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Non-Hodgkin lymphoma (NHL) is a common malignancy in the hematologic system, and traditional therapy has limited efficacy for people with recurrent/refractory NHL (R/R NHL), especially for patients with diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor (CAR) T-cell therapy is a novel and effective immunotherapy strategy for R/R hematopoietic malignancies, but relapses can occur due to the loss of CAR-T cells in vivo or the loss of antigen. One strategy to avoid antigen loss after CAR-T cell therapy is to target one more antigen simultaneously. Tandem CAR targeting CD19 and CD22 has demonstrated the reliability of tandem CAR-T cell therapy for R/R B-ALL. This study explores the therapeutic potential of tandem CD19/20 CAR-T in the treatment of R/R B cell NHL. The efficacy and safety of autologous CD19/20 CAR-T cells in eleven R/R B cell NHL adult patients were evaluated in an open-label, single-arm trial. Most patients achieved complete response, exhibiting the efficacy and safety of tandem CD19/20 CAR-T cells. The TCR repertoire diversity of CAR-T cells decreased after infusion. The expanded TCR clones in vivo were mainly derived from TCR clones that had increased expression of genes associated with immune-related signaling pathways from the infusion product (IP). The kinetics of CAR-T cells in vivo were linked to an increase in the expression of genes related to immune response and cytolysis/cytotoxicity.
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Antígenos CD19 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Masculino , Antígenos CD19/imunologia , Pessoa de Meia-Idade , Feminino , Imunoterapia Adotiva/métodos , Adulto , Receptores de Antígenos Quiméricos/imunologia , Idoso , Linfoma de Células B/terapia , Linfoma de Células B/imunologia , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/imunologiaRESUMO
Intramuscular fat (IMF) is vital for meat tenderness and juiciness. This study aims to explore the IMF deposition mechanism and the related molecular markers in sheep. Two populations, Small-tail Han Sheep (STH) and STH × Suffolk (SFK) F1 (SFK × STH), were used as the research object. Histological staining techniques compared the differences in the longissimus dorsi muscle among populations. A combination of transcriptome sequencing and biological information analysis screened and identified IMF-related target genes. Further, sequencing technology was employed to detect SNP loci of target genes to evaluate their potential as genetic markers. Histological staining revealed that the muscle fiber gap in the SFK × STH F1 was larger and the IMF content was higher. Transcriptome analysis revealed that PIK3R1 and PPARA were candidate genes. Histological experiments revealed that the expressions of PIK3R1 mRNA and PPARA mRNA were lower in SFK × STH F1 compared with the STH. Meanwhile, PIK3R1 and PPARA proteins were located in intramuscular adipocytes and co-located with the lipid metabolism marker molecule (FASN). SNP locus analysis revealed a mutation site in exon 7 of the PIK3R1 gene, which served as a potential genetic marker for IMF deposition. This study's findings will provide a new direction for meat quality breeding in sheep.
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Perfilação da Expressão Gênica , Cauda , Ovinos/genética , Animais , Cauda/metabolismo , Carne , Marcadores Genéticos , RNA Mensageiro/genéticaRESUMO
RATIONALE: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous type of leukemia known for its poor prognosis. The optimal treatment strategy for this condition currently lacks consensus, leaving uncertainty in its management. Nonetheless, a potential therapeutic option for patients with refractory MPAL who express target antigens is donor-derived chimeric antigen receptor T (CAR-T) cell therapy. PATIENT CONCERNS: We recently reported a 61-year-old woman with MPAL and elucidated its diagnosis and treatment. DIAGNOSIS: The diagnosis of MPAL was established based on the classification of World Health Organization in 2016. INTERVENTIONS: Despite undergoing 3 different acute lymphoblastic leukemia (ALL) regimens and 1 acute myelogenous leukemia (AML) regimen, the patient did not achieve remission. Subsequently, the patient received human CD19-targeted CAR-T cell therapy. OUTCOMES: The patient achieved a successful and complete remission after CAR-T cell therapy. Tragically, 8 months after CAR-T infusion, the patient experienced a relapse characterized by CD19-negative disease and ultimately passed away. LESSONS: This case underscores the potential efficacy and safety of human-derived CD19 CAR-T cell therapy in treating refractory MPAL. While this particular patient outcome was unfortunate, it suggests that CAR-T cell therapy may still hold promise as a viable treatment option for MPAL patients unresponsive to other therapies. Further research in this field is warranted to determine the most effective treatment strategies for managing this challenging disease.
