Nowadays, acute leukemia (AL) among children has favorable outcome, yet some of them get refractory or relapse mainly due to drug resistance. High-mobility group box 1 (HMGB1) has been proven to have ...a important role in drug resistance via upregulation of autophagy after chemotherapy treatment in acute leukemia. However, the mechanism how extracellular HMGB1 acts on AL cells and leads to chemoresistance remains elusive.
CCK8 was used to examine the toxicity of chemotherapeutic drug. Elisa was performed to detect the release of HMGB1. Western blot and mRFP-GFP-LC3 adenoviral particles as well as transmission electron microscopy were used to detect the autophagy flux. Western blot and flow cytometry were applied to evaluate the apoptosis. qPCR and western blot were conducted to detect the expression of drug efflux protein. Lentivirus infection was applied to knock down RAGE. In addition, T-ALL NOD/SCID mice xenograft model was used to observe the effect of inhibiting HMGB1/RAGE axis.
We found that extracellular HMGB1 do upregulate autophagy and in the meantime downregulate apoptosis, primarily through interaction with receptor for advanced glycation end products (RAGE). Suppression of RAGE by RNA interference alleviated the level of autophagy and enhanced apoptosis. What's more, HMGB1/RAGE induced autophagy was associated with the activation of ERK1/2 and decreased phosphorylation of mammalian target of rapamycin (mTOR), while HMGB1/RAGE limited apoptosis in a Bcl-2-regulated way mediated by P53. On the other hand, we found that HMGB1/RAGE activated the NF-κB pathway and promoted the expression of P-glycation protein (P-gp) as well as multidrug resistance-associated protein (MRP), both are ATP-binding cassette transporters. In vivo experiment, we found that blocking HMGB1/RAGE axis do have a mild pathological condition and a better survival in T-ALL mice.
HMGB1/RAGE have a important role in drug resistance after chemotherapy treatment, mainly by regulating autophagy and apoptosis as well as promoting the expression of drug efflux protein such as P-gp and MRP. HMGB1/RAGE might be a promising target to cure AL, especially for those met with relapse and refractory.
With advances in minimally invasive ophthalmic surgery (MIOS), novel vitreoretinal surgeries have been proposed to treat retinal diseases. Due to the limitations of manual techniques, surgical robots ...have been introduced for such surgeries. Among ophthalmic surgical robots, the remote center of motion (RCM) mechanism is widely used due to its unique advantages. In this paper, a novel RCM is proposed. Based on the configuration, the kinematics and singularity are analyzed. Subsequently, the planar workspace is analyzed based on ocular anatomy and the requirements of MIOS. The optimal configuration is selected according to the workspace coverage analysis, and the three-dimensional workspace is obtained. Finally, a prototype is built, and the motion is validated. When compared with the related prior RCM mechanisms, the resulting design has qualified workspace coverage, more concise kinematics, and reduced motion coupling with all actuators placed at the distal end of the base. The proposed RCM mechanism is suitable for common MIOS. Future research will further optimize the mechanical structure and control algorithm to improve the accuracy of the prototype.
Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 ...subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.
This study presents an investigation focusing on the advancement of a robot designed for subretinal injections in the context of macular degeneration treatment. The technique of subretinal injection ...surgery stands as the most efficacious approach for the successful transplantation of stem cells into the retinal pigment epithelium layer. This particular procedure holds immense significance in advancing research and implementing therapeutic strategies involving retinal stem cell transplantation. The execution of artificial subretinal surgery poses considerable challenges which can be effectively addressed through the utilization of subretinal injection surgery robots. The development process involved a comprehensive modeling phase, integrating computer-aided design (CAD) and finite element analysis (FEA) techniques. These simulations facilitated iterative enhancements of the mechanical aspects pertaining to the robotic arm. Furthermore, MATLAB was employed to simulate and visualize the robot’s workspace, and independent verification was conducted to ascertain the range of motion for each degree of freedom.
