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OBJECTIVE: TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). METHODS: This is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle. RESULTS: Twenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better. CONCLUSIONS: TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase.
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Mieloma Múltiple , Inhibidores de Proteasoma , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inhibidores de Proteasoma/uso terapéutico , Inhibidores de Proteasoma/farmacocinética , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/administración & dosificación , Administración Oral , Dosis Máxima Tolerada , Resultado del Tratamiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Relación Dosis-Respuesta a Droga , Resistencia a AntineoplásicosRESUMEN
Active disturbance rejection control (ADRC) is widely used in airborne optoelectronic stabilization platforms due to its minimal reliance on the mathematical model of the controlled object. The extended state observer (ESO) is the core of ADRC, which treats internal parameter variations and external disturbances as total disturbances, observes the disturbances as extended states, and then compensates them into the control loop to eliminate their effects. However, the ESO can only achieve a precise estimation of constant or slowly varying disturbances. When the disturbance is periodically changing, satisfactory results cannot be obtained. In this paper, a generalized high-order extended state observer (GHOESO) is proposed to achieve the precise estimation of known frequency sinusoidal disturbance signals and improve disturbance suppression levels. Through numerical simulations, a traditional ESO and GHOESO are compared in terms of disturbance observation capability and disturbance suppression ability for single and compound disturbances based on our prior knowledge of disturbance frequency. The effectiveness of the proposed GHOESO method is verified. Finally, the algorithm is applied to an airborne optoelectronic stabilization platform for a 1°/1 Hz swing experiment on a space hexapod swing table. The experimental results demonstrate the superiority of the GHOESO proposed in this paper.
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This study focuses on enhancing the inference speed of laparoscopic tool detection on embedded devices. Laparoscopy, a minimally invasive surgery technique, markedly reduces patient recovery times and postoperative complications. Real-time laparoscopic tool detection helps assisting laparoscopy by providing information for surgical navigation, and its implementation on embedded devices is gaining interest due to the portability, network independence and scalability of the devices. However, embedded devices often face computation resource limitations, potentially hindering inference speed. To mitigate this concern, the work introduces a two-fold modification to the YOLOv7 model: the feature channels and integrate RepBlock is halved, yielding the YOLOv7-RepFPN model. This configuration leads to a significant reduction in computational complexity. Additionally, the focal EIoU (efficient intersection of union) loss function is employed for bounding box regression. Experimental results on an embedded device demonstrate that for frame-by-frame laparoscopic tool detection, the proposed YOLOv7-RepFPN achieved an mAP of 88.2% (with IoU set to 0.5) on a custom dataset based on EndoVis17, and an inference speed of 62.9 FPS. Contrasting with the original YOLOv7, which garnered an 89.3% mAP and 41.8 FPS under identical conditions, the methodology enhances the speed by 21.1 FPS while maintaining detection accuracy. This emphasizes the effectiveness of the work.
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The accuracy of the line-of-sight of aviation photoelectric optoelectronic stabilization platforms is limited by two factors: external disturbance and sensor noise. An extended state observer (ESO) can effectively improve their anti-interference ability. However, due to the serious problem of gyroscope noise, further improvement of an ESO's disturbance suppression effect is limited. This article proposes a control structure that combines a Kalman filter (KF) and ESO, effectively improving upon the interference suppression ability of a traditional ESO under the influence of noise. Firstly, an ESO was used to observe the lumped disturbance of the system, and then, the observed disturbance was compensated for in the control loop. Secondly, based on the compensation servo control system, the state equation of the system was reconstructed using a Kalman filter. Finally, the reconstructed filtered state variables were iterated onto the universal state observer, achieving the observation of disturbances while filtering out sensor noise. Under the conditions of a laboratory flight simulation turntable, the line-of-sight stability accuracy level was improved under disturbance excitation. It can be seen that the combination of a Kalman filter and extended disturbance observer proposed in this project improves the ESO's anti-interference ability under the influence of noise.
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BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.
