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Abstract Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Abstract In the realm of large-area trauma flap transplantation, averting ischaemic necrosis emerges as a pivotal concern. Several key mechanisms, including the promotion of angiogenesis, the inhibition of oxidative stress, the suppression of cell death, and the mitigation of inflammation, are crucial for enhancing skin flap survival. Apoptotic bodies (ABs), arising from cell apoptosis, have recently emerged as significant contributors to these functions. This study engineered three-dimensional (3D)-ABs using tissue-like mouse adipose-derived stem cells (mADSCs) cultured in a 3D environment to compare their superior biological effects against 2D-ABs in bolstering skin flap survival. The findings reveal that 3D-ABs (85.74 ± 4.51) % outperform 2D-ABs (76.48 ± 5.04) % in enhancing the survival rate of ischaemic skin flaps (60.45 ± 8.95) % (all p

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins but have been linked to cancer development and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) influences crucial cancer hallmarks through intricate molecular mechanisms, including proliferation, invasion, angiogenesis, apoptosis, and the epithelial-mesenchymal transition (EMT). The current article highlights the involvement of MALAT-1 in drug resistance, making it a potential target to overcome chemotherapy refractoriness. It discusses the impact of MALAT-1 on immunomodulatory molecules, such as major histocompatibility complex (MHC) proteins and PD-L1, leading to immune evasion and hindering anti-tumor immune responses. MALAT-1 also plays a significant role in cancer immunology by regulating diverse immune cell populations. In summary, MALAT-1 is a versatile cancer regulator, influencing tumorigenesis, chemoresistance, and immunotherapy responses. Understanding its precise molecular mechanisms is crucial for developing targeted therapies, and therapeutic strategies targeting MALAT-1 show promise for improving cancer treatment outcomes. However, further research is needed to fully uncover the role of MALAT-1 in cancer biology and translate these findings into clinical applications.

Hardness and Young's modulus are critical indicators in the design of innovative Cu–Ni–Sn–Al alloys with desired elastic and strength properties. In this study, the composition-dependent hardness and Young's modulus in the fcc Cu–Ni–Sn–Al alloys were determined using high-throughput experiments, the CALPHAD (CALculation of PHAse Diagrams) approach, and machine learning (ML) model. By combining the diffusion-couples tool, nanoindentation, and electron probe microanalysis (EPMA) techniques, the 341 sets of composition-related hardness and Young's modulus in the fcc Cu–Ni–Sn–Al system, as well as its sub-binary and sub-ternary systems, were effectively determined. These measured data were subsequently utilized to establish the relationship of Young's modulus and hardness with respect to composition in the fcc Cu–Ni–Sn–Al system through the combined application of CALPHAD and back propagation (BP) artificial neural network machine learning models. A comparison between the two approaches revealed that the ML method achieves higher accuracy in ternary and quaternary alloys compared to the CALPHAD method. The impact of alloying elements on the values of hardness and Young's modulus was analyzed, demonstrating that the Ni content has the largest effect on hardness, while the Young's modulus increases with addition of Ni but decreases with the addition of Al and Sn. Finally, the effects of solute elements on the nanomechanical properties of aged Cu1-x(Ni3Sn)x and Cu–9Ni–6Sn-xAl alloys were examined.

Abstract Background Case-based learning (CBL) methods have gained prominence in medical education, proving especially effective for preclinical training in undergraduate medical education. Tetralogy of Fallot (TOF) is a congenital heart disease characterized by four malformations, presenting a challenge in medical education due to the complexity of its anatomical pathology. Three-dimensional printing (3DP), generating physical replicas from data, offers a valuable tool for illustrating intricate anatomical structures and spatial relationships in the classroom. This study explores the integration of 3DP with CBL teaching for clinical medical undergraduates. Methods Sixty senior clinical medical undergraduates were randomly assigned to the CBL group and the CBL-3DP group. Computed tomography imaging data from a typical TOF case were exported, processed, and utilized to create four TOF models with a color 3D printer. The CBL group employed CBL teaching methods, while the CBL-3DP group combined CBL with 3D-printed models. Post-class exams and questionnaires assessed the teaching effectiveness of both groups. Results The CBL-3DP group exhibited improved performance in post-class examinations, particularly in pathological anatomy and TOF imaging data analysis (P

