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
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
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
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
The ability to control transport behaviors in nanostructure is crucial for usage as a fundamental research platform as well as a practical device.In this study,we report a gate-controlled crossover of electron transpo...The ability to control transport behaviors in nanostructure is crucial for usage as a fundamental research platform as well as a practical device.In this study,we report a gate-controlled crossover of electron transport behaviors using graphene nanoconstrictions as a platform.The observed transport properties span from Coulomb blockade-dominated single electron transmission to electron-wave interference-dominated quantum behavior.Such drastic modulation is achieved by utilizing a single back gate on a graphene nanoconstriction structure,where the size of nanostructure in the constriction and coupling strength of it to the electrodes can be tuned electrically.Our results indicate that electrostatic field by gate voltage upon the confined nanostructure defines both the size of the nanoconstriction as well as its interaction to electrodes.Increasing gate voltage raises Fermi level to cross the energy profile in the nanoconstriction,resulting in decreased energy barriers which affect the size of nanoconstriction and transmissivity of electrons.The gate-tunable nanoconstriction device can therefore become a potential platform to study quantum critical behaviors and enrich electronic and spintronic devices.展开更多
Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ...Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns.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
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(antiEG...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
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
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
Maximum androgen blockade （MAB）, consisting of an antiandrogen plus either a luteinizing hormone- releasing hormone agonist （LHRHA） or orchiectomy, is a standard care for patients with prostate cancer. Although, c...Maximum androgen blockade （MAB）, consisting of an antiandrogen plus either a luteinizing hormone- releasing hormone agonist （LHRHA） or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB （orchiectomy or LHRHA＂Goserelin＂） and anti-androgen ＂Bicalutamide＂ with castration alone （orchiectomy or LHRHA） in previ- ously untreated metastatic prostate cancer patients. Methods： Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgically by orchiectomy or medically by receiving Goserelin （3.6 rag） depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgically by orchiectomy or medically by receiving Goserelin （3.6 mg） depot. Results： During the period from January 2011 to January 2013, with a median follow up of 18 months （range 6 to 24 months）, there were eight deaths （16%）, in MAB arm and ten deaths （20%） in castration alone arm. At three months, there were 35 patients （70%） with prostate specific antigen （PSA） normalization （-〈 4 mg/dL） in MAB arm versus 17 patients （34%） with PSA normalization in castration alone arm （P = 0.001）. The median progression free survival （PFS） times were 22.18 months （95% CI, 19.7 to 24.2 months） for MAB arm versus 22 months in castration alone arm （95% CI, 18 to 25.9 months; P = 0.045）. The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm （P 〉 0.05）. The median overall survival （OS） was not reached in either arm. Both hematological and non-hematological toxicities were com- parable in both arms. Conclusion： MAB significantly improves the PSA normalization rate at 12 weeks and PFS compared to castration alone with no significant difference in overall survival and with comparable acceptable toxicities. However further studies are needed to document such findings.展开更多
AIM： To study the effect of blocking the eo-2 pathwaon the development and severity of experimental autoimmune encephalomyelitis （EAE）. METHODS： We produced mAb directed against eo-2named D8. MOG35-55 induced-EAE ...AIM： To study the effect of blocking the eo-2 pathwaon the development and severity of experimental autoimmune encephalomyelitis （EAE）. METHODS： We produced mAb directed against eo-2named D8. MOG35-55 induced-EAE mice were dailintravenously injected with either 25 μg or 100 μg D8or with vehicle control alone [phosphate-buffered saline（PBS）], starting from day 0 post immunization and weremonitored for EAE clinical score （n = 10 in each group）Mice were sacrifced on day 58 and their sera were assessed for the presence of