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Garnet solid electrolyte Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) is an excellent inorganic ceramic-type solid electrolyte; however, the presence of Li2 CO3 impurities on its surface hinders Li-ion transport and increases the interface impedance. In contrast to traditional methods of mechanical polishing, acid corrosion, and high-temperature reduction for removing Li2 CO3 , herein, a straightforward "waste-to-treasure" strategy is proposed to transform Li2 CO3 into Li3 PO4 and LiF in LiPF6 solution under 60 °C. It is found that the formation of Li3 PO4 during LLZTO pretreatment facilitates rapid Li-ion transport and enhances ionic conductivity, and the LLZTO/PAN composite polymer electrolyte shows the highest Li-ion transference number of 0.63. Additionally, the dense LiF layer serves to safeguard the internal garnet solid electrolyte against solvent decomposition-induced chemical adsorption. Symmetric Li/Li cells assembled with treated LLZTO/PAN composite electrolyte exhibit a critical current density of 1.1 mA cm-2 and a long lifespan of up to 700 h at a current density of 0.2 mA cm-2 . The Li/LiFePO4 solid-state cells demonstrate stable cycling performances for 141 mAh g-1 at 0.5 C, with capacity retention of 93.6% after 190 cycles. This work presents a novel approach to converting waste into valuable resources, offering the advantages of simple processes, and minimal side reactions.
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BACKGROUND: Septic ankle arthritis is a devastating clinical problem with a high potential for permanent disability and amputation. Successful treatment of septic ankle arthritis remains a challenge for the surgeon and patient. Ankle arthrodesis combined with radical debridement may be an effective option to eradicate infection and salvage the limb. Although numerous fusion methods have been proposed, there is controversy about the most effective technique. QUESTIONS/PURPOSES: At a minimum follow-up of 6 years after ankle arthrodesis performed using an Ilizarov external fixator, we asked, (1) In what proportion of patients was bony fusion achieved? (2) What complications were observed, and what reoperations were performed in these patients? (3) How much did patient-reported outcomes improve from before surgery to the most recent follow-up in this group? METHODS: Between April 2010 to March 2015, we treated 59 patients for septic ankle arthritis. Of those, we considered patients who were at least 18 years of age with irreversible destruction of the joint as potentially eligible. During that time period, all patients met the prespecified criteria and were treated with ankle arthrodesis using an Ilizarov external fixator. Two percent (one of 59) of patients were excluded because they died in the second year after surgery for reasons unrelated to the procedure, and another 7% (four of 59) of patients were excluded because they were lost before the minimum study follow-up interval of 6 years. Finally, 92% (54 of 59) of patients were analyzed at a mean follow-up time of 9 ± 1 years. A total of 61% (33 of 54) were men, and they had a mean age of 48 ± 12 years. Forty-six percent (25 of 54) of patients were smokers, and 13% (seven of 54) of patients had Type 2 diabetes mellitus. All patients received radical debridement and primary arthrodesis with an Ilizarov external fixator, followed by antibiotic therapy. Postoperatively, patients were instructed to perform lower extremity functional exercises and external fixator care; weightbearing ambulation as tolerated was encouraged as early as possible. Fusion was assessed with a radiographic review that was performed by an individual who was not involved in the surgical care of these patients. We defined bony fusion as continuous trabeculae and complete cortical bridging in the fusion interface achieved before 9 months; delayed union was defined as fusion achieved by 9 to 12 months; and nonunion was defined as patients in whom fusion was not achieved by 12 months. Complications and reoperations were tallied through a record review that was performed by an individual who was not involved in the surgical care of these patients. We defined complications as any deviation from the expected postoperative course. We used the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the VAS active pain score, and the SF-12 questionnaire (including the physical component summary [PCS] score and mental component summary [MCS] score) to assess patient-reported outcomes. The minimum clinically important difference (MCID) for the AOFAS score was 30 points of 100, the MCID for the VAS active pain score was 2 points of 10, and the MCID of PCS and MCS scores was 7 points and 9 points, respectively. RESULTS: Primary bony fusion was achieved in 94% (51 of 54) of patients. Delayed union was found in 2% (one of 54) of patients. Nonunion was found in 6% (three of 54); one of these patients underwent autologous bone grafting during revision, and bony fusion was ultimately achieved. Final bony fusion was achieved in 96% (52 of 54) of patients. Recurrent infection was found in 2% (one of 54). The median (range) AOFAS score improved from 28 points (8 to 59) before surgery to 80 points (52 to 86) at the most recent follow-up (median difference 52; p < 0.001). The median (range) VAS active pain score decreased from 8 points (6 to 9) before surgery to 2 points (0 to 5) at the most recent follow-up (median difference -6; p < 0.001). For the Short Form 12-item score, the median (range) PCS score improved from 0 points (0 to 30) before surgery to 70 points (40 to 95) at the most recent follow-up (median difference 70; p < 0.001), and the median (range) MCS score improved from 46 points (21 to 75) before surgery to 75 points (50 to 92) at the most recent follow-up (median difference 29; p < 0.001). CONCLUSION: Ankle arthrodesis with Ilizarov external fixation might eradicate an infection and restore foot function in patients with septic ankle arthritis. However, patients should be fully informed of the complications related to the external fixator, such as pin-tract infections, recurrent infection, and nonunion. Standardized and professional pin care is important. Additionally, because Ilizarov external fixators can be inconvenient to the patients' daily lives, future studies should explore how psychologic support affects patients who undergo ankle arthrodesis with these devices. LEVEL OF EVIDENCE: Level IV, therapeutic study.
