BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadl...BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.展开更多
Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has...Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In th...The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In this study,we theoretically investigated the photon blockade phenomenon in a double-transmon system operating in an ultrastrong coupling regime.We considered the effect of the counter-rotating wave terms in the interaction Hamiltonian and derived the master equation in the eigenpresentation.We found that photon blockade occurred in only one of the eigenmodes,and the counter-rotating wave terms enhanced the blockade by reducing the minimum value of the second-order correlation function.This study will be beneficial for the design of single-photon devices in circuit QED systems,especially in the ultrastrong coupling regime.展开更多
We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons whe...We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons when the atoms are prepared in the same initial state.Such simplification is valid even when the atoms are not prepared in the inphase condition,since any partial in-phase initial state will evolve into the ground state through a relaxation process.Thus,we get a reduced group of differential equations by introducing the Dicke states,and the under-zero Lyapunov exponents verify its stability.We also work out the collective unconventional photon blockade(UCPB)and get two kinds of giant nonreciprocal UCPBs(NUCPBs)in the weak-driving approximation.Results show that we can employ N noninteracting bosonic atoms to generate a collective UCPB instead of a monoatomic UCPB as the UCPB conditions do not vary with the number of atoms.Furthermore,the forward giant NUCPB only occurring for N larger than a certain number as well as the backward giant NUCPB are controllable by the cavity asymmetry and by the number of atoms.Our findings suggest a prospective approach to the generation of quantum nonreciprocity by N identical atoms.展开更多
BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blocka...BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.展开更多
BACKGROUND The interplay between inflammation,immune dysregulation,and the onset of neurological disorders,including epilepsy,has become increasingly recognized.Interleukin(IL)-6,a pro-inflammatory cytokine,is suspect...BACKGROUND The interplay between inflammation,immune dysregulation,and the onset of neurological disorders,including epilepsy,has become increasingly recognized.Interleukin(IL)-6,a pro-inflammatory cytokine,is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients.The role of IL-6 receptor(IL6R)blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes.neuropsychiatric conditions due to neuroinflammation.METHODS Mendelian randomization(MR)analysis employing single nucleotide poly-morphisms(SNPs)in the vicinity of the IL6R gene(total individuals=408225)was used to evaluate the putative causal relationship between IL6R blockade and epilepsy(total cases/controls=12891/312803),focal epilepsy(cases/controls=7526/399290),and generalized epilepsy(cases/controls=1413/399287).SNP weights were determined by their effect on C-reactive protein(CRP)levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects.To address potential outlier and pleiotropic influences,sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions.RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk[inverse variance weighting:Odds ratio(OR):0.827;95%confidence interval(CI):0.685-1.000;P=0.05].Subtype analysis showed variability,with no significant effect observed in generalized,focal,or specific childhood and juvenile epilepsy forms.Beyond the primary inflammatory marker CRP,the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy,hinting at possible links to neuroinflammation,psychiatric symptoms,and associated mental disorders.CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence,likely mediated via complex neuroinflammatory pathways.These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy.The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.展开更多
In a two-frequency cavity driving and atom driving atom-cavity system,we find the photon blockade effect.In a truncated eigenstates space,we calculate the zero-delay second-order correlation function of the cavity mod...In a two-frequency cavity driving and atom driving atom-cavity system,we find the photon blockade effect.In a truncated eigenstates space,we calculate the zero-delay second-order correlation function of the cavity mode analytically and obtain an optimal condition for the photon blockade.By including three transition pathways,we find that higher excitations of the cavity mode can be further suppressed and the zero-delay second-order correlation function can be reduced additionally.Based on the master equation,we simulate the system evolution and find that the analytical solutions match well with the numerical results.Our scheme is robust with small fluctuations of parameters and may be used as a new type of single photon source.展开更多
In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608...In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.展开更多