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Mieloma Múltiple , Neutropenia , Humanos , Mieloma Múltiple/patología , Talidomida , Dexametasona , Recurrencia Local de Neoplasia/patología , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Objective: To examine the clinical characteristics and anemia-related factors in patients with newly diagnosed multiple myeloma (NDMM), as well as the effect and mechanism of erythroblastic islands (EBIs) and EBI macrophages in NDMM patients with anemia. Methods: We collected and analyzed clinical data to find anemia-related factors. Using flow cytometry, the numbers and ratios of erythroblasts and EBI macrophages were determined. RNA sequencing (RNA-seq) was used to determine the differences of EBI macrophages in NDMM patients with or without anemia. Results: Based on the clinical characteristics of NDMM patients with anemia, MCV, abnormal levels of albumin, osteolytic lesions, and Durie-Salmon (DS) stage are risk factors for anemia. Patients with anemia have fewer erythroblasts, erythroblastic islands (EBIs), and EBI macrophages in their bone marrow than patients without anemia. RNA-seq analysis of EBI macrophages from the bone marrow of patients with and without anemia revealed that macrophages from patients with anemia are impaired and tend to promote the production of interleukin-6, which has been demonstrated to be an essential survival factor of myeloma cells and protects them from apoptosis. Conclusion: In NDMM patients with anemia, EBI macrophages are impaired, which causes anemia in those patients. Our finding highlights the significance of EBI macrophages in anemia in NDMM patients and provides a new strategy for recovery from anemia in these patients.
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An open-label, single-center, phase 2 trial of a second-line therapy comprising low-dose decitabine (DAC) plus bortezomib (Bort) and dexamethasone (DXM) (Dvd) in relapsed and/or refractory multiple myeloma (RRMM) patients was conducted to screen available and inexpensive agents, aiming to work synergistically with other existing anti-melanoma drugs at reasonable prices, and effectively treat Bort and/or Len-refractory patients. Forty-seven patients were included according to the inclusion criteria, with only 1 withdrawal due to premature death. After 17.2 (range: 0.5-24.1) months of median follow-up, all the 46 cases had halted or completed DVd therapy per protocol, with an overall response rate (ORR) of 87.0%. Meanwhile, DVd was indicated to induce high, deep, and lasting responses, dependent of prior treatment or baseline characteristics. The results revealed that DVd is well-tolerated and highly effective in the treatment of first-relapsed RRMM (including those with Bort-refractory disease) patients.
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OBJECTIVE: To investigate the clinical efficacy and safety of percutaneous foraminal endoscopy in the treatment of lumbar lateral recess stenosis in elderly. METHODS: The clinical data of 31 elderly patients with lumbar lateral recess stenosis treated by percutaneous foraminal endoscopic decompression from March 2018 to August 2019 were retrospectively analyzed. Including 16 males and 15 females, aged from 65 to 81 years with an average of (71.13±5.20) years, the course of disease ranged from 3 months to 7 years with an average of (14.36±6.52) months. Visual analogue scale (VAS) and Oswestry disability index (ODI) were used to assess clinical symptom and functional status before operation and 1, 6, 12 months after operation. At the final follow-up, the modified Macnab standard was used to evaluate clinical efficacy. RESULTS: All patients were completed the operation successfully. The operation time was from 75 to 120 min with an average of (97.84±11.22 ) min. All 31 patients were followed up from 12 to 28 months with an average of (17.29±5.56) months. Postoperative lumbago-leg pain VAS and ODI were significantly improved at 1, 6, and 12 months(P<0.01). At the final follow-up, according to the modified Macnab standard to evaluate the effect, 23 got excellent results, 5 good, 3 fair. One patient had severe adhesions between peripheral tissues and nerve root, and postoperative sensory abnormalities in the lower extremities were treated conservatively with traditional Chinese medicine and neurotrophic drugs, which recovered at 2 weeks after surgery. No complications such as nerve root injury and infection occurred. CONCLUSION: The intervertebral foraminal endoscopy technique, which is performed under local anesthesia for a short period of operation, ensures adequate decompression while minimizing complications, and is a safe and effective surgical procedure for elderly patients with lumbar lateral recess stenosis.
