed with stage cT3N3M0(IIIc)adenocarcinoma of the lung.Auxiliary examinations revealed elevated cytokine[tumor necrosis factor-α,interleukin(IL)-1β,and IL-6]and inflammatory factor levels,which decreased after treatment with corticosteroids and immunoglobulin and when tumor growth was controlled following chemotherapy,radiotherapy,and antiangiogenesis therapy.However,tumor recurrence was observed.After administration of nivolumab as third-line treatment,the patient’s condition was transiently controlled;however,CRS-like symptoms suddenly emerged,which led to a resurgence of cytokines and inflammatory factors and rapid death.CONCLUSION CRS can develop in treatment-naïve lung cancer patients.Patients with tumorrelated CRS may be at risk of CRS recurrence,aggravation,and onset of immune checkpoint inhibitor-related adverse events.展开更多
Cancer stem cells(CSCs),a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation,lead to tumorigenesis,metastasis,and maintain tumor heterogeneity.Cancer continues to be a ...Cancer stem cells(CSCs),a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation,lead to tumorigenesis,metastasis,and maintain tumor heterogeneity.Cancer continues to be a significant global disease burden.In the past,surgery,radiotherapy,and chemotherapy were the main cancer treatments.The technology of cancer treatments continues to develop and advance,and the emergence of targeted therapy,and immunotherapy provides more options for patients to a certain extent.However,the limitations of efficacy and treatment resistance are still inevitable.Our review begins with a brief introduction of the historical discoveries,original hypotheses,and pathways that regulate CSCs,such as WNT/β-Catenin,hedgehog,Notch,NFkB,JAK/STAT,TGF-β,PI3K/AKT,PPAR pathway,and their crosstalk.We focus on the role of CSCs in various therapeutic outcomes and resistance,including how the treatments affect the content of CSCs and the alteration of related molecules,CSCs-mediated therapeutic resistance,and the clinical value of targeting CSCs in patients with refractory,progressed or advanced tumors.In summary,CSCs affect therapeutic efficacy,and the treatment method of targeting CSCs is stll difficult to determine.Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.展开更多
Tocilizumab has been reported to attenuate the“cytokine storm”in COVID-19 patients.We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit ...Tocilizumab has been reported to attenuate the“cytokine storm”in COVID-19 patients.We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment.We conducted a randomized,controlled,open-label multicenter trial among COVID-19 patients.The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone.The cure rate,changes of oxygen saturation and interference,and inflammation biomarkers were observed.Thirty-three patients were randomized to the tocilizumab group,and 32 patients to the control group.The cure rate in the tocilizumab group was higher than that in the control group,but the difference was not statistically significant(94.12%vs.87.10%,rate difference 95%CI−7.19%–21.23%,P=0.4133).The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12(P=0.0359).In moderate disease patients with bilateral pulmonary lesions,the hypoxia ameliorated earlier after tocilizumab treatment,and less patients(1/12,8.33%)needed an increase of inhaled oxygen concentration compared with the controls(4/6,66.67%;rate difference 95%CI−99.17%to−17.50%,P=0.0217).No severe adverse events occurred.More mild temporary adverse events were recorded in tocilizumab recipients(20/34,58.82%)than the controls(4/31,12.90%).Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative.For patients with bilateral pulmonary lesions and elevated IL-6 levels,tocilizumab could be recommended to improve outcome.展开更多
Most of the mast cells(MCs)in connective tissues,such as skin,are long-lived embryonic-derived immune cells that play important roles in host defense and in various immunological diseases,including allergies.Their emb...Most of the mast cells(MCs)in connective tissues,such as skin,are long-lived embryonic-derived immune cells that play important roles in host defense and in various immunological diseases,including allergies.Their embryonic origin and ontogeny remain to be fully studied since several overlapping waves of embryonic hematopoiesis have been reported to give rise to these cells.Here,combining single-cell RNA sequencing and new genetic fate mapping models,we identified a Cpa3-expressing population sequentially appearing in the yolk sac,fetal liver,and peripheral tissues which gives rise to dermal MCs during embryonic days 11.5 to 14.5.Using in vitro differentiation and in vivo transplantation assays,we identified a Ter119-F4/80-CD45+CD117+CD16/32+CD135-CD115-Ly6C-CD34^(lo)population as potential fetal liver MC precursors(MCPs).Fate mapping with Cpa3^(CreERT2)and Zbtb16^(CreERT2)models,as well as the granulocyte-monocyte progenitors(GMPs)fate mapping Ms4a3^(Creand) ElaneCremodels,demonstrated that MCs arise from Cpa3^(+)precursors rather than Ms4a3^(+)or Elane+GMPs.A corresponding population with a similar developmental trajectory was also identified in human early yolk sac and fetal liver,suggesting a conserved MC developmental program across species.These findings reveal a distinct developmental path of skin MCs in embryos,permitting future functional studies in immunity and development.展开更多
Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although spec...Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to treat.Consequently,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development.This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors.A total of 648 proteins exhibiting significant differential expression were identified.Gene Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups.Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate(IP3)kinase B(ITPKB)in the recurrence group,correlating with poor survival in glioma patients.In TMZ-resistant cells,the depletion of ITPKB led to an increase in reactive oxygen species(ROS)related to NADPH oxidase(NOX)activity and restored cell sensitivity to TMz.Mechanistically,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination.This,in turn,elevated ITPKB stability and impaired ROS production.Furthermore,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model.These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target forTMZ-resistant GBM.展开更多
Epstein-Barr virus(EBV)and human papillomavirus(HPV)infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma,respectively.However,clinical analyses demonstrate that EBV or HPV is associated wi...Epstein-Barr virus(EBV)and human papillomavirus(HPV)infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma,respectively.However,clinical analyses demonstrate that EBV or HPV is associated with improved response of patients,although underlying mechanism remains unclear.Here,we reported that the oncoproteins of DNA viruses,such as LMP1 of EBV and E7 of HPV,inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif.Inhibition of PERK led to increased level of reactive oxygen species(ROS)that promoted tumor and enhanced the efficacy of chemotherapy in vivo.Consistently,disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models.Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.展开更多
基金the Hunan Lung Cancer Clinical Medical Research Center(Grant No.2023SK4024 to LW)the Hunan Science and Technology Innovation Program(Grant No.2021SK51121 to LW)the Hunan Cancer Hospital Climb plan(Grant No.ZX2020005-5 to LW)。
文摘Global Cancer Statistics 2022 reported the prevalence and high mortality rate of lung cancer.Notably,non-small cell lung cancer(NSCLC)accounts for the majority of the histologic types1.Precision therapy for lung cancer has progressed rapidly and immune checkpoint inhibitors(ICIs)have become a leading research topic.Indeed,ICI therapy has been shown to improve the prognosis of lung cancer patients.
文摘Background and objective Anlotinib is a newly developed small molecule multiple receptor tyrosine kinase(RTK) inhibitor that was approved for the treatment of patients with lung cancer in China. We aim to report 3 cases of rare complication of anlotinib-bronchial fistula(BF) during the treatment of lung cancer patients and summarize the possible causes.Methods We collected three patients who developed BF due to anlotinib treatment, and conducted a search of Medline and Pub Med for medical literature published between 2018 and 2020 using the following search terms: "anlotinib," "lung cancer," and "fistula."Results Our literature search produced two case reports(three patients) which, in addition to our three patients. We collated the patients’ clinical characteristics including demographic information, cancer type, imaging features, treatment received, risk factors for anlotinib related BF, and treatment-related outcomes. The six patients shared some common characteristics: advanced age, male, concurrent infection symptoms, diabetes mellitus(DM), advanced squamous cell and small cell lung cancers, centrally located tumors, tumor measuring ≥5 cm in longest diameter, and newly formed tumor cavitation after multi-line treatment especially after receiving radiotherapy. Fistula types included broncho-pericardial fistula, broncho-pleural fistula, and esophagotracheobronchial fistula. Six patients all died within 6 months.Conclusion Although anlotinib is relatively safe, it is still necessary to pay attention to the occurrence of BF, a rare treatment side effect that threatens the quality of life and overall survival of patients. Anlotinib, therefore, requires selective use and close observation of high-risk patients.
