Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. METHODS: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. RESULTS: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). CONCLUSIONS: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.

Comparative transcriptome analyses under individual and combined nutrient starvations provide insights into N/P/K interactions in rice.

Crops often suffer from simultaneous limitations of multiple nutrients in soils, including nitrogen (N), phosphorus (P) and potassium (K), which are three major macronutrients essential for ensuring growth and yield. Although plant responses to individual N, P, and K deficiency have been well documented, our understanding of the responses to combined nutrient deficiencies and the crosstalk between nutrient starvation responses is still limited. Here, we compared the physiological responses in rice under seven kinds of single and multiple low nutrient stress of N, P and K, and used RNA sequencing approaches to compare their transcriptome changes. A total of 13,000 genes were found to be differentially expressed under all these single and multiple low N/P/K stresses, and 66 and 174 of them were shared by all these stresses in roots and shoots, respectively. Functional enrichment analyses of the DEGs showed that a group of biological and metabolic processes were shared by these low N/P/K stresses. Comparative analyses indicated that DEGs under multiple low nutrient stress was not the simple summation of single nutrient stress. N was found to be the predominant factor affecting the transcriptome under combined nutrient stress. N, P, or K availability exhibited massive influences on the transcriptomic responses to starvation of other nutrients. Many genes involved in nutrient transport, hormone signaling, and transcriptional regulation were commonly responsive to low N/P/K stresses. Some transcription factors were predicted to regulate the expression of genes that are commonly responsive to N, P, and K starvations. These results revealed the interactions between N, P, and K starvation responses, and will be helpful for further elucidation of the molecular mechanisms underlying nutrient interactions.

Arabidopsis CAMTA3/SR1 is involved in drought stress tolerance and ABA signaling.

Calcium/calmodulin signals are important for various cellular and physiological activities in plants. Calmodulin binding transcription activators also named Signal Responsive (SR) proteins belong to an important calcium/calmodulin-dependent transcription factor family that plays critical roles in stress responses. However, the role of SRs in abscisic acid (ABA) regulated plant responses to drought stress is largely unknown. Here, we characterized the role of Arabidopsis SR1 in drought stress tolerance and ABA response by analyzing the phenotypes of SR1 knockout and SR1-overexpression plants. sr1 mutants which accumulate salicylic acid (SA) were found more sensitive to drought stress and showed a higher water loss rate as compared with wild-type. By contrast, SR1-overexpression lines exhibited increased drought tolerance and less water loss than wild-type. Furthermore, sr1 mutants showed reduced ABA response in seed germination, root elongation, and stomatal closure, while SR1-overexpression lines displayed more sensitive to ABA than wild-type. In addition, the drought-sensitive and ABA-insensitive phenotypes of sr1 mutants were recovered by diminishing SA accumulation via knockouts of SA synthesizer ICS1 or activator PAD4, or through expression of SA-degrading enzyme NahG. Some drought/ABA-responsive genes exhibited differentially expressed in sr1 mutants and SR1-overexpression plants. These results suggest that SR1 plays a positive role in drought stress tolerance and ABA response, and drought/ABA responses are antagonized by SA accumulation that is negatively regulated by SR1.

Molecular regulation of zinc deficiency responses in plants.

Zinc (Zn) is an essential micronutrient for plants and animals. Because of its low availability in arable soils worldwide, Zn deficiency is becoming a serious agricultural problem resulting in decreases of crop yield and nutritional quality. Plants have evolved multiple responses to adapt to low levels of soil Zn supply, involving biochemical and physiological changes to improve Zn acquisition and utilization, and defend against Zn deficiency stress. In this review, we summarize the physiological and biochemical adaptations of plants to Zn deficiency, the roles of transporters and metal-binding compounds in Zn homeostasis regulation, and the recent progresses in understanding the sophisticated regulatory mechanisms of Zn deficiency responses that have been made by molecular and genetic analyses, as well as diverse 'omics' studies. Zn deficiency responses are tightly controlled by multiple layers of regulation, such as transcriptional regulation that is mediated by transcription factors like F-group bZIP proteins, epigenetic regulation at the level of chromatin, and post-transcriptional regulation mediated by small RNAs and alternative splicing. The insights into the regulatory network underlying Zn deficiency responses and the perspective for further understandings of molecular regulation of Zn deficiency responses have been discussed. The understandings of the regulatory mechanisms will be important for improving Zn deficiency tolerance, Zn use efficiency, and Zn biofortification in plants.

Molecular Dynamics Simulation of Methane Hydrate Decomposition in the Presence of Alcohol Additives.

The decomposition process of methane hydrate in pure water and methanol aqueous solution was studied by molecular dynamics simulation. The effects of temperature and pressure on hydrate structure and decomposition rate are discussed. The results show that decreasing pressure and increasing temperature can significantly enhance the decomposition rate of hydrate. After adding a small amount of methanol molecules, bubbles with a diameter of about 2 nm are formed, and the methanol molecules are mainly distributed at the gas-liquid interface, which greatly accelerates the decomposition rate and gas-liquid separation efficiency. The radial distribution function and sequence parameter analysis show that the water molecules of the undecomposed hydrate with ordered ice-like configuration at a temperature of 275 K evolve gradually into a long-range disordered liquid structure in the dynamic relaxation process. It was found that at temperatures above 280 K and pressures between 10 atm and 100 atm, the pressure has no significant effect on hydrate decomposition rate, but when the pressure is reduced to 1 atm, the decomposition rate increases sharply. These findings provided a theoretical insight for the industrial exploitation of hydrates.

[Finite element method-based optimal design of MRI permanent magnet].

This paper presents a simulation method to study and improve the technology of designing magnets. With the finite element method, it analyzes the magnetic field distribution of the magnet model constructed by CAD software. Based on the distribution characteristics of magnetic field, the redundancy parts of the magnet configuration are removed accurately. The experiment results show that this method can significantly lighten the magnet.

[Research on designing MRI permanent magnet].

Based on the theory of magnet circuits, the paper introduces the process of designing MRI (Magnetic Resonance Imaging) permanent magnet. The measurement of magnet properties is improved by simulation technology. In order to increase the magnetic field homogeneity. We have designed a shim-loop and a trapeziform shim-board to optimize the magnetic field distribution. The results of both simulation analysis and experiments show that the innovative design improves magnetic field properties significantly and the magnet structure accords with the technology requirements.

A method for artifact correction due to demodulation phase errors in magnetic resonance imaging.

In the process that MR signal is quadrature demodulated, the initial phases of sinusoid and cosinusoid used as demodulation reference signal exist errors, which results in artifacts in the image. It is typically overcome through precise control of the initial phases with the help of the special hardware, but the errors are not reduced completely. In this work, a method based on reference scan is proposed. Reference scan without frequency encoding gradient and phase encoding gradient is executed before FSE sequence, and an echo train is acquired. The phase errors of sinusoid and cosinusoid that are used to demodulate each echo in the reference echo train are calculated. Then the k-space data of image is corrected by these errors and artifacts are removed. The experiments using 0.35T MRI system demonstrate the effectiveness of this method.

[A rapid method of eddy current compensation in magnetic resonance imaging systems].

Imaging objects are spatially encoded by gradient magnetic fields in magnetic resonance imaging systems. The eddy current caused by rapid switches of gradient fields will result in artifacts in the images. A method of eddy current compensation based on pre-emphasis of gradient current is presented in this thesis. The compensation parameters are acquired rapidly utilizing Faraday's induction theorem and data fitting method. The experiments prove that the method is efficient for reduction of the debugging time and for the improvement of the image quality.