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Estenosis Espinal , Masculino , Femenino , Humanos , Anciano , Lactante , Constricción Patológica/cirugía , Estenosis Espinal/cirugía , Descompresión Quirúrgica/métodos , Estudios Retrospectivos , Vértebras Lumbares/cirugía , Endoscopía/métodos , Resultado del TratamientoRESUMEN
At present, the cogging torque of permanent magnet synchronous motors (PMSM) seriously limits the Los pointing accuracy of aviation photoelectric stabilization platforms based on PMSM, which also restricts the requirements of ultra-long-distance and high-precision aviation reconnaissance and detection. For this problem, an off-line iterative learning control (ILC) was designed, and on this basis, a control method of negative effect compensation of disturbance (NECOD) is proposed. Firstly, the "dominant disturbance torque" in the system, that is, the cogging torque with the characteristics of position periodicity, was suppressed by off-line ILC according to different positions. Then, for the "residual disturbance" after compensation, NECOD was used to suppress it. In the constant speed scanning experiment of the aviation photoelectric stabilization platform, the method of combining the off-line iterative learning controller and the negative effect compensation of disturbance (NECOD + ILC) proposed in this paper significantly improved the Los control accuracy of the platform when compared with the classical active disturbance rejection control (ADRC) and ADRC + ILC methods, and the Los pointing error of the constant speed scanning process had only increased by less than 5% when the system had ±15% parameter perturbation. In addition, NECOD + ILC has fewer parameters and is easy to adjust, which is conducive to engineering application and promotion.
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Algoritmos , Aviación , Imanes , TorqueRESUMEN
In the present paper, the effects of thermal insulation cover curing on the rise in temperature of concrete, and further on the mechanical properties of the concrete are measured experimentally. In the experiments, polyurethane foam boards of 100 mm thickness were used for thermal insulation, and three concrete strength grades of C30, C50 and C80, were used as concrete samples. Conventional standard curing, and two heat curing methods with a constant temperature of 40 °C and 60 °C were used for comparison. The pore structure of the cement paste subject to the different curing procedures, including insulation cover curing, heat curing and standard curing, was experimentally measured using mercury intrusion porosimetry. The test results show that rate of increase in compressive strength compared with standard curing is 22-34%, 16-26%, and 23-67%, respectively, for C30, C50, C80 concrete after being subject to 1 to 3 days thermal insulation cover curing in the initial period after concrete casting. As expected, initial heat curing of concrete will result in a reduction in the long-term strength of the concrete. At 28 days, the strength reduction rate compared with standard curing due to the insulation cover curing is 3.1-5.9%, 0.6-3.0%, 0-3.2%, respectively, for C30, C50, C80 concrete. By contrast, the compressive strength reduction compared with standard curing at 28 days is 8.6-10.5%, 8.6-9.1%, 4.7-5.6%, respectively, for C30, C50, C80 concrete after being subject to a constant heat curing of 40 °C and 60 °C in the initial period after concrete casting. Measurement of the pore structure of the paste subject to different curing procedures initially after casting shows that rising curing temperature leads to coarser pores, especially an increase in capillary pore fraction. Among the four curing methods used in the present study, the effect of insulation cover curing and low temperature (40 °C) heat curing on the capillary pore content is small, while the effect of high temperature (60 °C) heat curing is significant.
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Crossmodal information processing in sensory cortices has been reported in sparsely distributed neurons under normal conditions and can undergo experience- or activity-induced plasticity. Given the potential role in brain function as indicated by previous reports, crossmodal connectivity in the sensory cortex needs to be further explored. Using perforated whole-cell recording in anesthetized adult rats, we found that almost all neurons recorded in the primary somatosensory, auditory, and visual cortices exhibited significant membrane-potential responses to crossmodal stimulation, as recorded when brain activity states were pharmacologically down-regulated in light anesthesia. These crossmodal cortical responses were excitatory and subthreshold, and further seemed to be relayed primarily by the sensory thalamus, but not the sensory cortex, of the stimulated modality. Our experiments indicate a sensory cortical presence of widespread excitatory crossmodal inputs, which might play roles in brain functions involving crossmodal information processing or plasticity.