anti-myelin oligodendrocyteglycoprotein （anti-MOG） antibodies autoantibodies, awell as for the profle of pro-infammatory cytokines andchemokines. Histological analysis of brain sections waperformed by hematoxylin and eosin staining.RESULTS： Daily treatment of EAE induced mice with D8 signifcantly decreased the severity of EAE symp-toms. Treatment with both concentrations of D8 ame-liorated EAE symptoms compared to PBS treated mice, starting from day 42 post immunization （0.89 ± 0.35 in D8 25 μg and D8 100 μg treated groups vs 2.11 ± 0.38 in the PBS treated group, P = 0.03）. A signifcant im-provement in EAE clinical score compared to total IgG treated mice was observed with the higher concentra-tion of D8 （0.81 ± 0.38 in D8 100 μg treated group vs 2.11 ± 0.31 in IgG1 treated group, on day 56 post immunization, P = 0.04）. D8 treated mice with EAE did not signifcantly exhibit lower sera levels of anti-MOG autoantibodies compared to IgG-treated mice. How-ever, they expressed lower sera levels of the pro-in-fammatory cytokines： tumor necrosis factor （7.8 ± 0.2 pg/mL in D8 100 μg treated mice vs 19.9 ± 3.4 pg/mL in IgG treated mice, P = 0.005） and interferon-gamma （1.4 ± 0.6 pg/mL in D8 100 μg treated mice vs 3.6 ± 0.4 pg/mL in IgG treated mice, P = 0.02）, as well as reduced levels of the chemokine macrophage che-moattractant protein-1 （27.2 ± 3.1 pg/mL in D8 100 μg treated mice vs 63.7 ± 12.3 pg/mL in IgG treated mice, P = 0.03）. These fndings indicate that blocking the eo-2 pathway in EAE may affect not only eosino-phil infltration into the central nervous system （CNS）, but also have an effect on monocytes and T cells, but not humoral, mediated responses. Histological analysis of the brains of D8 treated mice with EAE support that this treatment decreases immune cells infltrates in the CNS.CONCLUSION： Taken together, these fndings suggest a role for eo-2 in EAE pathogenesis and consequen-tially may support a therapeutic potential of anti-eo-2 neutralizing mAb in multiple sclerosis.展开更多
OBJECTIVE: To observe the effect of Modified Erchen Decoction on cervical spondylotic vertebral arteriopathy with stagnation and blockade of phlegm-dampness syndrome and effects on cerebral blood flow parameters. METH...OBJECTIVE: To observe the effect of Modified Erchen Decoction on cervical spondylotic vertebral arteriopathy with stagnation and blockade of phlegm-dampness syndrome and effects on cerebral blood flow parameters. METHODS: A total of 80 cervical spondylotic vertebral arteriopathy(CSA) patients with stagnation and blockade of phlegmdampness syndrome admitted to our hospital from October 2016 to April 2017 were selected and randomly divided into observation group and control group, with 40 cases in each group. The observation group was treated with Modified Erchen Decoction and the control group was given conventional treatment with Western medicine. After 4 weeks of treatment, the main clinical symptoms and signs(vertigo, neck and shoulder pain, headache, psychological and social adjustment, daily life and work) and cerebral blood flow parameters [the peak values of intracranial vertebral-basal artery diastolic blood flow velocity(Vd) and systolic blood flow velocity(Vp)] were compared between the 2 groups. The total clinical effective rate and adverse reactions during treatment were also compared. RESULTS: After treatment, the total effective rate of the observation group was 90.0%, which was significantly higher than that of the control group(77.5%). The difference between the two groups was statistically significant(P < 0.05). After treatment, The scores of vertigo, neck and shoulder pain, headache, psychology and society adaptation, daily life and work were significantly increased(P < 0.05), and the above scores of the observation group were increased more obviously. The difference between the groups was statistically significant(P < 0.05). After treatment, the levels of Vd and Vp were significantly increased(P < 0.05), and the increase of the above indexes was more obvious in the observation group. The difference between the 2 groups was statistically significant(P < 0.05). There were no significant abnormalities in blood routine, urine routine, liver function and renal function. There was no significant difference in the incidence of adverse reactions between the 2 groups.(P > 0.05). CONCLUSION: The treatment of vertebral artery type cervical spondylopathy with stagnation and blockade of phlegm-dampness syndrome by Modified Erchen Decoction can effectively relieve the main clinical symptoms and signs, improve cerebral blood flow parameters, and improve the peak values of vertebral-basal artery diastolic blood flow velocity(Vd) and systolic blood flow velocity(Vp), which is safe and effective, and helps to promote the recovery of cervical function.展开更多