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Artritis Infecciosa , Diabetes Mellitus Tipo 2 , Técnica de Ilizarov , Masculino , Humanos , Adulto , Persona de Mediana Edad , Femenino , Tobillo , Estudios de Seguimiento , Reinfección/etiología , Articulación del Tobillo/diagnóstico por imagen , Articulación del Tobillo/cirugía , Artritis Infecciosa/diagnóstico por imagen , Artritis Infecciosa/cirugía , Artritis Infecciosa/etiología , Resultado del Tratamiento , Artrodesis/efectos adversos , Artrodesis/métodos , Fijadores Externos , Dolor/etiología , Estudios RetrospectivosRESUMEN
Lithium-oxygen batteries (LOBs) are well known for their high energy density. However, their reversibility and rate performance are challenged due to the sluggish oxygen reduction/evolution reactions (ORR/OER) kinetics, serious side reactions and uncontrollable Li dendrite growth. The electrolyte plays a key role in transport of Li+ and reactive oxygen species in LOBs. Here, we tailored a dilute electrolyte by screening suitable crown ether additives to promote lithium salt dissociation and Li+ solvation through electrostatic interaction. The electrolyte containing 100â mM 18-crown-6 ether (100-18C6) exhibits enhanced electrochemical stability and triggers a solution-mediated Li2 O2 growth pathway in LOBs, showing high discharge capacity of 10 828.8â mAh gcarbon -1 . Moreover, optimized electrode/electrolyte interfaces promote ORR/OER kinetics on cathode and achieve dendrite-free Li anode, which enhances the cycle life. This work casts new lights on the design of low-cost dilute electrolytes for high performance LOBs.
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BACKGROUND: Pipkin type III femoral head fractures are relatively rare injuries. Few studies have explored and described the treatment and outcomes of Pipkin type III femoral head fractures. The purpose of this study was to evaluate the efficacy of open reduction and internal fixation (ORIF) in treating Pipkin type III femoral head fractures. METHODS: We retrospectively reviewed 12 patients with Pipkin type III femoral head fractures who underwent ORIF from July 2010 and January 2018. The complications and reoperations were recorded. The visual analog scale (VAS) pain score, Harris hip score (HHS), Thompson-Epstein criteria, and SF-12 score [including the physical component summary (PCS) and the mental component summary (MCS)] were used for functional assessment. RESULTS: Among the 12 patients, ten were males and two were females, with a mean age of 34.2 ± 11.9 years. The median follow-up time was 6 years (range 4-8 years). Five patients (42%) developed osteonecrosis of the femoral head, and one patient (8%) developed nonunion. These six patients (50%) underwent total hip arthroplasty (THA). One patient (8%) developed heterotopic ossification and underwent ectopic bone excision; this patient also presented with post-traumatic arthritis. The mean final VAS pain score and HHS were 4.1 ± 3.1 points and 62.8 ± 24.4 points, respectively. According to the Thompson-Epstein criteria, there was one patient (8%) with excellent, four patients (33%) with good, one patient (8%) with fair, and six patients (50%) with poor outcomes. The PCS score and MCS score were 41.7 ± 34.7 points and 63.2 ± 14.5 points, respectively. CONCLUSION: Limited by the high incidence of osteonecrosis of the femoral head, it is difficult to achieve satisfactory functional outcomes when treating Pipkin type III femoral head fractures using ORIF, and a primary THA may be considered. However, for younger patients, considering the survivorship of prosthesis, ORIF may be recommended with the proviso that the patient is fully informed of the high complication rate associated with this procedure. LEVEL OF EVIDENCE: IV.