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Corteza Auditiva , Corteza Visual , Animales , Corteza Auditiva/fisiología , Plasticidad Neuronal/fisiología , Neuronas , Ratas , Tálamo , Corteza Visual/fisiologíaRESUMEN
Owing to the problems of guar gum fracturing fluid and conventional slickwater fracturing fluid systems in hydraulic fracturing of tight oil reservoirs, such as bad fracture network capacity, high damage, and low sand-carrying performance, researchers are actively looking for new alternative fracturing fluids. This study takes four commonly used additives for hydraulic fracturing of tight oil and gas reservoirs in western China, including the conventional polyacrylamide friction reducer EM30S, bioglue, thickener CHS-1, and high-viscosity friction reducer HVFR-1. By testing the water solubility, rheological properties, drag reduction, sand-carrying performance, imbibition oil displacement effect, and residue content of the four additives, the best additives suitable for hydraulic fracturing of tight oil and gas reservoirs were selected, and a set of indoor evaluations and the experimental method of screening hydraulic fracturing additives for tight oil and gas reservoirs were established. The research results show that the high-viscosity slickwater system composed of CND + HVFR-1 is more suitable for hydraulic fracturing of tight oil and gas reservoirs. Compared with the other three types of additives, CND + HVFR-1 fracturing fluid has good water solubility, and the dissolution time is less than 30 s. Therefore, in order to save construction time, the CND + HVFR-1 high-viscosity slickwater system is first recommended for field application. The research results of rheological properties show that although the apparent viscosity of high-concentration HVFR-1 + CND is low, the cross value of G' and Gâ³ is the smallest (0.006 Hz) and the elastic modulus is the largest (4.554 Pa) corresponding to 1 Hz. HVFR-1 + CND has better sand-carrying performance when used as a sand-carrying liquid. CND + HVFR-1 not only achieves a friction reduction rate of more than 60% but also has the effect of imbibition oil displacement to improve oil recovery; it can easily break gels, and its low residue content can ensure rapid flowback after construction is completed, and the lower residue content also causes the least damage to the reservoir. At the same time, the establishment of this evaluation method provides a certain reference for other researchers who select fracturing fluids for tight oil and gas reservoirs.
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A measurement system based on a simple double-beam interferometry is built to realize the measurement of air refractive index with high accuracy. The basic principle of the system is that, through measuring the change of optical path difference caused by rapid and smooth vacuumization, measurement of refractive index of air is converted to length measurement. Error correction and signal processing are studied to ensure high-accuracy measurement of the refractive index of air. Three applicable methods are used in system. The system based on the methods realize the subdivision and counting of interference fringe by software with three-error correction, error compensation for the end-window plates' thickness change caused by vacuumization, steady realization of high vacuum conditions. To verify the accuracy and reliability of the system, the measurement results are compared with that obtained from the method based on empirical Edlén's formula. Analysis result shows that the expanded measurement uncertainty of the system is U = 5×10-9, with k = 2. The system can be used to compensate the laser wavelength error caused by the refractive index of air with high accuracy.
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Compared to ordinary Portland cement (OPC), calcium sulfoaluminate cement (CSA) displays very early-age strength and faster heat-releasing rate during hydration. In the present paper, the early hydration heat of CSA paste with influences of supplementary cementitious materials (SCMs) and water to cement (or binder) ratio (w/c) is systematically studied by measuring the heat-releasing rate using a calorimeter. Three traditional SCMs-silica fume (SF), fly ash (FA) and ground granulated blast furnace slag (SL)-were used in the study. A water to cement or binder ratio (w/c) between 0.19 and 0.73 was used in the mixtures. The results show that three exothermic peaks were presented during hydration-dissolution exothermic peak and two reaction exothermic peaks. With the w/c of 0.3, the first and second reaction peaks of the CSA paste are as high as 17.8 times and 4.1 times that of OPC paste, and the occurring time is much earlier than that of the OPC paste. The second reaction peak appears earlier, and the third reaction peak appears later in the pastes with addition of SF than in those without SF. Decreasing w/c can greatly reduce the two reaction peaks of the paste, and it looks that there is a critical value of w/c between 0.24 and 0.30. Above the critical value, the effect of w/c is minor, and below that the influence is obvious. An optimal use of SCMs in CSA pastes under different w/c can greatly decrease the heat releasing while maintaining the required strength.
