查看更多>>摘要：Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients.Before the development of organ-specific metastasis,the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells.This review delves into the intricate landscape of the pre-metastatic niche,focusing on the roles of tumor-derived secreted factors,extracellular vesicles,and circulating tumor cells in shaping the metastatic niche.The discussion encompasses cellular elements such as macrophages,neutrophils,bone marrow-derived suppressive cells,and T/B cells,in addition to molecular factors like secreted substances from tumors and extracellular vesicles,within the framework of pre-metastatic niche formation.Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition,immunosuppression,extracellular matrix remodeling,metabolic reprogramming,vascular permeability and angiogenesis are provided.Furthermore,the landscape of pre-metastatic niche in different metastatic organs like lymph nodes,lungs,liver,brain,and bones is elucidated.Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche,as well as interventions targeting signaling pathways such as the TGF-β,VEGF,and MET pathways,are highlighted.This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
查看更多>>摘要：Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors.Yet,prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking.A phase Ⅱ clinical trial was initiated to evaluate the efficacy of toripalimab,a humanized lgG4K monoclonal antibody to human PD-1,in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high.A total of 15 patients were enrolled,14 of whom were assessed for treatment efficacy.There was a 21.4％overall response rate,with a disease control rate of 57.1％.The median overall survival and median progression-free survival were 17.9(95％Cl 13.5-not reach)months and 2.5(95％CI 1.4-not reach)months,respectively.For patients with exonuclease domain mutations,the objective response rate was 66.7％(2/3),with a disease control rate of 66.7％(2/3).For those with non-exonuclease domain mutations,the rates were 9.1％(1/11)and 54.5％(6/11),respectively.Notably,patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0％(3/4).This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy,urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.
查看更多>>摘要：Primary central nervous system lymphoma(PCNSL)is a rare and frequently fatal lymphoma subtype.The programmed death-1(PD-1)pathway has emerged as a potential therapeutic target,but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined.In this phase 2 trial(ChiCTR1 900027433)with a safety run-in,we included patients aged 18-70 with newly diagnosed PCNSL.Participants underwent six 21-day cycles of a SMTR regimen,which includes sintilimab(200 mg,Day 0),rituximab(375 mg/m2,Day 0),methotrexate(3.0 g/m2,Day 1 or 1.0 g/m2 for patients aged ≥65 years),and temozolomide(150mg/m2/d,Days 1-5).Among 27 evaluable patients,the overall response rate(ORR)was 96.3％(95％confidence interval:81-99.9％),with 25 complete responses.At a median follow-up of 24.4 months,the medians for duration of response,progression-free survival(PFS),and overall survival were not reached.The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase(17.9％)and aspartate aminotransferase(14.3％).Additionally,baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS,achieving areas under the curve of 0.88 and 0.84,respectively,at 2 years.Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group,while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group.These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL,warranting further investigation.
查看更多>>摘要：Cardiac biological pacing(BP)is one of the future directions for bradyarrhythmias intervention.Currently,cardiac pacemaker cells(PCs)used for cardiac BP are mainly derived from pluripotent stem cells(PSCs).However,the production of high-quality cardiac PCs from PSCs remains a challenge.Here,we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs.First,two PC markers,Shox2 and Hcn4,were selected to establish Shox2:EGFP;Hcn4:mCherry mouse PSC reporter line.Then,by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation,we designed the FSK method that increased the yield of SHOX2+;HCN4+cells with typical PC characteristics,which was 12 and 42 folds higher than that of the embryoid body(EB)and the monolayer M10 methods respectively.In addition,the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing(scRNA-seq),which resembled in vivo PCs development,and ZFP503 was verified as a key regulator of cardiac PCs differentiation.These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology,help with the understanding of PCs(patho)physiology,and benefit drug discovery for PC-related diseases as well.
查看更多>>摘要：The combination of ASC22,an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide,a HIV latency reversal agent,may serve as a strategy for antiretroviral therapy-free virological control for HIV.People living with HIV,having achieved virological suppression,were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy.Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+T cells(NCT05129189).15 participants completed the study.At week 8,CA HIV RNA levels showed a significant increase from baseline,and the values returned to baseline after discontinuing ASC22 and chidamide.The total HIV DNA was only transiently increased at week 4(P=0.014).In contrast,integrated HIV DNA did not significantly differ from baseline.Increases in the proportions of effector memory CD4+and CD8+T cells(TEM)were observed from baseline to week 24(P=0.034 and P=0.002,respectively).The combination treatment did not succeed in enhancing the function of HIV Gag/Pol-specific CD8+T cells.Nevertheless,at week 8,a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group(P=0.042 and P=0.034,respectively).Nine adverse events were solicited,all of which were graded 1 and resolved spontaneously.The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs.Further investigations are warranted in the context of analytic treatment interruption.