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Fracturas del Fémur , Fracturas de Cadera , Osteonecrosis , Masculino , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Cabeza Femoral/cirugía , Cabeza Femoral/lesiones , Estudios Retrospectivos , Resultado del Tratamiento , Fracturas del Fémur/cirugía , Fijación Interna de Fracturas/métodos , Dolor , Fracturas de Cadera/cirugíaRESUMEN
In the past, specificity and affinity were the priority for synthetic antibody library. However, therapeutic antibodies need good stability for medical use. Through carefully adjust the chemical diversity in CDRs, one hopes to design a synthetic antibody library with good developability. Here we thoroughly analyzed 296 nanobody sequences and structures, constructed a fully-functional synthetic nanobody library, evaluated the relationship between aggregation and isoelectric point, and found that high-pI nanobodies were more resistant to aggregation than low-pIs. As we used the same framework for constructing the library, CDRs charge played a crucial role in mediating nanobody aggregation. We also analyzed the theoretical pI of 296 nanobodies from PDB, about 75% had basic pI, only 25% were acidic. Those results provided useful guidelines for designing next-generation synthetic nanobody libraries and for identifying potent and safe nanobody therapeutics.
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Regiones Determinantes de Complementariedad/química , Anticuerpos de Dominio Único/química , Humanos , Biblioteca de Péptidos , Agregado de ProteínasRESUMEN
BACKGROUND: Few studies focus on the treatment of femoral head fracture combined with posterior hip dislocation, and the safe interval time between injury and hip reduction remains controversial. The purpose of this study was to evaluate and compare the outcome of early and delayed hip reduction in the surgical treatment of femoral head fracture combined with posterior hip dislocation. METHODS: A total of 71 patients were evaluated in this retrospective study. Based on the time to hip reduction, they were divided into early group (within 6 h after injury) and delayed group (between 6 and 12 h after injury). The two groups were compared in reference to hospital day, fracture healing time, the occurrence of complications and final functional outcome. The Thompson-Epstein criteria, modified Merle D'Aubigné and Postel scores, visual analog scale (VAS) and Medical Outcomes Short Form 12-item questionnaire score (SF-12) were used for final functional evaluation. RESULTS: The mean hospital stay and fracture healing time in the early group were significantly lower than those in the delayed group. The incidence of infection, post-traumatic osteoarthritis, and avascular necrosis of the femoral head (ANFH) in the delayed group were higher than that in the early group. The early group had better functional outcomes in terms of Thompson-Epstein criteria, modified Merle D'Aubigné and Postel scores and physical component scale (PCS) than the delayed group. CONCLUSIONS: For the treatment of femoral head fracture combined with posterior hip dislocation, the early and prompt hip reduction can effectively facilitate the fracture healing and patient rehabilitation, and obtain a better functional outcome.
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Cabeza Femoral , Cabeza Femoral/diagnóstico por imagen , Cabeza Femoral/cirugía , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: The topic that whether the injured deltoid ligament should be repaired when associated with ankle joint fractures is still discussed. The objective of this study was to compare the clinical effect of open reduction and internal fixation (ORIF) with deltoid ligament repair (DLR) or transarticular external fixation (TEF) in treating supination-external rotation type IV (SER IV) ankle fractures. METHODS: Between January 2012 and December 2015, 43 patients were diagnosed as SER IV ankle fractures, 20 underwent ORIF and transarticular external fixation (TEF) without DLR (group 1), 23 were treated with ORIF and DLR (group 2). The pre- and post-operative radiographic examination were performed, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the visual analog scale (VAS), the Medical Outcomes Short Form 36-item questionnaire score (SF-36), and the ankle range of motion (ROM) were used for functional evaluation. RESULTS: In both groups, the three scores improved significantly after surgery, but there was no significant difference between the two groups. At 6 weeks after surgery, patients in group 2 had better ankle ROM than group 1 (29.35 ± 2.033 vs. 40.35 ± 3.550, P < 0.001), but there was no difference at 12 months postoperatively. No cases of bone nonunion or post-traumatic arthritic changes were seen during the follow-up. Patients in group 1 required a shorter time to achieve fracture union than patients in group 2. CONCLUSIONS: ORIF with TIF is an optional strategy to manage SER IV ankle fractures as it achieves comparable functional results to ORIF with DLR. It also allows patients to start relatively earlier weight-bearing and may promote fracture union.