Wearable sensors are gradually enabling decentralized healthcare systems. However, these sensors need to be closely attached to skin, which is unsuitable for long‐term dynamic health monitoring of ...the patients, such as infants or persons with burn injuries. Here, a wearable capacitive sensor based on the capacitively coupled effect for healthcare monitoring in noncontact mode is reported. It consists of a ring‐shaped top electrode, a disk‐shaped bottom electrode, and a porous dielectric layer with low permittivity. This unique design enhanced the capacitively coupled effect of the sensor, which enables a high noncontact detectivity of capacitance change. When an object approaches the sensor, its capacitance change (ΔC/Ci = −38.7%) is 3–5 times higher than that of previously reported sensors. Meanwhile, the sensor is insensitive to the stretching strain and pressure (ΔC/Ci < 5%) due to the unique ring‐shaped electrode and the incompressible closed cells of the porous dielectric material, respectively. Finally, various human physiological signals (pulse and respiratory) are recorded in noncontact mode, where a person wears loose and soft clothes implanted with the sensor. Thus, it is promising to build smart healthcare clothes based on it to develop wearable decentralized healthcare systems.
A wearable capacitive sensor for noncontact healthcare monitoring consists of a ring‐shaped top electrode, a disk‐shaped bottom electrode, and a porous dielectric layer to enhance the capacitively coupled effect. When an object approaches, its capacitance change is 3–5 times higher than that of reported capacitive sensors. Smart clothing implanted with this sensor successfully records the physiological signals by noncontact mode.
Over the past two decades, the rapid evolution of transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis (AS) in the elderly. The prevalence of ...comorbidities in elderly AS patients presents a considerable challenge to the effectiveness and prognosis of patients after TAVR. In this article, we aim to summarize some of the clinical aspects of the current use of TAVR in elderly patients and attempt to highlight the challenges and issues that need further consideration.
In the context of the increasingly intensified innovation competition, improving industrial innovation efficiency is the key to achieving the sustainable development of the old industrial base. This ...paper adopts the thinking of regional research to study the laws of industrial innovation in the old industrial base and takes the lock-in effect as the connection point between the industrial evolution history and industrial innovation efficiency. Based on the perspective of the lock-in effect, the three-stage industrial innovation model, the lock-in effect identification method, and the extended Porter model are creatively constructed. This paper chooses Jilin Province in Northeast China as a case, dissects the evolution history of industrial innovation in detail, and uses super-efficiency DEA, the Granger test, geographical detectors, and the panel regression method for quantitative analysis. The results show the following: (1) The lock-in effect faced by the industrial innovation of the old industrial base is significant, which has an impact on industrial innovation through industrial structure, enterprise composition, management system, and degree of marketization. (2) The lock-in effect causes the old industrial base to fall into an unhealthy circle in which it is difficult for industrial enterprises to obtain sufficient benefits through industrial innovation and the ability of industrial enterprises to absorb regional innovation resources is weakened. (3) The impact mechanism of industrial innovation in the old industrial base is very complex and the lock-in effect factors are not all negative. The improvement of industrial innovation in the old industrial base needs to increase the role of market forces, reform large traditional enterprises, and increase foreign economic ties. However, it also needs policy support, and it should avoid overly radical industrial transformation and enterprise strategies.
We are developing an automated visualization system that helps users combine two or more existing information graphics to form an integrated view. To establish empirical foundations for building such ...a system, we designed and conducted two studies on Amazon Mechanical Turk to understand users’ comprehension and preferences of composite visualization under different conditions (e.g., data and tasks). In Study 1, we collected more than 1,500 textual descriptions capturing about 500 participants’ insights of given information graphics, which resulted in a task-oriented taxonomy of visual insights. In Study 2, we asked 240 participants to rank composite visualizations by their suitability for acquiring a given visual insight identified in Study 1, which resulted in ranked user preferences of visual compositions for acquiring each type of insight. In this article, we report the details of our two studies and discuss the broader implications of our crowdsourced research methodology and results to HCI-driven visualization research.
We describe the construction of a generic natural language query interface to an XML database. Our interface can accept an arbitrary English sentence as a query, which can be quite complex and ...include aggregation, nesting, and value joins, among other things. This query is translated, potentially after reformulation, into an XQuery expression. The translation is based on mapping grammatical proximity of natural language parsed tokens in the parse tree of the query sentence to proximity of corresponding elements in the XML data to be retrieved. Our experimental assessment, through a user study, demonstrates that this type of natural language interface is good enough to be usable now, with no restrictions on the application domain.
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