基金Supported by National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases(Lung Cancer)National Key R&D Program of China,No.2016YFC1303300Xiangya Clinical Big Data Project of Central South University(Clinical big data project of lung cancer).
文摘BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untreated non-small cell lung cancer to date.CASE SUMMARY A 44-year-old nonsmoking woman presented to the hospital due to fever,palpitation,nausea,and cough for 1 mo and was diagnosed with stage cT3N3M0(IIIc)adenocarcinoma of the lung.Auxiliary examinations revealed elevated cytokine[tumor necrosis factor-α,interleukin(IL)-1β,and IL-6]and inflammatory factor levels,which decreased after treatment with corticosteroids and immunoglobulin and when tumor growth was controlled following chemotherapy,radiotherapy,and antiangiogenesis therapy.However,tumor recurrence was observed.After administration of nivolumab as third-line treatment,the patient’s condition was transiently controlled;however,CRS-like symptoms suddenly emerged,which led to a resurgence of cytokines and inflammatory factors and rapid death.CONCLUSION CRS can develop in treatment-naïve lung cancer patients.Patients with tumorrelated CRS may be at risk of CRS recurrence,aggravation,and onset of immune checkpoint inhibitor-related adverse events.
基金This work was supported by Advanced Lung Cancer Targeted Therapy Research Foundation of China(CTONG-YC20210303)Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province(CXPJJH121005-01)+2 种基金National Multidisciplinary Cooperative Diagnosis and Treatment Capacity(lung cancer z027002)Health Research Project of Hunan Provincial Health Commission(W20242005)Postdoctoral Fellowship Programof CPSF(GZC20233187).
文摘Cancer stem cells(CSCs),a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation,lead to tumorigenesis,metastasis,and maintain tumor heterogeneity.Cancer continues to be a significant global disease burden.In the past,surgery,radiotherapy,and chemotherapy were the main cancer treatments.The technology of cancer treatments continues to develop and advance,and the emergence of targeted therapy,and immunotherapy provides more options for patients to a certain extent.However,the limitations of efficacy and treatment resistance are still inevitable.Our review begins with a brief introduction of the historical discoveries,original hypotheses,and pathways that regulate CSCs,such as WNT/β-Catenin,hedgehog,Notch,NFkB,JAK/STAT,TGF-β,PI3K/AKT,PPAR pathway,and their crosstalk.We focus on the role of CSCs in various therapeutic outcomes and resistance,including how the treatments affect the content of CSCs and the alteration of related molecules,CSCs-mediated therapeutic resistance,and the clinical value of targeting CSCs in patients with refractory,progressed or advanced tumors.In summary,CSCs affect therapeutic efficacy,and the treatment method of targeting CSCs is stll difficult to determine.Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
基金This work was supported by the Department of Science and Technology of Anhui Province and Health Commission of Anhui Province(No.202004a07020001)the China National Center for Biotechnology Development(No.2020YFC0843800).
文摘Tocilizumab has been reported to attenuate the“cytokine storm”in COVID-19 patients.We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment.We conducted a randomized,controlled,open-label multicenter trial among COVID-19 patients.The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone.The cure rate,changes of oxygen saturation and interference,and inflammation biomarkers were observed.Thirty-three patients were randomized to the tocilizumab group,and 32 patients to the control group.The cure rate in the tocilizumab group was higher than that in the control group,but the difference was not statistically significant(94.12%vs.87.10%,rate difference 95%CI−7.19%–21.23%,P=0.4133).The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12(P=0.0359).In moderate disease patients with bilateral pulmonary lesions,the hypoxia ameliorated earlier after tocilizumab treatment,and less patients(1/12,8.33%)needed an increase of inhaled oxygen concentration compared with the controls(4/6,66.67%;rate difference 95%CI−99.17%to−17.50%,P=0.0217).No severe adverse events occurred.More mild temporary adverse events were recorded in tocilizumab recipients(20/34,58.82%)than the controls(4/31,12.90%).Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative.For patients with bilateral pulmonary lesions and elevated IL-6 levels,tocilizumab could be recommended to improve outcome.