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Fracturas de Tobillo/cirugía , Articulación del Tobillo/fisiopatología , Músculo Deltoides/cirugía , Fijación de Fractura/métodos , Ligamentos Articulares/cirugía , Adolescente , Adulto , Fracturas de Tobillo/fisiopatología , Músculo Deltoides/lesiones , Músculo Deltoides/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Ligamentos Articulares/lesiones , Ligamentos Articulares/fisiopatología , Masculino , Persona de Mediana Edad , Rango del Movimiento Articular , Recuperación de la Función , Estudios Retrospectivos , Rotación , Supinación , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To evaluate and compare the effectiveness of the modified Heuter approach and the Kocher-Langenbeck approach in the treatment of Pipkin type I and II femoral head fractures. METHODS: The study cohort consisted of 39 patients with Pipkin type I or type II femoral head fractures who were treated by open reduction and internal fixation through the modified Heuter approach (the Heuter group) or the Kocher-Langenbeck approach (the K-L group) between June 2013 and January 2016. Standard radiographs and computed tomography (CT) scans were obtained before surgery and during the follow-up. The two approaches were compared in reference to operative time, amount of blood loss, the occurrence of complications, and final functional outcome. The Brooker classification was used to document heterotopic ossification and the Thompson-Epstein scores were used for final evaluation. RESULTS: The mean operative time and estimated blood loss in the Heuter group were lower than those in the K-L group (P < 0.001 for both measures). The incisions healed primarily in all patients after surgery, no infection or deep venous thromboses were detected in either group, post-operative imaging data showed that dislocation and fractures were reduced, and the fractures finally achieved bony union. There were no significant differences in the incidence of complications or final functional outcomes between the two groups. CONCLUSIONS: Compared with the Kocher-Langenbeck approach, the modified Heuter approach can effectively reduce the blood loss and operative time without increasing the risk of complications; this approach is simple, straightforward, and atraumatic and may be a viable option for open reduction and internal fixation of Pipkin type I and type II femoral head fractures.
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Cabeza Femoral/cirugía , Fijación Interna de Fracturas/métodos , Fracturas de Cadera/cirugía , Adulto , Femenino , Cabeza Femoral/diagnóstico por imagen , Cabeza Femoral/lesiones , Fijación Interna de Fracturas/efectos adversos , Fracturas de Cadera/clasificación , Fracturas de Cadera/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Reducción AbiertaRESUMEN
PURPOSE: To investigate the early and mid-term results of open reduction and internal fixation (ORIF) with transarticular external fixation (TEF) but no deltoid ligament repair (DLR) in the treatment of supination-external rotation type IV equivalent (SER IV E) ankle fractures (AO/OTA classification 44-B 3.1) and provide evidence for clinical practice. METHODS: This study cohort consisted of 22 patients with SER IV E ankle fractures that underwent ORIF with TEF but no DLR between December 2011 and December 2014. There were 13 males and 9 females, mean age 38.9 years (range, 17-73 years). Eight cases involved the left side and 14 the right side. The causes of fractures included road traffic accidents (11 cases), falling from height (6 cases) and sports injuries (5 cases). The mean period of hospitalization was 9.8 days (range, 6-14 days). For all the patients, MRI and three-dimensional CT were done before surgery and X-rays done preoperatively and during follow-ups. The external frame was kept for 8-10 weeks. The preoperative American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score was 56.86 ± 4.400, the Medical Outcomes Short Form 36-item (SF-36) questionnaire score was 57.41 ± 4.102 and the visual analog score (VAS) was 5.50 ± 1.058. Patients' main complaints about inconvenience of daily life were also recorded. RESULTS: All the 22 patients were followed up for 24-63 months (mean, 33.6 months). None of them developed nonunion during the follow-up; pin site infection was observed in one patient and posttraumatic osteoarthritis in another. At the final follow-up, the average AOFAS score, SF-36 score and VAS score were respectively 90.59 ± 5.096, 79.59 ± 5.394 and 1.82 ± 1.181, which were significantly improved compared with the preoperative data (t = 26.221, p < 0.001; t = 11.910, p < 0.001; t = 11.571, p < 0.001). The therapeutic effect was excellent in 13 cases, good in 7 cases and fair in 2 cases, with a good-excellent rate of 90.9%. Patients' main complaints were inconvenience of clothing (17 cases) and extremity cleaning (5 cases). CONCLUSION: In the treatment of SER IV E ankle fractures, ORIF with TEF but no DLR can achieve satisfactory outcome, but long-term effect should be confirmed by large sample randomized controlled trials.
