RESUMEN
Strongly correlated systems containing d/f electrons present a challenge to conventional density functional theory such as the local density approximation or generalized gradient approximation. We developed a doubly screened Coulomb correction (DSCC) approach to perform on-site Coulomb interaction correction for strongly correlated materials. The on-site Coulomb interaction between localized d/f electrons is self-consistently determined from a model dielectric function that includes both the static dielectric and Thomas-Fermi screening. We applied DSCC to simulate the electronic and magnetic properties of typical 3d, 4f, and 5f strongly correlated systems. The accuracy of DSCC is comparable to that of hybrid functionals but an order of magnitude faster. In addition, DSCC can reflect the difference in the Coulomb interaction between metallic and insulating situations, similar to the popular but computationally expensive constrained random phase approximation approach. This feature suggests that DSCC is also a promising method for simulating Coulomb interaction parameters.
RESUMEN
BACKGROUND: Jackstone is a rare entity of calculi in urinary tracts and has the characteristic appearance resembling toy jacks. They are nearly always reported to occur in the urinary bladder, we first report a rare case of jackstone located in the obstructed renal calyx. CASE SUMMARY: We report a 46-year-old man presenting with intermittent, painless gross hematuria and left flank pain. Urinary computed tomography revealed staghorn stones and secondary hydronephrosis. A jackstone with radiating branches was found in one of the dilated renal calyx. Percutaneous nephrolithotomy was performed and endoscopic images were recorded during the operation. Postoperative stone composition analysis revealed it as calcium oxalate monohydrate stones. CONCLUSION: Jackstones can occur in the renal collecting system besides the bladder. The unique appearance and imaging manifestations are the most important factors in the diagnosis of jackstones, and further exploration of the formation mechanism is required.
RESUMEN
As correlation strength has a key influence on the simulation of strongly correlated materials, many approaches have been proposed to obtain the parameter using first-principles calculations. However, a comparison of the different Coulomb strengths obtained using these approaches and an investigation of the mechanisms behind them are still needed. Taking lanthanide metals as an example, we research the factors that affect the effective Coulomb interaction strength, Ueff, by local screened Coulomb correction (LSCC), linear response (LR), and constrained random-phase approximation (cRPA) in the Vienna Ab initio Simulation Package. The Ueff LSCC value increases from 4.75 to 7.78 eV, Ueff LR is almost stable at about 6.0 eV (except for Eu, Er, and Yb), and Ueff cRPA shows a two-stage decreasing trend in both light and heavy lanthanides. To investigate these differences, we establish a scheme to analyze the coexistence and competition between the orbital localization and the screening effect. We find that LSCC and cRPA are dominated by the orbital localization and the screening effect, respectively, whereas LR shows the balance of the competition between the two factors. Additionally, the performance of these approaches is influenced by different starting points from the Perdew-Burke-Ernzerhof (PBE) and PBE + U, especially for cRPA. Our results provide useful knowledge for understanding the Ueff of lanthanide materials, and similar analyses can also be used in the research of other correlation strength simulation approaches.
Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevención & control , Humanos , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Recombinant batroxobin (S3101) is a thrombin-like serine protease that binds to fibrinogen or is taken up by the reticuloendothelial system. A literature survey showed no adequate method that could determine sufficient concentrations to evaluate pharmacokinetic parameters for phase I clinical studies. Therefore, a sensitive method is urgently needed to support the clinical pharmacokinetic evaluation of S3101. In this study, a sensitive bioanalytical method was developed and validated, using a Quanterix single molecular array (Simoa) assay. Moreover, to thoroughly assess the platform, enzyme-linked immunosorbent assay and electrochemiluminescence assay were also developed, and their performance was compared with that of this novel technology platform. The assay was validated in compliance with the current guidelines. Measurements with the Simoa assay were precise and accurate, presenting a valid assay range from 6.55 to 4000 pg/mL. The intra- and inter-run accuracy and precision were within -19.3% to 15.3% and 5.5% to 17.0%, respectively. S3101 was stable in human serum for 280 days at -20°C and -70°C, for 2 h prior to pre-treatment and 24 h post pre-treatment at room temperature (22°C-28°C), respectively, and after five and two freeze-thaw cycles at -70°C and -20°C, respectively. The Simoa assay also demonstrated sufficient dilution linearity, assay sensitivity, and parallelism for quantifying S3101 in human serum. The Simoa assay is a sensitive and adequate method for evaluating the pharmacokinetic parameters of S3101 in human serum.