Frozen ground (FG) plays an important role in global and regional climates and environments through changes in land freeze‒thaw processes, which have been conducted mainly in different regions. However, the changes in land surface freeze‒thaw processes under climate change on a global scale are still unclear. Based on ERA5-Land hourly land skin temperature data, this study evaluated changes in the global FG area, global land surface first freeze date (FFD), last freeze date (LFD) and frost-free period (FFP) from 1950 to 2020. The results show that the current FG areas (1991–2020 mean) in the Northern Hemisphere (NH), Southern Hemisphere (SH), and globe are 68.50 × 106, 9.03 × 106, and 77.53 × 106 km2, which account for 72.4%, 26.8%, and 60.4% of the exposed land (excluding glaciers, ice sheets, and water bodies) in the NH, SH and the globe, respectively; further, relative to 1951–1980, the FG area decreased by 1.9%, 8.8%, and 2.8%, respectively. Seasonally FG at lower latitudes degrades to intermittently FG, and intermittently FG degrades to non-frozen ground, which caused the global FG boundary to retreat to higher latitudes from 1950 to 2020. The annual FG areas in the NH, SH, and globe all show significant decreasing trends (p

Abstract Background The objective of this investigation is to analyze the levels and clinical relevance of serum PYCARD (Pyrin and CARD domain-containing protein, commonly known as ASC—apoptosis-associated speck-like protein containing a caspase activation and recruitment domain), interleukin-38 (IL-38), and interleukin-6 (IL-6) in individuals afflicted with rheumatoid arthritis (RA). Methods Our study comprised 88 individuals diagnosed with RA who sought medical attention at the Affiliated Hospital of Chengde Medical University during the period spanning November 2021 to June 2023, constituting the test group. Additionally, a control group of 88 individuals who underwent health assessments at the same hospital during the aforementioned timeframe was included for comparative purposes. The study involved the assessment of IL-38, IL-6, PYCARD, anti-cyclic citrullinated peptide antibody (anti-CCP), and erythrocyte sedimentation rate (ESR) levels in both groups. The research aimed to explore the correlations and diagnostic efficacy of these markers, employing pertinent statistical analyses for comprehensive evaluation. Results The test group had higher expression levels of PYCARD, IL-6, and IL-38 than the control group (P

Background: How to improve flap necrosis in distal flaps is still a popular topic in clinical flap research. Zingerone (ZIN), as a plant extract, has therapeutic effects on many diseases. The purpose of our study was to explore whether ZIN can promote the survival of ischaemic skin flaps and its specific mechanism. Methods: An ischemic flap model was established in the dorsal region of mice. The changes of angiogenesis, oxidative stress, apoptosis and Keap1-Nrf2 related proteins in the skin flap were detected by immunofluorescence, western blot and qPCR. Overexpression of Keap1 by adeno-associated virus (AAV) was used to study the specific pathway and mechanism. Results: The results showed that ZIN can induce angiogenesis and reduce oxidative stress and apoptosis to promote flap survival. Increased expression of Keap1 reversed the therapeutic effect of ZIN. Conclusion: ZIN activates Nrf2 by inhibiting Keap1 activation, thus promoting angiogenesis and inhibiting oxidative stress and apoptosis.

Abstract The precision of stereopsis and vergence are ultimately limited by internal binocular disparity noise. Here we propose an equivalent noise model with both global and local internal disparity noises to provide a unified explanation of both absolute and relative disparity thresholds. To test this model, we developed a psychophysical procedure to measure the equivalent internal disparity noise by adding external disparity noise to random-Gabor-patch stereograms. We used the method of constant stimuli to measure the minimum and maximum disparity thresholds (Dmin and Dmax) for both absolute and relative disparity. Consistent with previous studies, we found that Dmin thresholds are substantially worse for absolute disparity than for relative disparity. We tested three relative disparity mechanisms: (1) the difference between the monocular separations of targets projecting to the two eyes; (2) the direct measurement of relative disparity; and (3) the difference of absolute disparities of targets. Computing the difference of absolute disparities when detecting relative disparity, Mechanism 3 cancels global noise, resulting in a much lower relative Dmin threshold, and provides a reasonable fit to the experimental data. We also found that the presence of as much as 2400 arcsec of external disparity noise does not appear to affect the Dmax threshold. This observation suggests that Dmax is implicated in a mechanism that disregards the disparity variance of individual items, relying instead on the average disparity across all items, supporting the depth model proposed in our previous study (Ding & Levi, 2021), which posits distinct mechanisms governing Dmin and Dmax thresholds.