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Fracturas de Tobillo/cirugía , Fijación de Fractura/métodos , Reducción Abierta/métodos , Adolescente , Adulto , Anciano , Femenino , Fijación de Fractura/efectos adversos , Humanos , Ligamentos Articulares/cirugía , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Estudios Retrospectivos , Rotación , Supinación , Adulto JovenRESUMEN
PURPOSE: To investigate the mid-term curative effects of the treatment of Pipkin type IV femoral head fractures using a reconstruction plate and bioabsorbable screws and provide the evidence for clinical practice. METHODS: From February 2010 to September 2014, 21 patients with Pipkin type IV femoral head fractures were treated surgically. There were 13 males and 8 females with an average age of 41.1 years (range, 20-65 years). The causes of the fractures included traffic accidents (13 cases), falls from a height (four cases), heavy lifting injuries (three cases), and sport injury (one case). All patients were followed up with radiography and three-dimensional reconstruction computed tomography and other checks and any complications were actively managed. Closed reduction of fracture-dislocation of the hip was attempted under general anesthesia using the Kocher-Langenbeck approach. Femoral head fractures were treated with internal fixation or excision based on the size of the fracture fragments, whereas acetabular fractures were fixed with a reconstruction plate and screws following anatomic reduction. RESULTS: The incisions healed by primary intention in all patients after surgery, without any infection, deep venous thrombosis, or other complications. All 21 patients were followed up for 36-76 months, with an average follow-up duration of 49 months. Postoperative imaging data showed that all dislocations and fractures were anatomically reduced, and bony union of the fractures was achieved. Heterotopic ossification was found in four patients, post-traumatic osteoarthritis in three, and avascular necrosis of the femoral head in two. At the final follow-up, the assessment of hip joint function according to the Thompson-Epstein scoring scale was excellent in 10 cases, good in six cases, fair in three cases, and poor in two cases. The rate of excellent and good functional outcomes was 76.1%. CONCLUSION: The mid-term curative effects of a reconstruction plate and bioabsorbable screws in the treatment of Pipkin type IV femoral head fractures is significant, and such the treatment can significantly improve the patient's joint function and quality of life.
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Placas Óseas , Tornillos Óseos , Cabeza Femoral/lesiones , Fracturas de Cadera/cirugía , Procedimientos de Cirugía Plástica/métodos , Acetábulo/lesiones , Adulto , Anciano , Femenino , Estudios de Seguimiento , Fracturas de Cadera/etiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Spleen tyrosine kinase (Syk) is an attractive target for the discovery of new treatments for inflammatory and autoimmune disorders. Structure-based virtual screening was performed for identifying novel scaffolds of Syk inhibitors. A total of 16 hits were discovered in the enzyme assay and 8 compounds had an IC50 value lower than 10µM. In particular, compound 11 (IC50=3.2µM) was active in the cellular Syk assay and could inhibit lymphocytes proliferation in a dose-dependent manner, which could be used as a good starting point for the discovery of new class of Syk inhibitors.
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Indazoles/química , Indazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Syk/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/enzimología , Simulación del Acoplamiento Molecular , Quinasa Syk/metabolismoRESUMEN
The anti-ErbB2 humanized antibody trastuzumab was approved for ErbB2-positive metastatic gastric and gastro-esophageal junction cancer in 2010. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2-targeting therapy. Down-regulation of surface receptors induced by monoclonal antibody (mAb) contributes to its antitumor efficacy. Previous studies have demonstrated that if two anti-ErbB2 mAbs did not compete with each other for binding to ErbB2, the combination of them can enhance ErbB2 internalization. In the present study, we investigated ErbB2 internalization-inducing ability of non-competitive anti-ErbB2 mAb combinations and surprisingly found that most of the mAb combinations tested did not down-regulate ErbB2. Only 4 of 18 non-competitive mAb pairs efficiently induced ErbB2 internalization. Interestingly, although the non-competitive anti-ErbB2 mAbs trastuzumab and pertuzumab, either alone or in combination, were ineffective at inducing ErbB2 internalization, TPL, a bispecific antibody engineered from trastuzumab and pertuzumab, potently down-regulated the ErbB2 molecule. Importantly, TPL exhibited a far greater antitumor effect on ErbB2-overexpressing gastric cancer cell line than trastuzumab plus pertuzumab, suggesting that it may be a promising agent for the treatment of gastric cancer.