The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of t...The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of the contribution of the pore and access region, and the latter becomes dominant when the nanopore thickness gradually decreases to atomic layer thickness. Based on the existing model of nanopore resistance, a simplified model which describes the relative current blockade during the X-DNA translocation through the nanopores is deduced to quantitatively present the relationship between nanopore thickness and relative current blockade. Results show that the relative current blockade is effectively increased by reducing the nanopore diameter but it decreases with the decreasing nanopore thickness. A two-stage schematic is proposed to increase the relative current blockade by setting a much smaller resistance region. Experimental results show a 21. 9% increase in the relative current blockade with the proposed schematic.展开更多
Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR ...Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies)have clinical activity in patients with metastatic CRC.The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency.Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade.Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS,BRAF,PIK3CA and PTEN could be intrinsically resistant to EGFR blockade.Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients.While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC,further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.展开更多
The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the a...The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.展开更多
BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate...BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate the application effect of deep neuromuscular blockade(NMB)combined with reduced pneumoperitoneum pressure in LRG for gastric cancer(GC)in elderly patients and its influence on inflammation.METHODS Totally 103 elderly patients with GC treated in our hospital between January 2020 and January 2022 were retrospectively analyzed.Among them,45 patients treated with surgery based on deep NMB and conventional pneumoperitoneum pressure were assigned to the control group,while the rest of the 58 patients who underwent surgery based on deep NMB and reduced pneumoperitoneum pressure were assigned to the observation group.The two groups were compared in the changes of the Leiden-surgical rating scale score,serum tumor necrosis fact-α(TNF-α)and interleukin 6(IL-6)before and after therapy.The visual analogue scale(VAS)was adopted for evaluating the shoulder pain of patients at 8 h,24 h and 48 h after the operation.The driving pressure of the two groups at different time points was also compared.Additionally,the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room,TOF%=90%time and post-anesthetic recovery room(PACU)stay time were all recorded,and adverse PACU-associated respiratory events were also recorded.The postoperative hospitalization time and postoperative expenses of the two groups were counted and compared.RESULTS No significant difference was found between the two groups at the time of skin incision,60 minutes since the operation and abdominal closure after surgery(P>0.05).The observation group exhibited significantly lower VAS scores than the control group at 24 and 48h after surgery(P<0.05).Additionally,the observation group had significantly lower driving pressure than the control group at 5 min and 60 min after the establishment of pneumoperitoneum(P<0.05).Additionally,the two groups were similar in terms of the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room and TOF%=90%time(P>0.05),and the observation group showed significantly lower TNF-αand IL-6 Levels than the control group at 24 h after therapy(P<0.05).Moreover,the incidence of adverse events was not significantly different between the two groups(P>0.05),and the observation group experienced significantly less hospitalization time and postoperative expenses than the control group(P<0.05).CONCLUSION Deep NMB combined with reduced pneumoperitoneum pressure can decrease the VAS score of shoulder pain and inflammatory reaction,without hindering the surgical vision and increasing adverse PACU-associated respiratory events,and can thus shorten the hospitalization time and treatment cost for patient.展开更多
During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is...During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.展开更多
BACKGROUND Rocuronium,a nondepolarizing muscle relaxant,is usually administered during general anesthesia to facilitate endotracheal intubation and keep patients immobile during the surgery.Sugammadex,the selective re...BACKGROUND Rocuronium,a nondepolarizing muscle relaxant,is usually administered during general anesthesia to facilitate endotracheal intubation and keep patients immobile during the surgery.Sugammadex,the selective reversal agent of rocuronium,fully reverses the neuromuscular blockade(NMB)at the end of surgery.Most reports show that sugammadex rapidly achieves a ratio of train-offour(TOF),a quantitative method of neuromuscular monitoring,of 0.9 which ensures adequate recovery for safe extubation.However,very rare patients with neuromuscular diseases may respond poorly to sugammadex.CASE SUMMARY A 69-year-old female presented with abdominal fullness and nausea,and was diagnosed with gastroparesis.She underwent gastric peroral endoscopic myotomy under general anesthesia with rocuronium(0.7 mg/kg).At the end of surgery,sugammadex 3.6 mg/kg was administered when TOF showed 2 counts.Afterward,the TOF ratio recovered to 0.65 in 30 min.She was awake but could not fully open her eyelids.The tidal volume during spontaneous breathing was low.After additional doses of sugammadex(up to 7.3 mg/kg)in the following 3 h,the TOF ratio was 0.9,and the endotracheal tube was smoothly removed.After excluding possible mechanisms underlying the prolonged recovery course,we speculated our patient may have had an undiagnosed neuromuscular disease,hinted by her involuntary movement of the tongue and mouth.Furthermore,her poor renal function and history of delayed recovery from general anesthesia may be related to the long duration of rocuronium.CONCLUSION In our case,both prolonged rocuronium-induced NMB and poor response to sugammadex were noted.To optimize the dose of rocuronium,perioperative TOF combined with other neuromuscular monitoring is suggested.展开更多