Abstract Extracting rare earth elements (REEs) from wastewater is essential for the growth and an eco-friendly sustainable economy. However, it is a daunting challenge to separate individual rare earth elements by their subtle differences. To overcome this difficulty, we report a unique REE nanotrap that features dense uncoordinated carboxyl groups and triazole N atoms in a two-fold interpenetrated metal-organic framework (named NCU-1). Notably, the synergistic effect of suitable pore sizes and REE nanotraps in NCU-1 is highly responsive to the size variation of rare-earth ions and shows high selectivity toward light REE. As a proof of concept, Pr/Lu and Nd/Er are used as binary models, which give a high separation factor of SF Pr/Lu = 796 and SF Nd/Er = 273, demonstrating highly efficient separation over a single step. This ability achieves efficient and selective extraction and separation of REEs from mine tailings, establishing this platform as an important advance for sustainable obtaining high-purity REEs.

It is economically desirable to develop a material that can simultaneously detect and recover uranium. Herein, a CC-bridged two-dimensional metal-covalent organic framework (Cu-BTAN-AO MCOF) was constructed by condensation of metal single crystals with a rigid structure (Cu3(PyCA)3) and cyano monomers (BTAN) via Knoevenagel reaction for simultaneous detection and adsorption of uranium. The amidoxime group within the pore and the presence of unsaturated Cu(I) in the framework facilitate the adsorption of uranyl ions onto the amidoxime group, leading to fluorescence quenching via the photoinduced electron transfer (PET) mechanism, achieving a detection limit of as low as 167 nM uranyl ions. Furthermore, Cu-BTAN-AO demonstrates exceptional efficiency in capturing uranium from wastewater characterized by rapid kinetics and superior selectivity. It is noteworthy that Cu-BTAN-AO is the first example of simultaneous detection, adsorption and chemical reduction of uranium using metal centers and functional groups in MCOF, indicating that Cu-BTAN-AO has great potential for the detection and recovery of uranium-containing wastewater. This design strategy may also be applicable to advancing sensing and energy materials for other important metal ions.

Oral verrucous carcinoma (OVC) and proliferative verrucous leukoplakia (PVL) share similar histological characteristics and may have a common origin. When they appear simultaneously, the risk of malignant transformation in PVL increases. In elderly patients with both conditions, a safe, effective, simple, and minimally invasive treatment is preferable. Photodynamic therapy (PDT), a non-invasive treatment, utilizes specific wavelengths of light to activate photosensitizers, generating reactive oxygen species that selectively target malignant tissues with cytotoxic effects. This case report describes an elderly patient with coexisting extensive leukoplakia, PVL, and OVC, who achieved complete remission with no recurrence at 10 months following PDT. The treatment resulted in a satisfactory clinical outcome, preserving both the appearance and function of the oral cavity.

Abstract Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast‐like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival. It is also found that ABs inhibited cell death and oxidative stress and promoted M1‐to‐M2 polarization in macrophages. Transcriptome sequencing and protein level testing demonstrated that ABs promoted ischaemic flap survival in endothelial cells and macrophages by inhibiting ferroptosis via the KEAP1‐Nrf2 axis. Furthermore, microRNA (miR) sequencing data and in vitro and in vivo experiments demonstrated that ABs inhibited KEAP1 by delivering miR‐339‐5p to exert therapeutic effects. In conclusion, FSCT cell‐derived ABs inhibited ferroptosis, promoted the macrophage M1‐to‐M2 transition via the miR‐339‐5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. These results provide a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.