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Leucemia Mieloide Aguda , Receptores de Antígenos Quiméricos , Feminino , Humanos , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/etiologia , Imunoterapia Adotiva/efeitos adversos , Resultado do Tratamento , Doença Aguda , Antígenos CD19 , FenótipoRESUMO
BACKGROUND: Breast cancer, the most common malignancy in women worldwide, has been proven to have both altered plasma cell-free DNA (cfDNA) methylation and fragmentation profiles. Nevertheless, simultaneously detecting both of them for breast cancer diagnosis has never been reported. Moreover, although fragmentation pattern of cfDNA is determined by nuclease digestion of chromatin, structure of which may be affected by DNA methylation, whether cfDNA methylation and fragmentation are biologically related or not still remains unclear. METHODS: Improved cfMeDIP-seq were utilized to characterize both cfDNA methylation and fragmentation profiles in 49 plasma samples from both healthy individuals and patients with breast cancer. The feasibility of using cfDNA fragmentation profile in hypo- and hypermethylated regions as diagnostic markers for breast cancer was evaluated. RESULTS: Mean size of cfDNA fragments (100-220 bp) mapped to hypomethylated regions decreased more in patients with breast cancer (4.60 bp, 172.33 to 167.73 bp) than in healthy individuals (2.87 bp, 174.54 to 171.67 bp). Furthermore, proportion of short cfDNA fragments (100-150 bp) in hypomethylated regions when compared with it in hypermethylated regions was found to increase more in patients with breast cancer in two independent discovery cohort. The feasibility of using abnormality of short cfDNA fragments ratio in hypomethylated genomic regions for breast cancer diagnosis in validation cohort was evaluated. 7 out of 11 patients were detected as having breast cancer (63.6% sensitivity), whereas no healthy individuals were mis-detected (100% specificity). CONCLUSION: We identified enriched short cfDNA fragments after 5mC-immunoprecipitation (IP) in patients with breast cancer, and demonstrated the enriched short cfDNA fragments might originated from hypomethylated genomic regions. Furthermore, we proved the feasibility of using differentially methylated regions (DMRs)-dependent cfDNA fragmentation profile for breast cancer diagnosis.
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Neoplasias da Mama , Ácidos Nucleicos Livres , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Metilação de DNA , Ácidos Nucleicos Livres/genética , Cromatina , GenômicaRESUMO
Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of gene regulatory network (GRN) stabilization as well as developmental canalization against constant but small environmental perturbations. To analyze mild perturbations, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs by, on average, â¼20%. The defining characteristic of stabilizers is that, when their capacity is compromised, GRNs do not change their short-term behaviors. Indeed, even with such broad reductions across all miRNAs, the changes in the transcriptome are very modest during development in stable environment. By comparison, broad knockdowns of other regulatory genes (esp. transcription factors) by the same method should lead to drastic changes in the GRNs. The consequence of destabilization may thus be in long-term development as postulated by the theory of canalization. Flies with modest miRNA reductions may gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by â¼90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be a solution to weak but constant environmental perturbations.
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MicroRNAs , Transcriptoma , Animais , MicroRNAs/genética , Drosophila/genética , Longevidade , Fenótipo , Redes Reguladoras de GenesRESUMO
[This corrects the article DOI: 10.1039/C9RA04065J.].
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The dataset presented in this article is the supplementary data for the research article Fang et al., 2019 [1] and provided detailed data profile to support that sludge is an effective NOX reducing agent, as reductive gas components produce during sludge combustion. The instantaneous concentrations of the main gaseous products during sludge combustion were detected by using Fourier transform infrared spectroscopy (FTIR, DX-4000, Gasmet Technologies). The results showed the distribution and concentration level of gaseous products during sludge combustion and evidenced the feasibility of using sludge as a deNOX agent in cement industry.
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The magneto-optical Kerr effect, especially the Kerr slope, is of great significance to magneto-optical devices. Herein, we developed a method to tune the magneto-optical effect by the nanograting cross section. Both the simulation and experiment confirm that the resonance strength of the plasmon can be modulated by the nanograting cross section, resulting in the large Kerr slope and Kerr rotation. By designing the nanograting cross section, we obtained the Kerr slope of 0.397°/nm, which is 4 orders of magnitude higher than the reported results. And the Kerr rotation of the magnetic nanograting reaches up to 1.218°, which is 24 times higher than the flat Co film. Such a huge enhancement on the Kerr slope and the Kerr rotation may have profound applications in magneto-optical devices in the future.