Asunto(s)
Batroxobina/sangre , Ensayo de Inmunoadsorción Enzimática , Proteínas Recombinantes/sangre , Batroxobina/aislamiento & purificación , Batroxobina/farmacocinética , Femenino , Fibrinógeno/metabolismo , Humanos , Masculino , Unión Proteica/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacocinéticaRESUMEN
In the field of remote sensing image processing, the classification of hyperspectral image (HSI) is a hot topic. There are two main problems lead to the classification accuracy unsatisfactory. One problem is that the recent research on HSI classification is based on spectral features, the relationship between different pixels has been ignored; the other is that the HSI data does not contain or only contain a small amount of labeled data, so it is impossible to build a well classification model. To solve these problems, a dual-channel CNN model has been proposed to boost its discriminative capability for HSI classification. The proposed dual-channel CNN model has several distinct advantages. Firstly, the model consists of spectral feature extraction channel and spatial feature extraction channel; the 1-D CNN and 3-D CNN are used to extract the spectral and spatial features, respectively. Secondly, the dual-channel CNN have been used for fusing the spatial-spectral features, the fusion feature is input into the classifier, which effectively improves the classification accuracy. Finally, due to considering the spatial and spectral features, the model can effectively solve the problem of lack of training samples. The experiments on benchmark data sets have demonstrated that the proposed dual-channel CNN model considerably outperforms other state-of-the-art method.
RESUMEN
A solid solution is one of the important ways to enhance the structural and functional performance of materials. In this work, we develop a structural modeling approach to solid solutions based on the similar atomic environment (SAE). We propose a similarity function associated with any type of atom cluster to describe quantitatively the configurational deviation from the desired solid-solution structure that is fully disordered or contains short-range order (SRO). In this manner, the structural modeling for solid solutions is transferred to a minimization problem in the configuration space. Moreover, we strive to enhance the practicality of this approach. The approach and implementation are demonstrated by cross validations with the special quasi-random structure method. We apply the SAE method to the typical quinary CoCrFeMnNi high-entropy alloy, continuous binary Ta-W alloy, and ternary CoCrNi medium-entropy alloy with SRO as prototypes. In combination with ab initio calculations, we investigate the structural properties and compare the calculation results with experiments.
RESUMEN
We present a simple and robust LC-MS/MS assay for the simultaneous quantitation of an antibody cocktail of trastuzumab and pertuzumab in monkey serum. The LC-MS/MS method saved costs, decreased the analysis time, and reduced quantitative times relative to the traditional ligand-binding assays. The serum samples were digested with trypsin at 50°C for 60 min after methanol precipitation, ammonium bicarbonate denaturation, dithiothreitol reduction, and iodoacetamide alkylation. The tryptic peptides were chromatographically separated using a C18 column (2.1 × 50 mm, 2.6 µm) with mobile phases of 0.1% formic acid in water and acetonitrile. The other monoclonal antibody, infliximab, was used as internal standards to minimize the variability during sample processing and detection. A unique peptide for each monoclonal antibody was simultaneously quantified using LC-MS/MS in the multiple reaction monitoring mode. Calibration curves were linear from 2.0 to 400 µg/mL. The intra- and inter-assay precision (%CV) was within 8.9 and 7.4% (except 10.4 and 15.1% for lower limit of quantitation), respectively, and the accuracy (%Dev) was within ±13.1%. The other validation parameters were evaluated, and all results met the acceptance criteria of the international guiding principles. Finally, the method was successfully applied to a pharmacokinetics study after a single-dose intravenous drip administration to cynomolgus monkeys.
Asunto(s)
Anticuerpos Monoclonales Humanizados/sangre , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Trastuzumab/sangre , Animales , Anticuerpos Monoclonales Humanizados/farmacocinética , Femenino , Modelos Lineales , Macaca fascicularis , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Trastuzumab/farmacocinéticaAsunto(s)
Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Inmunogenética , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Caracteres Sexuales , Antígenos de Neoplasias/química , Perfilación de la Expresión Génica , Humanos , Neoplasias/inmunología , Neoplasias/patología , PronósticoRESUMEN
Stem cell therapy represents the potential alternative effective strategy for some diseases that lack effective treatment currently. Correspondingly, it is crucial to establish high-sensitive and reliable quantification assay for tracing exogenous cell migration. In the present study, we first used both bioluminescence imaging (BLI) indirect labeling (human norepinephrine transporter-luciferase reporter system) and 89zirconium (89Zr)-hNSCs direct labeling combined with positron emission tomography/computer tomography (PET/CT) system for tracking human neural stem cells (hNSCs) migration into the brain via nasal administration in preclinical study. But the above two methods failed to give the biodistribution profile due to their low sensitivity. Considering its superior sensitivity and absolute quantitation capability, we developed and validated the droplet digital PCR (ddPCR) targeting species-specific gene in frozen and paraffin sections, slices, and whole blood with the sensitivity of 100-200 hNSCs. Accurate and high throughput quantification could be performed using ddPCR with the coefficient of variation (CVs) of lower quality control (LQC) below 30%. In combination with immunohistochemistry and ddPCR, we confirmed the migration of hNSCs into the brain via nasal administration, which supported the efficacy of hNSCs in MPTP-treated mice, an animal model of Parkinson's disease. In conclusion, the present study is the first to report the application of ddPCR in the pharmacokinetics profile description of tracking of hNSCs in preclinical studies.