基金supported by the National Key Research and Development Program of China(2021YFA1301400)the National Natural Science Foundation of China(NSFC)(31930035,32070880,32270916,31900630,32170895)+4 种基金Research Fund for Foreign Senior Scholars(3231101303)Shanghai Science and Technology Commission(22JC1402600)Shanghai Jiao Tong University Scientific and Technological Innovation Funds(21X010200648)Shanghai Jiao Tong University 2030 Initiative(WH510363001–16)Shanghai Rising-Star Program(20QA1408500)。
文摘Most of the mast cells(MCs)in connective tissues,such as skin,are long-lived embryonic-derived immune cells that play important roles in host defense and in various immunological diseases,including allergies.Their embryonic origin and ontogeny remain to be fully studied since several overlapping waves of embryonic hematopoiesis have been reported to give rise to these cells.Here,combining single-cell RNA sequencing and new genetic fate mapping models,we identified a Cpa3-expressing population sequentially appearing in the yolk sac,fetal liver,and peripheral tissues which gives rise to dermal MCs during embryonic days 11.5 to 14.5.Using in vitro differentiation and in vivo transplantation assays,we identified a Ter119-F4/80-CD45+CD117+CD16/32+CD135-CD115-Ly6C-CD34^(lo)population as potential fetal liver MC precursors(MCPs).Fate mapping with Cpa3^(CreERT2)and Zbtb16^(CreERT2)models,as well as the granulocyte-monocyte progenitors(GMPs)fate mapping Ms4a3^(Creand) ElaneCremodels,demonstrated that MCs arise from Cpa3^(+)precursors rather than Ms4a3^(+)or Elane+GMPs.A corresponding population with a similar developmental trajectory was also identified in human early yolk sac and fetal liver,suggesting a conserved MC developmental program across species.These findings reveal a distinct developmental path of skin MCs in embryos,permitting future functional studies in immunity and development.
基金supported by grants from the National Natural Science Foundation of China (82272659,82030087)the Science and Technology Innovation Program of Hunan Province (2022RC1210,2021RC3029)the Hunan Provincial Natural Science Foundation Project (2022JJ30073,2021JC0002).
文摘Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to treat.Consequently,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development.This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors.A total of 648 proteins exhibiting significant differential expression were identified.Gene Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups.Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate(IP3)kinase B(ITPKB)in the recurrence group,correlating with poor survival in glioma patients.In TMZ-resistant cells,the depletion of ITPKB led to an increase in reactive oxygen species(ROS)related to NADPH oxidase(NOX)activity and restored cell sensitivity to TMz.Mechanistically,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination.This,in turn,elevated ITPKB stability and impaired ROS production.Furthermore,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model.These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target forTMZ-resistant GBM.
基金This work was funded by the following grants and associations:National Natural Science Foundations of China(81530084 and 81702721)Hunan province natural science funds for Yong scholars(2018JJ3816).
文摘Epstein-Barr virus(EBV)and human papillomavirus(HPV)infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma,respectively.However,clinical analyses demonstrate that EBV or HPV is associated with improved response of patients,although underlying mechanism remains unclear.Here,we reported that the oncoproteins of DNA viruses,such as LMP1 of EBV and E7 of HPV,inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif.Inhibition of PERK led to increased level of reactive oxygen species(ROS)that promoted tumor and enhanced the efficacy of chemotherapy in vivo.Consistently,disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models.Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.