Programmed cell death protein 1(PD-1)/programmed cell death ligand 1(PD-L1)blockade is an important therapeutic strategy for melanoma,despite its low clinical response.It is important to identify genes and pathways th...Programmed cell death protein 1(PD-1)/programmed cell death ligand 1(PD-L1)blockade is an important therapeutic strategy for melanoma,despite its low clinical response.It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients.We analyzed clinical dataset GSE96619,which contains clinical information from five melanoma patients before and after anti-PD-1 therapy(five pairs of data).We identified 704 DEGs using these five pairs of data,and then the number of DEGs was narrowed down to 286 in patients who responded to treatment.Next,we performed KEGG pathway enrichment and constructed a DEG-associated protein-protein interaction network.Smooth muscle actin 2(ACTA2)and tyrosine kinase growth factor receptor(KDR)were identified as the hub genes,which were significantly downregulated in the tumor tissue of the two patients who re-sponded to treatment.To confirm our analysis,we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xeno-graft model.This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD-1/PD-L1 blockade therapy.展开更多
Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-...Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy.In this study,sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood,blocked neutrophil accumulation in tumors,and attenuated the inhibitory effect of infiltrating neutrophils on T cells.Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer.Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils.Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8^(+) T lymphocytes in the tumor.The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.展开更多
During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune c...During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.展开更多
文摘BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.
基金supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金supported by the National Natural Science Foundation of China(Nos.U23A20591 and 52273158)the Science and Technology Development Program of Jilin Province(Nos.20240101002JJ and 20210504001GH).
文摘Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
基金supported by the National Science Foundation of China(Grant No.12105026)Climbing Plan of Changchun University(Grant No.ZKP202010)Educational Commission of Jilin Province of China(Grant No.JJKH20230663KJ)。
文摘The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In this study,we theoretically investigated the photon blockade phenomenon in a double-transmon system operating in an ultrastrong coupling regime.We considered the effect of the counter-rotating wave terms in the interaction Hamiltonian and derived the master equation in the eigenpresentation.We found that photon blockade occurred in only one of the eigenmodes,and the counter-rotating wave terms enhanced the blockade by reducing the minimum value of the second-order correlation function.This study will be beneficial for the design of single-photon devices in circuit QED systems,especially in the ultrastrong coupling regime.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12164022 and 12174288)Natural Science Foundation of Jiangxi Province of China(Grant No.20232BAB201044)+1 种基金Scientific Research Foundation of the Education Department of Jiangxi Province of China(Grant No.GJJ211039)China Postdoctoral Science Foundation(Grant No.2023M732028)。
文摘We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons when the atoms are prepared in the same initial state.Such simplification is valid even when the atoms are not prepared in the inphase condition,since any partial in-phase initial state will evolve into the ground state through a relaxation process.Thus,we get a reduced group of differential equations by introducing the Dicke states,and the under-zero Lyapunov exponents verify its stability.We also work out the collective unconventional photon blockade(UCPB)and get two kinds of giant nonreciprocal UCPBs(NUCPBs)in the weak-driving approximation.Results show that we can employ N noninteracting bosonic atoms to generate a collective UCPB instead of a monoatomic UCPB as the UCPB conditions do not vary with the number of atoms.Furthermore,the forward giant NUCPB only occurring for N larger than a certain number as well as the backward giant NUCPB are controllable by the cavity asymmetry and by the number of atoms.Our findings suggest a prospective approach to the generation of quantum nonreciprocity by N identical atoms.
基金Supported by Shaoxing Health Science and Technology Program,No.2022SY016,No.2022KY010.
文摘BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.