Complete and reliable neuromuscular reversal is important to successful anaesthetic recovery in the morbidly obese patient undergoing laparoscopic surgery.Our goal was to determine whether sugammadex,a selective rever...Complete and reliable neuromuscular reversal is important to successful anaesthetic recovery in the morbidly obese patient undergoing laparoscopic surgery.Our goal was to determine whether sugammadex,a selective reversal agent is associated with better respiratory recovery than neostigmine following the reversal of anaesthesia-associated neuromuscular blockade by rocuronium in the morbidly obese.Peak Expiratory Flow Rate a surrogate marker for respiratory function,was the primary outcome measured and secondary outcome measures included post-operative nausea and vomiting,pain and head lifting.We found that patients reversed with sugammadex had a significantly higher post-operative PEFR as compared to those reversed with neostigmine and glycopyrrolate group.展开更多
Neuromuscular blocking agents(NMBAs)were introduced into clinical anesthesia in the 1940s^([1]),and have enabled anesthesiologists to safely anesthetize patients with significant cardiopulmonary diseases.By employing ...Neuromuscular blocking agents(NMBAs)were introduced into clinical anesthesia in the 1940s^([1]),and have enabled anesthesiologists to safely anesthetize patients with significant cardiopulmonary diseases.By employing neuromuscular blockade patient movement could be abolished, without producing excessive cardiovascular depression.展开更多
We investigate the effect of the mechanical motion of a quantum dot on the transport properties of a quantum dot shuttle, Employing the equation of motion method for the nonequilibrium Green＇s function, we show that ...We investigate the effect of the mechanical motion of a quantum dot on the transport properties of a quantum dot shuttle, Employing the equation of motion method for the nonequilibrium Green＇s function, we show that the oscillation of the dot, i.e., the time-dependent coupling between the dot＇s electron and the reservoirs, can destroy the Kondo effect. With the increase in the oscillation frequency of the dot, the density of states of the quantum dot shuttle changes from the Kondo-like to a Coulomb-blockade pattern. Increasing the coupling between the dot and the electrodes may partly recover the Kondo peak in the spectrum of the density of states. Understanding of the effect of mechanical motion on the transport properties of an electron shuttle is important for the future application of nanoelectromechanical devices.展开更多
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.
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.
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.
基金Project supported by the National Basic Research Program of China(Grant No.2016YFA0200800)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant Nos.XDB30000000 and XDB07030100)the Sinopec Innovation Scheme(Grant No.A-527).
文摘The ability to control transport behaviors in nanostructure is crucial for usage as a fundamental research platform as well as a practical device.In this study,we report a gate-controlled crossover of electron transport behaviors using graphene nanoconstrictions as a platform.The observed transport properties span from Coulomb blockade-dominated single electron transmission to electron-wave interference-dominated quantum behavior.Such drastic modulation is achieved by utilizing a single back gate on a graphene nanoconstriction structure,where the size of nanostructure in the constriction and coupling strength of it to the electrodes can be tuned electrically.Our results indicate that electrostatic field by gate voltage upon the confined nanostructure defines both the size of the nanoconstriction as well as its interaction to electrodes.Increasing gate voltage raises Fermi level to cross the energy profile in the nanoconstriction,resulting in decreased energy barriers which affect the size of nanoconstriction and transmissivity of electrons.The gate-tunable nanoconstriction device can therefore become a potential platform to study quantum critical behaviors and enrich electronic and spintronic devices.
基金supported by a Foundation Project:National Natural Science Foundation of China(Nos.82100417,81760094),ChinaThe Foundation of Jiangxi Provincial Department of Science and Technology Project(Nos.20202ACBL206001,20212BAB206022,20181BAB205026).
文摘Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns.
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.
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.