Asunto(s)
Células-Madre Neurales/citología , Enfermedad de Parkinson/terapia , Trasplante de Células Madre , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Imagen Óptica , Enfermedad de Parkinson/genética , Reacción en Cadena de la Polimerasa , Tomografía Computarizada por Tomografía de Emisión de Positrones , Distribución Tisular , Circonio/químicaRESUMEN
We investigate the valence transition in three-dimensional topological Kondo insulator through slave-boson analysis of periodic Anderson model. By including the effect of intra-atomic Coulomb correlation [Formula: see text] between conduction and local electrons, we find a first-order valence transition from Kondo region to mixed valence state upon ascending of local f- level above a critical [Formula: see text], and this valence transition usually occurs very close to or simultaneously with a topological transition. Near the parameter region of zero-temperature valence transition, rise of temperature can generate a thermal valence transition from mixed valence to Kondo region, accompanied by a first-order topological transition. Remarkably, above a critical [Formula: see text] which is considerably smaller than that generating paramagnetic valence transition, the original continuous antiferromagnetic transition is shifted to first order one, at which a discontinuous valence shift takes place. Upon increasing [Formula: see text], the paramagnetic valence transition approaches then converges with the first-order antiferromagnetic transition, leaving a significant valence shift on the magnetic boundary. The continuous antiferromagnetic transition, first-order antiferromagnetic transition, paramagnetic valence transition and topological transitions are all summarized in a global phase diagram. Our proposed exotic transition processes can help to understand the thermal valence variation as well as the valence shift around the pressure-induced magnetic transition in topological Kondo insulator candidates and in other heavy-fermion systems.
RESUMEN
Beryllium has recently been discovered to harbor a Dirac nodal line (DNL) in its bulk phase and the DNL-induced nontrivial surface states (DNSSs) on its (0001) surface, rationalizing several already-existing historic puzzles [Phys. Rev. Lett. 117, 096401 (2016)PRLTAO0031-900710.1103/PhysRevLett.117.096401]. However, to date the underlying mechanism as to why its (0001) surface exhibits an anomalously large electron-phonon coupling effect (λ_{e-ph}^{s}≈1.0) remains unresolved. Here, by means of first-principles calculations, we show that the coupling of the DNSSs with the phononic states mainly contributes to its novel surface e-ph enhancement. Besides the fact that the experimentally observed λ_{e-ph}^{s} and the main Eliashberg coupling function (ECF) peaks are reproduced well in our current calculations, we decompose the ECF α^{2}F(k,q;v) and the e-ph coupling strength λ(k,q;v) as a function of each electron momentum (k), each phonon momentum (q), and each phonon mode (v), evidencing the robust connection between the DNSSs and both α^{2}F(k,q;v) and λ(k,q;v). The results reveal the strong e-ph coupling between the DNSSs and the phonon modes, which contributes over 80% of the λ_{e-ph}^{s} coefficient on the Be (0001) surface. It highlights that the anomalously large e-ph coefficient on the Be (0001) surface can be attributed to the presence of its DNL-induced DNSSs, clarifying the long-debated mechanism.
RESUMEN
Aim: The reliable measurement of receptor occupancy (RO) provides informative data for efficacy and safety evaluation. This study aimed to assess factors affecting RO measurement of anti-PD-1 antibodies in clinical studies. Materials & methods: RO performance was assessed using different T-cell activation markers measured by flow cytometry. The validated methodology was then used in support of a clinical study. Results: The optimized active cell population was comprised of CD45RO+ or CD45RA- T cells. The bioanalytical method was validated for inter- and intra-assay precision (coefficient of variation ≤30%) and sample storage stability for 3 days. Consistent RO saturation was observed in Phase Ia clinical trial, although receptor regulation appeared to be different. The formation of anti-drug antibodies had markedly influenced pharmacokinetics and RO. Conclusion: RO measurement in combination with pharmacokinetics and anti-drug antibodies data could allow the integrated evaluation and better understanding of efficacy and safety.