文摘BACKGROUND The interplay between inflammation,immune dysregulation,and the onset of neurological disorders,including epilepsy,has become increasingly recognized.Interleukin(IL)-6,a pro-inflammatory cytokine,is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients.The role of IL-6 receptor(IL6R)blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes.neuropsychiatric conditions due to neuroinflammation.METHODS Mendelian randomization(MR)analysis employing single nucleotide poly-morphisms(SNPs)in the vicinity of the IL6R gene(total individuals=408225)was used to evaluate the putative causal relationship between IL6R blockade and epilepsy(total cases/controls=12891/312803),focal epilepsy(cases/controls=7526/399290),and generalized epilepsy(cases/controls=1413/399287).SNP weights were determined by their effect on C-reactive protein(CRP)levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects.To address potential outlier and pleiotropic influences,sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions.RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk[inverse variance weighting:Odds ratio(OR):0.827;95%confidence interval(CI):0.685-1.000;P=0.05].Subtype analysis showed variability,with no significant effect observed in generalized,focal,or specific childhood and juvenile epilepsy forms.Beyond the primary inflammatory marker CRP,the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy,hinting at possible links to neuroinflammation,psychiatric symptoms,and associated mental disorders.CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence,likely mediated via complex neuroinflammatory pathways.These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy.The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.
基金Project supported by the National Natural Science Foundation of China(Grant No.61601196).
文摘In a two-frequency cavity driving and atom driving atom-cavity system,we find the photon blockade effect.In a truncated eigenstates space,we calculate the zero-delay second-order correlation function of the cavity mode analytically and obtain an optimal condition for the photon blockade.By including three transition pathways,we find that higher excitations of the cavity mode can be further suppressed and the zero-delay second-order correlation function can be reduced additionally.Based on the master equation,we simulate the system evolution and find that the analytical solutions match well with the numerical results.Our scheme is robust with small fluctuations of parameters and may be used as a new type of single photon source.
基金Acknowledgment We thank Professor Qiao Zhou from the Department of Pathology, West China Hospital, Dr Jing Gong from the Laboratory of Pathology, the State Key Laboratory of Biotherapy, and many other clinicians from the Department of Urology, West China hospital for their kind assistance. This work was supported by the National Natural Science Foundation of China （No. NSFC30700977, No. NSFC30800637 and No. NSFC30871383）.
文摘In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.
基金The Natural Science Foundation of Jiangsu Province(No.BK20160935)the Natural Science Foundation of Higher Education Institutions of Jiangsu Province(No.16KJB460015)
文摘The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of the contribution of the pore and access region, and the latter becomes dominant when the nanopore thickness gradually decreases to atomic layer thickness. Based on the existing model of nanopore resistance, a simplified model which describes the relative current blockade during the X-DNA translocation through the nanopores is deduced to quantitatively present the relationship between nanopore thickness and relative current blockade. Results show that the relative current blockade is effectively increased by reducing the nanopore diameter but it decreases with the decreasing nanopore thickness. A two-stage schematic is proposed to increase the relative current blockade by setting a much smaller resistance region. Experimental results show a 21. 9% increase in the relative current blockade with the proposed schematic.
文摘Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies)have clinical activity in patients with metastatic CRC.The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency.Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade.Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS,BRAF,PIK3CA and PTEN could be intrinsically resistant to EGFR blockade.Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients.While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC,further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.
基金Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110654the National Natural Science Foundation of China,No.82103448China Organ Transplantation Development Foundation,No.YZLC-2021-003.
文摘The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.