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Multiple myeloma (MM), a hematological malignancy, has a poor prognosis and requires an invasive procedure. Reports have implicated miRNAs in the diagnosis, treatment and prognosis of hematological malignancies. In our study, we evaluated the expression profiles of miR-17-3p in plasma and bone marrow mononuclear cells of monoclonal gammopathy of undetermined significance (MGUS) and MM patients and healthy subjects. The results showed that the plasma and mononuclear cell expression levels of miR-17-3p in MM patients were higher than those in MGUS patients and normal controls. In addition, the expression of miR-17-3p was positively correlated with diagnostic indexes, such as marrow plasma cell abundance and serum M protein level, and positively correlated with the International Staging System stage of the disease. Receiver operating characteristic curve analysis suggested that miR-17-3p might be a diagnostic index of MM. Moreover, miR-17-3p regulated cell proliferation, apoptosis and the cell cycle through P21 in MM cell lines and promoted MM tumor growth in vivo. Furthermore, we predicted and verified LMLN as a functional downstream target gene of miR-17-3p. Negatively regulated by miR-17-3p, LMLN inhibits MM cell growth, exerting a tumor suppressive function through P21. Taken together, our data identify miR-17-3p as a promising diagnostic biomarker for MM in the clinic and unveil a new miR-17-3p-LMLN-P21 axis in MM progression.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Metaloendopeptidasas/genética , MicroARNs/genética , Mieloma Múltiple/patología , Regulación hacia Arriba , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metaloendopeptidasas/metabolismo , Ratones , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Trasplante de NeoplasiasRESUMEN
BACKGROUND: This study sought to examine the use of glutathione combined with mecobalamin in the prevention and treatment peripheral neuropathy (PN) in multiple myeloma (MM) patients, observe its effectiveness and safety, and explore the risk factors and prognostic factors of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients in the study group were administered 2.4 g of glutathione intravenously once daily 2-3 days before chemotherapy, combined with 500 µg of mecobalamin administered intravenously once every other day until the end of the chemotherapy cycle. Patients who did not use this regimen were selected as a control group. Differences in adverse reactions, treatment efficiency, progression-free survival (PFS), and overall survival (OS) between the two groups were retrospectively analyzed. PFS and OS curves were plotted using the Kaplan-Meier method. The univariate analysis rates were compared using the χ2 test. The multivariate analysis was performed by a logistic regression analysis. The proportional hazard regression model was used for the univariate and multivariate proportional hazards model analyses. RESULTS: The incidence of PN, especially grade 2 and 3 PN, was more decreased in the study group than the control group. The history of diabetes (P=0.032) and the method of bortezomib injection (P=0.043) was found to affect the PN grade. The multivariate logistic regression analysis showed that diabetes was an independent risk factor of PN in MM patients [odds ratio (OR) =3.484, P=0.020]. The Proportional hazards model multivariate analysis showed that extramedullary disease (EMD) [hazard ratio (HR) =2.373, P=0.006] and elevated lactic dehydrogenase (LDH) (HR =1.934, P=0.009) were independent prognostic factors for MM patients. CONCLUSIONS: Glutathione combined with mecobalamin significantly reduced the incidence and severity of CIPN in MM patients, and did not increase the adverse reactions of patients with MM. Diabetes and bortezomib intravenously increased the incidence and severity of PN in patients with MM.
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Antineoplásicos , Mieloma Múltiple , Enfermedades del Sistema Nervioso Periférico , Antineoplásicos/uso terapéutico , Glutatión/uso terapéutico , Humanos , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Estudios Retrospectivos , Vitamina B 12/análogos & derivadosRESUMEN
Reduced osteogenic capacity of bone marrow mesenchymal stem cells (BMSCs) has been causally linked to the development of aplastic anemia. In this work, we aimed to identify novel microRNAs (miRNAs) that participate in the regulation of differentiation of BMSCs from patients with aplastic anemia. We show that miR-144-3p is significantly upregulated in BMSCs from patients with aplastic anemia relative to control equivalents. Depletion of miR-144-3p significantly enhances osteogenic differentiation of BMSCs from patients with aplastic anemia after culturing in osteogenesis-inducing medium. Conversely, overexpression of miR-144-3p blocks osteogenic differentiation of BMSCs. Mechanistically, miR-144-3p negatively regulates the expression of ten-eleven translocation 2 (TET2) in BMSCs. Reduced TET2 expression is associated with a significant decrease in global 5-hydroxymethyl-cytosine (5hmC) levels and osteogenic gene expression. Knockdown of miR-144-3p elevates the expression of TET2 and total 5hmC levels in BMSCs. Silencing of TET2 inhibits the osteogenic differentiation of BMSCs. Overexpression of TET2 reverses miR-144-3p-mediated inhibition of osteogenesis. In addition, there is a significant negative correlation between the expression of miR-144-3p and TET2 in BMSCs from patients with aplastic anemia. Overall, miR-144-3p impairs the osteogenic capacity of BMSCs from patients with aplastic anemia through repression of TET2. Therefore, the targeting of miR-144-3p may be a therapeutic strategy against aplastic anemia.