Asunto(s)
Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/inmunología , Análisis Químico de la Sangre/métodos , Ensayos Clínicos como Asunto , Receptor de Muerte Celular Programada 1/inmunología , Calibración , Humanos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To investigate the association of the grades of histologic prostatic inflammation (HPI) with prostate cancer in biopsy specimens for male patients with total serum PSA (tPSA) of 4ï¼10 µg/L. METHODS: We performed prostate biopsy for 200 patients with tPSA of 4ï¼10 µg/L from January 2015 to December 2017. We determined the location, extent and intensity of HPI and analyzed the correlation of the grades of HPI with the risk of prostate cancer. RESULTS: Of the 200 biopsy specimens, BPH was detected in 169 (84.5%) and PCa in 31 (15.5%). Statistically significant differences were found in the positive rates of PCa between grades 1, 2 and 3 HPI, which were 19.3%, 25.8% and 54.8% based on the location (P < 0.01), 77.4%, 19.4% and 3.2% based on the extent (P < 0.01), and 51.6%, 29.0% and 19.4% based on the intensity of the lesion (P < 0.01), but not in the positive rates of BPH (P > 0.05). Multivariate logistic regression analysis showed that the risk of PCa was correlated negatively with the location (95% CI: 0.052ï¼0.407, OR = 0.113, P = 0.001, r = ï¼2.078) and extent of HPI (95% CI: 0.068ï¼0.819, OR = 0.231, P = 0.023, r = ï¼1.526) but not correlated with its intensity (95% CI: 0.796ï¼4.193, OR = 1.804, P = 0.215). The positive predictive value, negative predictive value, sensitivity and specificity of the combined application of the location and extent of HPI in differentiating PCa from BPH were 51.2%, 90.3%, 91.5% and 50.8%, respectively. CONCLUSIONS: The location and extent of HPI are negatively while its intensity is not correlated with the risk of PCa. The grading of HPI based on its location and extent could help reduce the repetition of prostate biopsy.
Asunto(s)
Neoplasias de la Próstata/complicaciones , Prostatitis/complicaciones , Prostatitis/diagnóstico , Biopsia , Humanos , Masculino , Antígeno Prostático Específico/sangreRESUMEN
PURPOSE: To study the association between the preoperative PROSTATE scoring system and the prediction of biochemical recurrence (BCR) risk, after radical prostatectomy (RP) in prostate cancer patients. PATIENTS AND METHODS: A total of 340 patients who underwent a laparoscopic radical prostatectomy in Peking University First Hospital between November 2007 and March 2016 were included in the study. The preoperative PROSTATE scoring system was measured and calculated. The performance of the scoring system to predict BCR risk was estimated using the receiver operating characteristic curve (ROC curve). BCR-free survival was analyzed using the Kaplan- Meier method, and the log-rank test was applied to compare the differences in risk among the patient groups. The Cox proportional hazards regression was used to analyze the performance of the grouped PROSTATE scores. RESULTS: Of the total population, 91 (26.8%) patients had BCR. The PROSTATE score was significantly different between the BCR-developed and BCR-free groups (P<0.001). The ROC curve analysis of the scoring system showed an accuracy of 70.7% (95% CI 0.643-0.771) (P<0.001). The percentage of BCR in the high-risk (10-15), moderate-risk (5-9) and low-risk (0-4) groups was 63.3%, 24.6% and 10.3% respectively (P<0.001). The Cox proportional hazards regression analysis revealed that the grouped score was an independent predictor of BCR after RP (HR=2.002; 95% CI 1.222-3.280) (P=0.006). CONCLUSION: The PROSTATE scoring system performed adequately in predicting the risk of BCR after RP. The scoring system can assist in decision-making about the operation and post- operative follow-up for patients with high-risk.