文摘Maximum androgen blockade （MAB）, consisting of an antiandrogen plus either a luteinizing hormone- releasing hormone agonist （LHRHA） or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB （orchiectomy or LHRHA＂Goserelin＂） and anti-androgen ＂Bicalutamide＂ with castration alone （orchiectomy or LHRHA） in previ- ously untreated metastatic prostate cancer patients. Methods： Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgically by orchiectomy or medically by receiving Goserelin （3.6 rag） depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgically by orchiectomy or medically by receiving Goserelin （3.6 mg） depot. Results： During the period from January 2011 to January 2013, with a median follow up of 18 months （range 6 to 24 months）, there were eight deaths （16%）, in MAB arm and ten deaths （20%） in castration alone arm. At three months, there were 35 patients （70%） with prostate specific antigen （PSA） normalization （-〈 4 mg/dL） in MAB arm versus 17 patients （34%） with PSA normalization in castration alone arm （P = 0.001）. The median progression free survival （PFS） times were 22.18 months （95% CI, 19.7 to 24.2 months） for MAB arm versus 22 months in castration alone arm （95% CI, 18 to 25.9 months; P = 0.045）. The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm （P 〉 0.05）. The median overall survival （OS） was not reached in either arm. Both hematological and non-hematological toxicities were com- parable in both arms. Conclusion： MAB significantly improves the PSA normalization rate at 12 weeks and PFS compared to castration alone with no significant difference in overall survival and with comparable acceptable toxicities. However further studies are needed to document such findings.
文摘AIM： To study the effect of blocking the eo-2 pathwaon the development and severity of experimental autoimmune encephalomyelitis （EAE）. METHODS： We produced mAb directed against eo-2named D8. MOG35-55 induced-EAE mice were dailintravenously injected with either 25 μg or 100 μg D8or with vehicle control alone [phosphate-buffered saline（PBS）], starting from day 0 post immunization and weremonitored for EAE clinical score （n = 10 in each group）Mice were sacrifced on day 58 and their sera were assessed for the presence of anti-myelin oligodendrocyteglycoprotein （anti-MOG） antibodies autoantibodies, awell as for the profle of pro-infammatory cytokines andchemokines. Histological analysis of brain sections waperformed by hematoxylin and eosin staining.RESULTS： Daily treatment of EAE induced mice with D8 signifcantly decreased the severity of EAE symp-toms. Treatment with both concentrations of D8 ame-liorated EAE symptoms compared to PBS treated mice, starting from day 42 post immunization （0.89 ± 0.35 in D8 25 μg and D8 100 μg treated groups vs 2.11 ± 0.38 in the PBS treated group, P = 0.03）. A signifcant im-provement in EAE clinical score compared to total IgG treated mice was observed with the higher concentra-tion of D8 （0.81 ± 0.38 in D8 100 μg treated group vs 2.11 ± 0.31 in IgG1 treated group, on day 56 post immunization, P = 0.04）. D8 treated mice with EAE did not signifcantly exhibit lower sera levels of anti-MOG autoantibodies compared to IgG-treated mice. How-ever, they expressed lower sera levels of the pro-in-fammatory cytokines： tumor necrosis factor （7.8 ± 0.2 pg/mL in D8 100 μg treated mice vs 19.9 ± 3.4 pg/mL in IgG treated mice, P = 0.005） and interferon-gamma （1.4 ± 0.6 pg/mL in D8 100 μg treated mice vs 3.6 ± 0.4 pg/mL in IgG treated mice, P = 0.02）, as well as reduced levels of the chemokine macrophage che-moattractant protein-1 （27.2 ± 3.1 pg/mL in D8 100 μg treated mice vs 63.7 ± 12.3 pg/mL in IgG treated mice, P = 0.03）. These fndings indicate that blocking the eo-2 pathway in EAE may affect not only eosino-phil infltration into the central nervous system （CNS）, but also have an effect on monocytes and T cells, but not humoral, mediated responses. Histological analysis of the brains of D8 treated mice with EAE support that this treatment decreases immune cells infltrates in the CNS.CONCLUSION： Taken together, these fndings suggest a role for eo-2 in EAE pathogenesis and consequen-tially may support a therapeutic potential of anti-eo-2 neutralizing mAb in multiple sclerosis.