基金Zhejiang Health Science and Technology Plan 2022,No.2022KY320。
文摘BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate the application effect of deep neuromuscular blockade(NMB)combined with reduced pneumoperitoneum pressure in LRG for gastric cancer(GC)in elderly patients and its influence on inflammation.METHODS Totally 103 elderly patients with GC treated in our hospital between January 2020 and January 2022 were retrospectively analyzed.Among them,45 patients treated with surgery based on deep NMB and conventional pneumoperitoneum pressure were assigned to the control group,while the rest of the 58 patients who underwent surgery based on deep NMB and reduced pneumoperitoneum pressure were assigned to the observation group.The two groups were compared in the changes of the Leiden-surgical rating scale score,serum tumor necrosis fact-α(TNF-α)and interleukin 6(IL-6)before and after therapy.The visual analogue scale(VAS)was adopted for evaluating the shoulder pain of patients at 8 h,24 h and 48 h after the operation.The driving pressure of the two groups at different time points was also compared.Additionally,the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room,TOF%=90%time and post-anesthetic recovery room(PACU)stay time were all recorded,and adverse PACU-associated respiratory events were also recorded.The postoperative hospitalization time and postoperative expenses of the two groups were counted and compared.RESULTS No significant difference was found between the two groups at the time of skin incision,60 minutes since the operation and abdominal closure after surgery(P>0.05).The observation group exhibited significantly lower VAS scores than the control group at 24 and 48h after surgery(P<0.05).Additionally,the observation group had significantly lower driving pressure than the control group at 5 min and 60 min after the establishment of pneumoperitoneum(P<0.05).Additionally,the two groups were similar in terms of the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room and TOF%=90%time(P>0.05),and the observation group showed significantly lower TNF-αand IL-6 Levels than the control group at 24 h after therapy(P<0.05).Moreover,the incidence of adverse events was not significantly different between the two groups(P>0.05),and the observation group experienced significantly less hospitalization time and postoperative expenses than the control group(P<0.05).CONCLUSION Deep NMB combined with reduced pneumoperitoneum pressure can decrease the VAS score of shoulder pain and inflammatory reaction,without hindering the surgical vision and increasing adverse PACU-associated respiratory events,and can thus shorten the hospitalization time and treatment cost for patient.
文摘During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
基金Far-Eastern Memorial Hospital,No.FEMH-2022-C-057.
文摘BACKGROUND Rocuronium,a nondepolarizing muscle relaxant,is usually administered during general anesthesia to facilitate endotracheal intubation and keep patients immobile during the surgery.Sugammadex,the selective reversal agent of rocuronium,fully reverses the neuromuscular blockade(NMB)at the end of surgery.Most reports show that sugammadex rapidly achieves a ratio of train-offour(TOF),a quantitative method of neuromuscular monitoring,of 0.9 which ensures adequate recovery for safe extubation.However,very rare patients with neuromuscular diseases may respond poorly to sugammadex.CASE SUMMARY A 69-year-old female presented with abdominal fullness and nausea,and was diagnosed with gastroparesis.She underwent gastric peroral endoscopic myotomy under general anesthesia with rocuronium(0.7 mg/kg).At the end of surgery,sugammadex 3.6 mg/kg was administered when TOF showed 2 counts.Afterward,the TOF ratio recovered to 0.65 in 30 min.She was awake but could not fully open her eyelids.The tidal volume during spontaneous breathing was low.After additional doses of sugammadex(up to 7.3 mg/kg)in the following 3 h,the TOF ratio was 0.9,and the endotracheal tube was smoothly removed.After excluding possible mechanisms underlying the prolonged recovery course,we speculated our patient may have had an undiagnosed neuromuscular disease,hinted by her involuntary movement of the tongue and mouth.Furthermore,her poor renal function and history of delayed recovery from general anesthesia may be related to the long duration of rocuronium.CONCLUSION In our case,both prolonged rocuronium-induced NMB and poor response to sugammadex were noted.To optimize the dose of rocuronium,perioperative TOF combined with other neuromuscular monitoring is suggested.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences[2017-I2M-1-010].
文摘Programmed cell death protein 1(PD-1)/programmed cell death ligand 1(PD-L1)blockade is an important therapeutic strategy for melanoma,despite its low clinical response.It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients.We analyzed clinical dataset GSE96619,which contains clinical information from five melanoma patients before and after anti-PD-1 therapy(five pairs of data).We identified 704 DEGs using these five pairs of data,and then the number of DEGs was narrowed down to 286 in patients who responded to treatment.Next,we performed KEGG pathway enrichment and constructed a DEG-associated protein-protein interaction network.Smooth muscle actin 2(ACTA2)and tyrosine kinase growth factor receptor(KDR)were identified as the hub genes,which were significantly downregulated in the tumor tissue of the two patients who re-sponded to treatment.To confirm our analysis,we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xeno-graft model.This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD-1/PD-L1 blockade therapy.
基金This work was supported by the National Natural Science Foundation of China[grant number:81973271].
文摘Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy.In this study,sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood,blocked neutrophil accumulation in tumors,and attenuated the inhibitory effect of infiltrating neutrophils on T cells.Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer.Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils.Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8^(+) T lymphocytes in the tumor.The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-001)the National High-tech Research and Development Projects(863)(2015AA020303)the National Natural Science Foundation of China(31500818)
文摘During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.