RESUMEN
Antiferromagnetic topological insulator (AFTI) is a topological matter that breaks time-reversal symmetry. Since its proposal, explorations of AFTI in strong-correlated systems are still lacking. In this paper, we show for the first time that a novel AFTI phase can be realized in three-dimensional topological Kondo insulator (TKI). In a wide parameter region, the ground states of TKI undergo a second-order transition to antiferromagnetic insulating phases which conserve a combined symmetry of time reversal and a lattice translation, allowing us to derive a [Formula: see text]-classification formula for these states. By calculating the [Formula: see text] index, the antiferromagnetic insulating states are classified into AFTI or non-topological antiferromagnetic insulator (nAFI) in different parameter regions. On the antiferromagnetic surfaces in AFTI, we find topologically protected gapless Dirac cones inside the bulk gap, leading to metallic Fermi rings exhibiting helical spin texture with weak spin-momentum locking. Depending on model parameters, the magnetic transitions take place either between AFTI and strong topological insulator, or between nAFI and weak topological insulator. By varying some model parameters, we find a topological transition between AFTI and nAFI, driving by closing of bulk gap. Our work may account for the pressure-induced magnetism in TKI compound SmB6, and helps to explore richer AFTI phases in heavy-fermion systems as well as in other strong-correlated systems.
RESUMEN
Traditional laparoscopic radical prostatectomy is a treatment choice in many developing countries and regions for most patients with localized prostate cancer; however, no system for predicting surgical difficulty and risk has been established. This study aimed to propose a simple and standard preoperative classification system of prostate cancer using preoperative data to predict surgical difficulty and risk and to evaluate the relationship between the data and postoperative complications. We collected data from 236 patients and divided them into three groups to evaluate and validate the relationships among preoperative, operative, and postoperative data. This new scoring system is based on the body mass index, ultrasonic prostate volume, preoperative prostate-specific antigen level, middle lobe protrusion, and clinical stage. In the scoring group, we classified 89 patients into two groups: the low-risk group (score of <4) and high-risk group (score of ≥4), and then compared the postoperative data between the two groups. The positive surgical margin rate was higher in the high-risk group than low-risk group. The results in validation Groups A and B were similar to those in the scoring group. The focus of our scoring system is to allow for preliminary assessment of surgical difficulty by collecting the patients' basic information. Urologists can easily use the scoring system to evaluate the surgical difficulty and predict the risks of a positive surgical margin and urinary incontinence in patients undergoing laparoscopic radical prostatectomy.
Asunto(s)
Prostatectomía/estadística & datos numéricos , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/cirugía , Índice de Masa Corporal , Humanos , Laparoscopía , Masculino , Estadificación de Neoplasias , Complicaciones Posoperatorias/epidemiología , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Próstata/diagnóstico por imagen , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/diagnóstico por imagen , Medición de Riesgo , UltrasonografíaRESUMEN
INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. METHODS: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7HER3-high, BT474HER3-high, and 293THER3-negative cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. RESULTS: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7-bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. CONCLUSION: The results indicate that targeted chemotherapy using the aptamer-drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs.
Asunto(s)
Aptámeros de Nucleótidos/metabolismo , Cardiotoxicidad/etiología , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Receptor ErbB-3/metabolismo , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Liposomas/química , Células MCF-7 , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/toxicidad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3.0 and 3.1 nmol/L, respectively. Furthermore, JS-001 displayed distinct species cross-reactivity: it could bind to the PD-1 antigen on the peripheral blood mononuclear cells (PBMCs) of humans and cynomolgus monkeys, but not to those of mice and woodchucks; the Kd values for the interaction between JS-001 and PD-1 antigens on CD8+ T cells of human and cynomolgus monkey were 2.1 nmol/L and 1.2 nmol/L, respectively. In vitro, treatment with JS-001 (0.01-10 µg/mL) dose-dependently stimulated human T cell proliferation, as well as IFN-γ and TNF-α secretion. In HBsAg-vaccinated cynomolgus monkeys, the expression of PD-1+/CD4+ and PD-1+/CD8+ was significantly elevated, intramuscular injection of JS-001 (1 and 10 mg/kg) resulted in dramatic decreases in PD-1+/CD4+ and PD-1+/CD8+ expression in a dose-dependent manner, which was supported by PD-1 receptor occupancy (RO) results. In the PK study, 18 cynomolgus monkeys treated with single, ascending doses of 1, 10, and 75 mg/kg, and another 6 cynomolgus monkeys received 10 mg/kg successive administration. The plasma clearance of JS-001 followed a linear PK profile with single administration in the 1 and 10 mg/kg groups and a non-linear PK profile in the 75 mg/kg group. In the successive 10 mg/kg administration group, no drug accumulation was observed. But the AUC from the last exposure was lower than that of the first administration, which was probably due to the production of ADAs, as demonstrated in immunogenicity study. These non-clinical data are encouraging and provide a basis for the efficacy and safety of JS-001 in clinical trials.