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Manipulating spins by ultrafast pulse laser provides a new avenue to switch the magnetization for spintronic applications. While the spin-orbit coupling is known to play a pivotal role in the ultrafast laser-induced demagnetization, the effect of the anisotropic spin-orbit coupling on the transient magnetization remains an open issue. This study uncovers the role of anisotropic spin-orbit coupling in the spin dynamics in a half-metallic La0.7 Sr0.3 MnO3 film by ultrafast pump-probe technique. The magnetic order is found to be transiently enhanced or attenuated within the initial sub-picosecond when the probe light is tuned to be s- or p-polarized, respectively. The subsequent slow demagnetization amplitude follows the fourfold symmetry of the d x 2 - y 2 orbitals as a function of the polarization angles of the probe light. A model based on the Elliott-Yafet spin-flip scatterings is proposed to reveal that the transient magnetization enhancement is related to the spin-mixed states arising from the anisotropic spin-orbit coupling. The findings provide new insights into the spin dynamics in magnetic systems with anisotropic spin-orbit coupling as well as perspectives for the ultrafast control of information process in spintronic devices.
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An experimental study on the effects of CO2 concentration on the release of reducing gases and the NO reduction efficiency by sludge reburning was carried out in a pilot scale cement precalciner. The results indicate that sludge reburning shows an ideal NO reduction activity. The best NO reduction efficiency of 54% is reached when the CO2 concentration is 25 vol%. Characteristic analysis of the sludge shows that the main types of reducing gases generated by sludge reburning are HCN, NH3, CO and CH4. Among them, CO2 concentration plays a crucial role in the release of HCN, CO and CH4. The mechanistic study indicates that NO reduction is dominated by homogeneous reduction during the sludge reburning process, in particular the reducing gases of CO and NH3 have significant influences on the NO reduction. Meanwhile, the effect of CO2 concentration on NO reduction is mainly due to the difference in CO release. The results of the present study not only provide insight into the mechanism of NO reduction by sludge reburning, but could also contribute to the development of NO X removal technology in the cement industry.
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Recently, Lu et al. claimed that Xie et al.'s three-party password-authenticated key agreement protocol (3PAKA) using chaotic maps has three security vulnerabilities; in particular, it cannot resist offline password guessing attack, Bergamo et al.'s attack and impersonation attack, and then they proposed an improved protocol. However, we demonstrate that Lu et al.'s attacks on Xie et al.'s scheme are unworkable, and their improved protocol is insecure against stolen-verifier attack and off-line password guessing attack. Furthermore, we propose a novel scheme with enhanced security and efficiency. We use formal verification tool ProVerif, which is based on pi calculus, to prove security and authentication of our scheme. The efficiency of the proposed scheme is higher than other related schemes.
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Segurança Computacional , Algoritmos , Identificação Biométrica , Confidencialidade , HumanosRESUMO
The sensing performance of one-dimensional magnetic nanograting based on magnetoplasmons was investigated. The predictable Kerr reversal and enhancement are achieved in our experiment. The further result shows that the shift of the Kerr null point has a linear relationship with the surrounding refractive index in a wide range. In addition, a huge figure of merit (FoM) of 1728/refractive index unit is achieved, which is 1 order of magnitude higher than the results reported. The experiment and theory confirm that the excitation of surface plasmons leads to the Kerr reversal and enhancement, resulting in a huge FoM.
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Pulmonary artery hypertension (PAH) is a rare and fatal disorder that involves extensive remodeling of the pulmonary arteries mediated by hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Aberrant platelet-derived growth factor (PDGF) activity can lead to hyperproliferation of PASMCs; however, little is known about the role of long noncoding RNA (lncRNA) in this process. Using RNA sequencing, we identified 725 lncRNAs in rat PASMCs, 95 of which were expressed differentially in response to PDGF-BB treatment. Depletion of four lncRNAs affected the proliferation of rat PASMCs as measured by 5-ethynyl-2'-deoxyuridine incorporation assay. Among these, one lncRNA, named LnRPT (lncRNA regulated by PDGF and transforming growth factor ß), was found to be the most potent in promoting the proliferation of PASMCs when knocked down. In contrast, proliferation of PASMCs was repressed when LnRPT was overexpressed. Mechanistically, LnRPT inhibited the expression of two genes involved in the Notch signaling pathway (notch3 and jag1) as well as the cell-cycle-regulating gene ccna2. In addition, downregulation of LnRPT induced by PDGF-BB was abrogated when phosphatidylinositol 3'-kinase activity was inhibited with pictilisib. Downregulation of LnRPT was also observed in the pulmonary arteries of rats with monocrotaline-induced PAH. This study provides novel insights into the effects of PDGF-BB on lncRNA expression in PASMCs, and identifies one lncRNA, LnRPT, that plays a role in PAH development as a regulator of PASMC proliferation by mediating the Notch signaling pathway and cell cycle.