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Neuronal oscillations in the hippocampus are critical for many brain functions including learning and memory. The underlying mechanism of oscillation generation has been extensively investigated in terms of chemical synapses and ion channels. Recently, electrical synapses have also been indicated to play important roles, as reported in various brain areas in vivo and in brain slices. However, this issue remains to be further clarified, including in hippocampal networks. Here, using the completely isolated hippocampus, we investigated in vitro the effect of electrical synapses on slow CA1 oscillations (0.5 Hz-1.5 Hz) generated intrinsically by the hippocampus. We found that these oscillations were totally abolished by bath application of a general blocker of gap junctions (carbenoxolone) or a specific blocker of electrical synapses (mefloquine), as determined by whole-cell recordings in both CA1 pyramidal cells and fast-spiking cells. Our findings indicate that electrical synapses are required for the hippocampal generation of slow CA1 oscillations.
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Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Sinapsis Eléctricas/efectos de los fármacos , Sinapsis Eléctricas/fisiología , Potenciales de Acción , Animales , Carbenoxolona/farmacología , Uniones Comunicantes , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Mefloquina/farmacología , Neuronas/fisiología , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Sinapsis , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: This study aims to compare the efficacy and adverse reactions of bortezomib for treating newly diagnosed multiple myeloma (MM) through two different administration methods: intravenous (IV) injection and subcutaneous (SC) injection. METHODS: A retrospective analysis was performed in 205 patients with newly diagnosed MM, who were treated by the Department of Hematopathology, Henan Cancer Hospital, from June 2009 to December 2017. These patients were divided into two groups according to the treatment methods: IV injection group, IV injection of bortezomib; SC injection group, SC injection of bortezomib. RESULTS: After the first course of treatment, the effect of very good partial remission (VGPR) or above (≥VGPR) in the IV injection group (IV group) and SC injection group (SC group) was 31.0% and 14.3%, respectively (P=0.004), while the overall response rate (ORR) was 72.0% and 49.5%, respectively (P=0.001). From the 2nd course to the 6th course of treatment, the ORR was not statistically different between these two groups. No significant difference was found in median progression-free survival (37 vs 45 months) and overall survival (63 vs 59 months). A lower frequency of adverse events, especially Grade 3 peripheral neuropathy, was observed in SC group compared with the IV group. CONCLUSION: Compared with IV administration, SC bortezomib can provide a better balance between efficacy and toxicity.
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BACKGROUND: miR-886-5p plays an important role in many tumors, but it has been rarely investigated in multiple myeloma (MM). We studied the expression of miR-886-5p in the plasma of MM patients and in MM cell lines, and evaluated its biological function to identify its potential involvement in MM. METHODS: We recruited 16 subjects including 10 newly diagnosed MM patients who had not received treatment and 6 healthy individuals. The expression of miR-886-5p in plasma and MM cell lines was examined by quantitative reverse transcription polymerase chain reaction. Cell Counting Kit-8, colony formation assay, and 7-amino-actinomycin D/allophycocyanin double staining were performed to detect the function of miR-886-5p in MM cell lines. The expression of Bax and p53 was determined by western blot. RESULTS: The expression of miR-886-5p in the plasma of MM patients was higher than that in normal individuals and its level in MM cell lines was higher than that in peripheral blood mononuclear cells isolated from healthy individuals. miR-886-5p could trigger the cell proliferation and inhibition of apoptosis and affect the cell cycle. CONCLUSION: miR-886-5p triggered MM cell growth and may act as a diagnostic plasma biomarker for MM, potentially contributing to resistance to chemotherapy.