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Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all "single mutant active" with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of "single mutant active" ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) "double mutant active" ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities ("singe mutant active" versus "double mutant active") rather than the loosely-defined "generational" (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.

Problems of large settlements and uneven settlements on the road always happen during service stage. Reinforced embankments can reduce these problems. But currently the study on the mechanical properties of reinforced embankments during service stage are so few, and lack of measured data. This study uses numerical simulation and on-site measured data analysis to set up a geogrid creep damage model and traffic load model. Based on the analysis of the mechanical properties of reinforced embankment under the conditions of new test section and widening test section, the influence laws of traffic load amplitude, frequency and driving interval on reinforced embankment are obtained. When the traffic load amplitude is 2q0, there is little difference in settlement between the two test sections, but the settlement ratio gets the maximum value of 0.028 mm/d when the amplitude is 2q0. When the traffic load frequency increases from 1 Hz to 4 Hz, the embankment settlement is in the sudden settlement stage, and the settlement is almost stable after 4 Hz. When the driving interval is greater than 4 s, the rebound value and rebound time are almost stable.

AbstractThe wet desulfurization yields slurry with a moderate temperature and stable supply and thus holds promise for waste heat utilization. However, the corrosive nature and solid particle content of desulfurization slurry from the wet desulfurization process pose potential erosion challenges in waste heat utilization heat exchangers, which is an aspect scarcely explored in the existing literature. The present study aimed to investigate the erosion characteristics in desulfurization slurry heat exchangers using numerical simulation approaches, which can offer crucial insights for practical application in low-grade energy recovery. The result identified slurry mass flow rate and composition as essential factors of erosion distribution. Higher mass flow rates enhance heat transfer efficiency. Still, paradoxically, lower flow rates lead to more pronounced erosion, with a slurry mass flow rate of 35 kg/s resulting in nearly double the erosion compared to the benchmark condition of 56 kg/s. This phenomenon is ascribed to lower fluid velocities in the heat tubes, where the influence of changed velocity diminishes, but slurry exhibits more stable flow at higher mass flow rates. Furthermore, it is also observed that both elevated solids content and particle size lead to an increase in erosion rates. The difference in erosion caused by solid particles with particle sizes in the range of 200–350 µm is marginal. The heat exchanger structure and arrangement also impact fluid flow and erosion. While the difference in fluid flow between vertically and horizontally arranged heat exchangers is negligible, the erosion was significantly reduced to 1/10 in the vertical arrangement. The no-tube-in-window heat exchangers, designed to minimize vibration, exhibit reduced heat transfer capacity alongside diminished and more uniform erosion. The augmentation of tube passes reduces overall erosion but focalizes severe erosion at the slurry inlet, which presents a potential design solution. [ABSTRACT FROM AUTHOR]

In this paper, a calculation method for the tangential velocity solution of radar target based on linear vector method is proposed. It makes full use of the advantage of high precision radial velocity measurement of radar, and realizes the accurate computation of tangential velocity of radar target. Based on the actual measurement capability of continuous wave (CW) radar, the accuracy of the tangential velocity is analyzed. The feasibility of calculation method and accuracy analysis method is verified by simulation experiment and measured data of shooting range.

Every disaster outbreak in human history has either implicitly or explicitly promoted literary creation. The new epidemic sweeping today has become a great catastrophe common to all humankind since the new century. Under the epidemic, what does literature do? It is an inevitable question that must be answered in the post-epidemic era of literary transformation. Therefore, this paper, while feeling grateful for literature’s eagerness to respond to the call of reality and intervene in human psychological healing, creatively uses the concept of human destiny to look at the empirical and theoretical expansion of disaster narratives, explores the comprehensive and diversified expression of such “epidemic” themes in literary creation, and considers how to write about disasters while taking into account aesthetics In addition, we explore the comprehensive and diversified expressions of such “epidemic” themes in literary creation, and consider how disaster writing can take into account the three essential dimensions of individual trauma, collective experience, and identity construction while taking into account aesthetics, to continuously rewrite and even expand the connotation of epidemic literature and actively promote the literary turn in the post-epidemic era.

In order to study the influence of discharge parameters on the electric spark deposition process, an automatic electric spark deposition device is built by a closed-loop control system of discharge parameters. An automatic electric spark deposition test is carried out at different control voltages. By analyzing the effective discharge waveform parameters, transfer efficiency, deposition efficiency, contact force in the deposition process, surface morphology, and cross-sectional morphology of the deposition layer under different control voltages, etc. Analysis of the results shows that changing the control voltage has a direct effect on the number of discharge types in the deposition process. With the appropriate control voltage, better transfer efficiency and deposition quality can be achieved. Contact discharge has a greater effect on material transfer efficiency than other types of discharge. The transfer of the electrode to the material on the workpiece is mainly achieved by contact discharge. Automatic control of discharge parameters can also be applied to automatic control of discharge pulse types. [ABSTRACT FROM AUTHOR]