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Hipertensão Pulmonar/patologia , Miócitos de Músculo Liso/patologia , Proteínas Proto-Oncogênicas c-sis/metabolismo , Artéria Pulmonar/patologia , RNA Longo não Codificante/genética , Animais , Becaplermina , Proliferação de Células , Células Cultivadas , Ciclina A2/metabolismo , Regulação para Baixo , Indazóis/farmacologia , Proteína Jagged-1/metabolismo , Masculino , Monocrotalina/farmacologia , Miócitos de Músculo Liso/citologia , Inibidores de Fosfoinositídeo-3 Quinase , Fator de Crescimento Derivado de Plaquetas/metabolismo , Artéria Pulmonar/citologia , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptor Notch3/metabolismo , Sulfonamidas/farmacologiaRESUMO
Myogenic differentiation, which occurs during muscle development, is a highly ordered process that can be regulated by E2F transcription factors. Available data show that E2F3b, but not E2F3a, is upregulated and required for myogenic differentiation. However, the regulation of E2F3b expression in myogenic differentiation is not well understood. To investigate whether E2Fb expression is controlled by miRNAs, we used bioinformatics to combine the database of microRNAs downregulated during myogenesis and those predicted to target E2F3. This identified miR-17 and miR-20a as miRNAs potentially involved in E2F3 regulation. We found that miR-17-92 controls the expression of E2F3b in C2C12 cells during myogenic differentiation. Moreover, we confirmed that miR-20a regulates the expression of E2F3b proteins in vivo using a muscle regeneration model.
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Fator de Transcrição E2F3/genética , MicroRNAs/genética , Desenvolvimento Muscular/genética , Mioblastos/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Cardiotoxinas , Diferenciação Celular/genética , Linhagem Celular , Fator de Transcrição E2F3/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Immunoblotting , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Desenvolvimento Muscular/fisiologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/fisiopatologia , Mioblastos/citologia , Regeneração/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Myogenesis involves myoblast proliferation and differentiation to myocytes, followed by fusion and hypertrophy to form myotubes during muscle development. Increasing evidence showed that microRNAs (miRNAs) play important roles in the regulation of myogenesis. We have previously revealed that miR-34b is steadily increased during this process. This miRNA regulates differentiation in various cell types, though its function in myogenesis remains to be elucidated. In this study, we show that miR-34b represses muscle cell proliferation and promotes myotube formation. Our quantitative iTRAQ-based proteomic analysis reveals 97 proteins are regulated by miR-34b in mouse myoblast C2C12. We identified that miR-34b targets 14-3-3 protein gamma, adenosylhomocysteinase and nucleolin by binding to their 3'UTR. Further analysis of these proteins expression patterns show that nucleolin is a cognate target of miR-34b during myogenic differentiation. Here, we proved that a moderate reduction of nucleolin in cells enhanced the myotube formation. However, nucleolin is required for myogenesis, as cells with low levels of nucleolin reduced cell proliferation rate and are unable to differentiate. Our data demonstrated that nucleolin regulates myogenesis in a protein-abundance-dependent manner. J. Cell. Biochem. 118: 4285-4295, 2017. © 2017 Wiley Periodicals, Inc.