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Anticuerpos Monoclonales/administración & dosificación , Proliferación Celular/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antineoplásicos/administración & dosificación , Antineoplásicos/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Línea Celular Tumoral , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Gástricas/patología , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/inmunología , Resultado del TratamientoRESUMEN
Despite of the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, trastuzumab resistance emerges as a major and common clinical problem. Thus, circumventing trastuzumab resistance has become an urgent need. Recently, Src inhibitor saracatinib has drawn great attention for its key role in trastuzumab response. As shown in our previous study, H2-18, an anti-ErbB2 antibody, could potently induce programmed cell death (PCD) in trastuzumab-resistant breast cancer cells. Here we combined H2-18 and a Src inhibitor, saracatinib, and studied the antitumor activity of this drug combination in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and saracatinib could synergistically inhibit cell proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cell lines in vitro. H2-18 plus saracatinib could also inhibit the HCC-1954 tumor growth more effectively in vivo than each drug alone. H2-18 plus saracatinib showed a significantly more potent PCD-inducing activity compared with either H2-18 or saracatinib alone. We conclude that enhanced PCD may contribute to the superior antitumor efficacy of this combination therapy. The combination of H2-18 and SRC inhibitor has the potential to be translated into clinic.
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Antineoplásicos/administración & dosificación , Benzodioxoles/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Quinazolinas/administración & dosificación , Trastuzumab/administración & dosificación , Animales , Anticuerpos/química , Antineoplásicos/química , Apoptosis , Benzodioxoles/química , Neoplasias de la Mama/metabolismo , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Quinazolinas/química , Especies Reactivas de Oxígeno/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/química , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Pro-antibody-drug conjugate (PDC) is a hybrid structural format of immunoconjugate, where the structural complexity of pro-antibody and intrinsic heterogeneity of ADCs impose a prominent analytical challenge to the in-depth characterization of PDCs. In the present study, we successfully prepared and characterized PanP-DM1 as a model of PDCs, which is an anti-EGFR pro-antibody following conjugation with DM1 at lysine residues. The drug-to-antibody ratio (DAR) of PanP-DM1 was determined by LC-MS after deglycosylation, and verified by UV/vis spectroscopy. Following reduction or IdeS digestion, the pro-antibody fragments linked with DM1 were investigated by middle-down mass spectrometry. Furthermore, more than 20 modified lysine conjugation sites were determined by peptide mapping after trypsin digestion. Additionally, more than ten glycoforms of PanP-DM1 were also identified and quantified. In summary, critical quality attributes (CQAs) of PDCs including DAR, drug load distribution, and conjugation sites were fully characterized, which would contribute to the development of other PDCs for cancer treatment.
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Cromatografía Liquida/métodos , Inmunoconjugados/química , Espectrometría de Masas/métodos , Anticuerpos Monoclonales/química , Profármacos/químicaRESUMEN
Despite the effectiveness of the anti-CD20 chimeric antibody (mAb), rituximab, in treating B-cell lymphomas, its efficacy remains variable and often modest. Hu8E4 is an anti-CD20 humanized antibody which exhibits markedly higher antitumor activity compared with rituximab. Previous studies have indicated that rituximab and almost all known anti-CD20 murine mAbs recognize the A170/P172 motif within the large extracellular loop of CD20. In this study, we demonstrated that hu8E4 also recognized the A170/P172 motif, suggesting that the epitopes recognized by rituximab and hu8E4 are very similar. Based on this, three single mutations (D57E, Y102K and Y102T) at the heavy chain variable region that can improve the affinity of rituximab were transferred to hu8E4. The results showed that D57E and Y102T but not Y102K successfully enhanced the binding of hu8E4 to CD20. Out of these hu8E4 mutants, hu8E4D57E exhibited the highest affinity. The in vitro and in vivo antitumor activity of hu8E4D57E was further investigated. Our data indicated that hu8E4D57E was as effective as hu8E4 in mediating CDC and inducing apoptosis in B-lymphoma cells, but it was more potent in ADCC than hu8E4. Importantly, hu8E4D57E was shown to be significantly more effective than Hu8E4 in prolonging the survival of SCID mice bearing disseminated B-lymphoma cells, suggesting that it might be a promising therapeutic agent for B-cell lymphomas. Moreover, this study also suggests that the mutations that can improve the affinity of rituximab may be transferred to other anti-CD20 murine mAbs to enhance their binding to CD20.