查看更多>>摘要：Treatment options for patients with relapsed extensive-stage small cell lung cancer(ES-SCLC)remain scarce.This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients.This is a phase Ⅱ clinical trial(ChiCTR2100049390)conducting at Shandong Cancer Hospital.Patients with ES-SCLC and received at least one prior systemic treatment were enrolled.The trial design involved a combination therapy(sintilimab,anlotinib,and nab-paclitaxel)administered over six 21-day cycles,followed by maintenance sintilimab therapy.The primary endpoint was objective response rate(ORR).Circulating tumor DNA sequencing was employed for exploratory analysis.From July 2021 to April 2023,25 eligible patients were enrolled.The confirmed ORR was 60％(95％CI:38.7-78.9％)and the DCR was 76％(95％CI:54.9-90.6％).The mPFS was 6.0 months(95％CI:5.4-9.7),and the 6-month PFS rate was 49.2％.The mOS was 13.4 months(95％CI:11.8-NR),with a 12-month survival rate of 62.2％.Treatment-related adverse events(TRAEs)of any grade occurred in 80％of patients,with the most common being fatigue(40％)and nausea(32％).TRAEs of Grade 3 or higher were reported in 12％of patients.ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance.This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC,with genomic insights providing potential biomarkers for treatment response.
查看更多>>摘要：The various mutations in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pose a substantial challenge in mitigating the viral infectivity.The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations.In this study,potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells.Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4(Alpha-actinin-4)mRNA leads to a decrease in mRNA stability and translation efficiency,ultimately inhibiting ACTN4 expression.In addition,ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex,thereby impeding viral replication.Furthermore,two ACTN4 agonists,YS-49 and demethyl-coclaurine,were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice.Collectively,this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection,offering novel insights into the intricate interplay between the virus and host cells,and reveals two potential candidates for future anti-SARS-CoV-2 drug development.
查看更多>>摘要：Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1 α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1 943,p-MYH9(Ser1 943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1 α in lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1 943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1 943)/USP22/HIF-1 α axis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1 943),USP22,and HIF-1 α might be valuable as novel biomarkers and targets.
查看更多>>摘要：Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma(PDAC)who have undergone prior gemcitabine-based therapies.This randomized,double-blind,parallel-controlled,multicenter phase 3 study(NCT05074589)assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil(5-FU)and leucovorin(LV)in this patient population.Patients with unresectable,locally advanced,or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1∶1 to receive either HR070803(60mg/m2 anhydrous irinotecan hydrochloride,equal to 56.5 mg/m2 free base)or placebo,both in combination with 5-FU(2000 mg/m2)and LV(200 mg/m2),all given intravenously every two weeks.The primary endpoint of the study was overall survival(OS).A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV(HR070803 group,n=149)or placebo plus 5-FU/LV(placebo group,n=149).Median OS was significantly improved in the HR070803 group compared to the placebo group(7.4 months[95％CI 6.1-8.4]versus 5.0 months[95％CI 4.3-6.0);HR 0.63[95％CI 0.48-0.84];two-sided p=0.0019).The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase(19.0％versus 11.6％in placebo group)and decreased neutrophil count(12.9％versus 0 in placebo group).No treatment-related deaths occurred in the HR070803 group,while the placebo group reported one treatment-related death(abdominal infection).HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting,representing a potential option in this patient population.
查看更多>>摘要：Liver metastasis remains the primary cause of mortality in patients with colon cancer.Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets.To explore clonal evolution and genetic heterogeneity within the metastasis,we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor,liver metastasis,and lymphatic metastasis from a stage Ⅳ colon cancer patient.The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor.Notably,the liver metastasis was derived directly from the primary tumor,bypassing the lymph nodes.Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor.This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell(CTC)of a polyclonal origin,rather than from a single cell from the primary tumor.Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis.Additionally,a mutation in the TRPS1(Transcriptional repressor GATA binding 1)gene,TRPS1 R544Q,was enriched in the single cells from the liver metastasis.The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis.Further TRPS1 mutations were detected in additional colon cancer cases,correlating with advanced-stage disease and inferior prognosis.These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.
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