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MicroRNAs/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/fisiologia , Mioblastos/fisiologia , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Regiões 3' não Traduzidas , Adenosil-Homocisteinase/genética , Adenosil-Homocisteinase/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Camundongos , MicroRNAs/fisiologia , Modelos Animais , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/fisiologia , Proteômica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , NucleolinaRESUMO
Myocytes withdraw from the cell cycle to differentiate during muscle development. Given the capacity of microRNAs (miRNAs) to regulate gene expression during development, we screened for miRNAs that were associated with muscle development. S-Poly(T) Plus analysis of 273 miRNAs in porcine longissimus dorsi muscles revealed 14 miRNAs that were strongly upregulated with age of postnatal muscle development in vivo, including miR-195 and miR-497. These two miRNAs were also strongly upregulated at late differentiation stages of mouse skeletal myoblast C2C12 cells, and demethylation treatment induced significant upregulation of miR-195/497. Manipulation of miR-195/497 expression resulted in dramatic changes in the proliferation and differentiation of C2C12 cells. We identified high-mobility group AT-hook 1 (Hmga1) mRNA as a highly conserved target of miR-195/497 in C2C12 myoblasts. Overexpression of miR-195/497 or Hmga1 silencing in C2C12 cells promoted myogenic differentiation. Moreover, we showed that miR-195/497 repressed Hmga1, which in turn downregulated one of the HMGA1 downstream targets Id3, whose inhibitory effect on myogenic differentiation is well established. Our study revealed a subset of potential development-associated miRNAs and suggests a novel regulatory axis for myogenesis in which miR-195/497 promote myogenic differentiation by repressing the HMGA1-Id3 pathway.
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Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas HMGA/metabolismo , MicroRNAs/genética , Desenvolvimento Muscular/fisiologia , Mioblastos/citologia , Mioblastos/metabolismo , Regiões 3' não Traduzidas/genética , Regiões 3' não Traduzidas/fisiologia , Animais , Western Blotting , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Proteínas HMGA/genética , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , MicroRNAs/fisiologia , Desenvolvimento Muscular/genética , Plasmídeos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SuínosRESUMO
Many two-factor challenge-response based session initiation protocol (SIP) has been proposed, but most of them are vulnerable to smart card stolen attacks and password guessing attacks. In this paper, we propose a novel three-factor SIP authentication scheme using biometrics, password and smart card, and utilize the pi calculus-based formal verification tool ProVerif to prove that the proposed protocol achieves security and authentication. Furthermore, our protocol is highly efficient when compared to other related protocols.
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The properties of optics and magneto-optical Faraday effects in a metal-dielectric tri-layer structure with subwavelength rectangular annular arrays are investigated. It is noteworthy that we obtained the strongly enhanced Faraday rotation of the desired sign along with high transmittance by optimizing the parameters of the nanostructure in the visible spectral ranges. In this system, we obtained two extraordinary optical transmission (EOT) resonant peaks with enhanced Faraday rotations, whose signs are opposite, which may provide the possibility of designing multi-channel magneto-optical devices. Study results show that the maximum of the figure of merit (FOM) of the structure can be obtained between two EOT resonant peaks accompanied by an enhanced Faraday rotation. The positions of the maximum value of the FOM and resonant peaks of transmission along with a large Faraday rotation can be tailored by simply adjusting the geometric parameters of our models. These research findings are of great importance for future applications of magneto-optical devices.
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Magneto-optical (MO) Kerr effect and optical reflectance are investigated in the visible light region for one-dimensional orderly nanocorrugation of magnetic quadrilayer films. We find that the MO enhancement originates from the combined action between cavity effect and surface plasmon resonance. The coupling between surface plasmon polaritions and localized surface plasmons cannot only enhance the magnitude of Kerr angle, but also alter the sign of Kerr rotation. In addition, the MO properties on the nanocomposite films can be tuned by the thickness of the intermediate HfO2 layer due to the cavity effect in multilayer.
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The study aims to investigate the effect of the ratio of long axis to short axis (RLS) of upright polypropylene infusion bag on discharging process and to search the best RLS. Aiming at five different RLS (1. 5 : 1, 2 : 1, 3 : 1, 4 : 1 and 5 : 1, respectively) with the volume of 100 mL, 250 mL and 500 mL, respectively, based on finite element method, analyzing the variation of stress distribution, emptying rate, drugging space and steadiness coefficient, etc. For the bags of the same volume, emptying rate increased with increasing of RLS, but the steadiness coefficient decreased with increasing of RLS. The specific increasing amplitude of emptying rate and decreasing range of steadiness coefficient were as follows: 20% and 49% for 100 mL infusion bag, 9% and 51% for 250 mL infusion bag, and 11% and 46% for 500 mL infusion bag, respectibvely, when RLS increased from 1. 5 : 1 to 5 : 1. Comparatively speaking, the increasing amplitude of the emptying rate is remarkably less than the decreasing range of the steadiness coefficient. By comprehensive consideration of both emptying rate and steadiness coefficient, lower RLS is recommended for upright polypropylene infusion bag.