文摘OBJECTIVE: To observe the effect of Modified Erchen Decoction on cervical spondylotic vertebral arteriopathy with stagnation and blockade of phlegm-dampness syndrome and effects on cerebral blood flow parameters. METHODS: A total of 80 cervical spondylotic vertebral arteriopathy(CSA) patients with stagnation and blockade of phlegmdampness syndrome admitted to our hospital from October 2016 to April 2017 were selected and randomly divided into observation group and control group, with 40 cases in each group. The observation group was treated with Modified Erchen Decoction and the control group was given conventional treatment with Western medicine. After 4 weeks of treatment, the main clinical symptoms and signs(vertigo, neck and shoulder pain, headache, psychological and social adjustment, daily life and work) and cerebral blood flow parameters [the peak values of intracranial vertebral-basal artery diastolic blood flow velocity(Vd) and systolic blood flow velocity(Vp)] were compared between the 2 groups. The total clinical effective rate and adverse reactions during treatment were also compared. RESULTS: After treatment, the total effective rate of the observation group was 90.0%, which was significantly higher than that of the control group(77.5%). The difference between the two groups was statistically significant(P < 0.05). After treatment, The scores of vertigo, neck and shoulder pain, headache, psychology and society adaptation, daily life and work were significantly increased(P < 0.05), and the above scores of the observation group were increased more obviously. The difference between the groups was statistically significant(P < 0.05). After treatment, the levels of Vd and Vp were significantly increased(P < 0.05), and the increase of the above indexes was more obvious in the observation group. The difference between the 2 groups was statistically significant(P < 0.05). There were no significant abnormalities in blood routine, urine routine, liver function and renal function. There was no significant difference in the incidence of adverse reactions between the 2 groups.(P > 0.05). CONCLUSION: The treatment of vertebral artery type cervical spondylopathy with stagnation and blockade of phlegm-dampness syndrome by Modified Erchen Decoction can effectively relieve the main clinical symptoms and signs, improve cerebral blood flow parameters, and improve the peak values of vertebral-basal artery diastolic blood flow velocity(Vd) and systolic blood flow velocity(Vp), which is safe and effective, and helps to promote the recovery of cervical function.
文摘Complete and reliable neuromuscular reversal is important to successful anaesthetic recovery in the morbidly obese patient undergoing laparoscopic surgery.Our goal was to determine whether sugammadex,a selective reversal agent is associated with better respiratory recovery than neostigmine following the reversal of anaesthesia-associated neuromuscular blockade by rocuronium in the morbidly obese.Peak Expiratory Flow Rate a surrogate marker for respiratory function,was the primary outcome measured and secondary outcome measures included post-operative nausea and vomiting,pain and head lifting.We found that patients reversed with sugammadex had a significantly higher post-operative PEFR as compared to those reversed with neostigmine and glycopyrrolate group.
基金supported by University of California Davis HealthNIH grant UL1 TR001860 of the University of Califomia Davis Health
文摘Neuromuscular blocking agents(NMBAs)were introduced into clinical anesthesia in the 1940s^([1]),and have enabled anesthesiologists to safely anesthetize patients with significant cardiopulmonary diseases.By employing neuromuscular blockade patient movement could be abolished, without producing excessive cardiovascular depression.
基金Project supported by the National Natural Science Foundation of China(Grant No.11204016)
文摘We investigate the effect of the mechanical motion of a quantum dot on the transport properties of a quantum dot shuttle, Employing the equation of motion method for the nonequilibrium Green＇s function, we show that the oscillation of the dot, i.e., the time-dependent coupling between the dot＇s electron and the reservoirs, can destroy the Kondo effect. With the increase in the oscillation frequency of the dot, the density of states of the quantum dot shuttle changes from the Kondo-like to a Coulomb-blockade pattern. Increasing the coupling between the dot and the electrodes may partly recover the Kondo peak in the spectrum of the density of states. Understanding of the effect of mechanical motion on the transport properties of an electron shuttle is important for the future application of nanoelectromechanical devices.