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Anticuerpos Monoclonales Humanizados/inmunología , Antígenos CD20/inmunología , Epítopos/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales Humanizados/genética , Citotoxicidad Celular Dependiente de Anticuerpos , Apoptosis , Epítopos/química , Humanos , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Homología de Secuencia de AminoácidoRESUMEN
Although monoclonal antibodies, including CD20 antibody rituximab, are standard therapeutics for several cancers, their efficacy remains variable and often modest. There is an urgent need to enhance the efficacy of the current generation of anticancer antibodies. Flt3 ligand, a soluble protein, has the ability to induce substantial expansion of dendritic cells (DCs). In this study, we constructed a bispecific immunoglobulin G-like bispecific fusion protein (BiFP) targeting both CD20 and Flt3 (CD20-Flex) by using CrossMab technology. We found that the BiFP exhibited stabilities that were comparable with the parental antibody rituximab and were able to bind to both targets with unaltered binding affinity. Notably, our data indicated that CD20-Flex BiFP could not only eliminate lymphoma temporarily but also potentiate tumor-specific T-cell immunity, which affords a long-lasting protection from tumor recurrence. The results showed that the expansion and infiltration of DCs into tumor tissues by CD20-Flex BiFP could be an effective way to generate protective immune responses against cancer, suggesting that the CD20-Flex BiFP could be a promising therapeutic agent against B-cell lymphomas.
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Anticuerpos Biespecíficos/farmacología , Anticuerpos Monoclonales de Origen Murino/farmacología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/farmacocinética , Anticuerpos Monoclonales de Origen Murino/inmunología , Anticuerpos Monoclonales de Origen Murino/farmacocinética , Antígenos CD20/inmunología , Antineoplásicos/inmunología , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Células Cultivadas , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Recurrencia Local de Neoplasia/prevención & control , Rituximab , Tirosina Quinasa 3 Similar a fms/inmunologíaRESUMEN
There is a dearth of dental scientific literature on the effect of different oxidation heat treatments (OHTs) (as surface pretreatments) on the bonding performance of cast and milled cobalt-chromium (CoCr) alloys. The objective of this study was to evaluate the effect of different OHTs on the bond strength between a ceramic and cast and milled CoCr alloys. Cobalt-chromium metallic specimens were prepared using either a cast or a milled method. Specimens were subjected to four different OHT methods: without OHT; OHT under normal atmospheric pressure; OHT under vacuum; and OHT under vacuum followed by sandblasting. The metal-ceramic bond strength was evaluated using a three-point bending test according to ISO9693. Scanning electron microscopy and energy-dispersive spectroscopy were used to study the specimens' microstructure and elemental composition. The bond strength was not affected by the CoCr manufacturing method. Oxidation heat treatment performed under normal atmospheric pressure resulted in the highest bond strength. The concentration of oxygen on the alloy surfaces varied with the different pretreatment methods in the following order: OHT under normal atmospheric pressure > OHT under vacuum > without OHT ≈ OHT under vacuum followed by sandblasting.
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Aleaciones de Cromo/química , Recubrimiento Dental Adhesivo , Porcelana Dental/química , Aleaciones de Cerámica y Metal/química , Aluminio/análisis , Óxido de Aluminio/química , Presión Atmosférica , Cromo/análisis , Cobalto/análisis , Diseño Asistido por Computadora , Revestimiento para Colado Dental/química , Grabado Dental/métodos , Calor , Humanos , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Oxidación-Reducción , Oxígeno/análisis , Oxígeno/química , Docilidad , Silicio/análisis , Espectrometría por Rayos X , Estrés Mecánico , Propiedades de Superficie , Tungsteno/análisis , VacioRESUMEN
OBJECTIVE: To find out the occurrence of cesarean section (CS) and related factors among child-bearing women in China. METHODS: The survey was conducted during October, 2010 in 40 counties selected from 30 provinces. Size proportional sampling method was employed in sampling. A face to face questionnaire investigation was conducted among 8 420 women who experienced pregnancies from 1978 to 2010. Information on demographic characteristics, history of pregnancy and birth were obtained, and related factors of CS occurrence were analyzed. RESULTS: A total of 11 440 living births have been given by 8 420 women, and 1 725 CS happened. As the time goes on, there is a growing trend of CS occurrence, from 2.0% (14/701) in 1978-1985 to 36.6% (813/2 224) in 2006-2010, and there is a most fast increase from 2001 to 2010. CS rate in Mid-China (42.3%, 257/608) is the highest from 2006 to 2010. And also, the rate of CS requested by the pregnant women or their family members was increasing year by year, from 14.3% (2/14) in 1978-1985 to 43.7% (255/813) in 2006-2010. Women who were above 25 years old (21.4%, 960/4 485) , with an education degree of high school or above (24.5%, 568/2 317), engaged in nonagricultural work (22.4%, 663/2 956), living in eastern provinces of China (18.6%, 757/4 074), fetal malposition (45.4%, 247/544) , with a heavier birth weight(4 000 gram or above) (36.5%, 175/479) , have accepted B ultrasound exam (18.8%, 1 633/8 687) with an increasing of blood pressure (28.0%, 172/614) and convulsion experiences (24.8%, 131/528) during pregnancy were more likely to have CS. CONCLUSION: The CS rate among child-bearing women in China was rather high, and was related with factors of demographic characteristics(age of childbearing, education, vocation, residence) and some medical factors(neonatal weight, having accepted B ultrasound exam, fetal malposition, an increase of blood pressure and convulsions during pregnancy).
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Cesárea/estadística & datos numéricos , Cesárea/tendencias , Demografía , China , Femenino , Humanos , Embarazo , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
Background: Our aim was to examine trends in the bibliometric analysis of synovial for osteoarthritis over the last 10 years. Methods: Publications relevant to synovial in osteoarthritis from 2013 to 2022 were retrieved from the Science Citation Index Expanded (SCI-E), Social Sciences Citation Index (SSCI), and Web of Science Core Collection (WoSCC) databases. The countries/regions, institutions, authors, journals, references, and keywords related to this topic were extracted using Citespace and Vosviewer. Citespace and Vosviewer were also used to identify and analyze this field's research hotspots and trends. Results: Over the past 10 years, 5738 articles addressing the role of synovium in osteoarthritis have been published. Between 2013 and 2022, 2021 had the highest amount of published articles (a total of 756 published articles, or 13.18 % of the total articles) covering synovial in osteoarthritis. China was the country that published the most articles, while Duke University was the institution that published the most articles. Osteoarthritis and Cartilage was the journal with the most publications related to the study of Synovium in osteoarthritis. The National Nature Science Foundation of China provided the most funding. According to the analysis of keyword burst detection, human cartilage, control experiment, and exosomes were the most searched at different points in time. Conclusion: In the last ten years, both the number of citations and the article discussing synovial in osteoarthritis have increased. The top 10 most searched keywords were "osteoarthritis","synovial fluid", "inflammation", "cartilage", "expression","rheumatoid arthritis","articular cartilage", "knee osteoarthritis", "synovial", "knee". According to the timeline view of co-citation clustering, synovial components and their expressions have emerged as hotspots of research associated with synovial osteoarthritis.
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The use of electric furnace ferronickel slag (FNS) as a supplementary cementitious material is the current focus of research. This study investigates the effect of mechanical grinding and chemical additives on the activity excition of FNS, as well as the associated synergistic mechanisms. This study shows that the addition of triethanolamine (TEA) increases the fine-grained content in FNS powder, which facilitates the depolymerization of FNS and the early hydration of aluminum tricalcium. Furthermore, the addition of Ca(OH)2 raises the alkalinity of the cementitious system, which promotes the availability of Ca2+ ions and accelerates the hydration process, resulting in the generation of additional hydration products. The enhancement of late hydration of C3S by TEA and its combination with the secondary hydration of Ca2+ at high alkalinity are the pivotal factors to improve the strength of cementitious composite. A mixture of FNS and 0.03% TEA is subjected to grinding for 90 min, using the obtained micropowder which replaces 20% of the cement, and subsequently, after being excited with 3% Ca(OH)2, the FNS micropowder reaches the quality standards of S95 slag powder. It is worth remarking that the micropowder prepared by mixing FNS with 3% Ca(OH)2 and 0.03% TEA and grinding it for 81 min also meets the S95 standard for slag powder. The larger dosage of FNS in cement is supported by the observed synergy between TEA and Ca(OH)2. This research will provide valuable insights for the expanded application of FNS in construction materials.