BackgroundLarge Hemispheric Infarction (LHI) poses significant mortality and morbidity risks, necessitating predictive models for in-hospital mortality. Previous studies have explored LHI progression to malignant cerebral edema (MCE) but have not comprehensively addressed in-hospital mortality risk, especially in non-decompressive hemicraniectomy (DHC) patients.MethodsDemographic, clinical, risk factor, and laboratory data were gathered. The population was randomly divided into Development and Validation Groups at a 3:1 ratio, with no statistically significant differences observed. Variable selection utilized the Bonferroni-corrected Boruta technique (p

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Nowadays, heat, ventilation and air conditioning system are an essential part in a building. In order to achieve energy saving, the heating, ventilation, and air conditioning (HVAC) system have to enhance the designs of their various types of integrated electrical and mechanical components so that to control and operate plant optimally. This paper presented the development of smart sensor controller for heat, ventilation and air conditioning system by using Arduino. Smart sensor controller can be regarded a device that can control the speed of the motor based on the number of person detected by the infrared sensor. The motor used in this project will represent the fan motor of the normal air conditioner. The objective of the smart sensor controller is to prove the energy saving concept and to reduce the electrical consumption for the HVAC system. The experiment conducted show that the implementation of the smart sensor controller provides an average energy saving efficiency of 45.13 % compare to HVAC system without smart sensor controller.

The dwindling reserves of fossil fuels have spurred the expansion of photovoltaic power systems, widely regarded as an alluring solution. Yet, a formidable challenge arises when it comes to optimizing the output of PV systems exposed to irregular irradiance stemming from external environmental factors. Consequently, this research endeavors to advocate the use of the Moth Flame Optimization (MFO) algorithm to search for the highest power output of a solar energy harvesting system. The distinctive behavior of moths proves instrumental in thorough searching of the feasible space, mitigating the risk of entrapment in local optima. To evaluate its efficacy, this algorithm’s performance is validated by comparing its outcomes with those of the Butterfly Optimization Algorithm (BOA). Both algorithms are subjected to experimentation to search for the Global Maximum Power Points (GMPPs) of the PV system under two distinct Partial Shading Condition (PSC) scenarios: Case 1 and Case 2. The results indicate that BOA tends to produce outcomes with a broader data dispersion range relative to the mean, unlike MFO. Specifically, for Case 1, the standard deviation values for MFO and BOA are 2.327040E−02 and 5.777913E−02, respectively, while for Case 2, they are 5.0567340E−02 and 8.519362E−02, respectively. Hence, the proposed approach demonstrates faster and more precise convergence.

The reduction of operation and maintenance costs as well as the improvement of reliability of wind energy conversion systems are of top priorities in the renewable energy industry as the demand for wind energy continuously grow tremendously. With that, the condition monitoring system (CMS) plays a crucial role in maximizing the potential of wind energy in generating electricity. Therefore, this review paper vividly captures the fact that the recent advancements in embedded control in CMS in wind energy conversion systems are able deliver tangible benefits to the renewable energy technology (RET) industry as a whole. It is proven that CMS based maintenance is deemed to be more suitable in multiple aspects with fewer drawbacks, as compared to scheduled and corrective maintenance. In this review paper, an attempt to evaluate the viability of CMS is being made. The main purpose is to shed some light on the significant contributions provided by CMS in shortening the downtime and increasing the production rate of the wind energy conversion system. Forthcoming promising applications with good potential to surpass the recent dilemmas were also explored and analyzed at the end of this paper.

Abstract Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome‐host‐drug interactions. Here, it is showed that low‐dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti‐programmed death‐1 (anti‐PD‐1) therapy without causing intestinal toxicity. Mechanistically, low‐dose chemotherapy causes DNA damage restricted to highly‐proliferative ileal epithelial cells, resulting in the accumulation of cytosolic dsDNA and the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2‐dependent IL‐18 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, impairing the local antimicrobial host defense and resulting in ileal microbiome change. Intestinal epithelium‐specific knockout of AIM2 in mice significantly attenuates CPT‐11‐caused IL‐18 secretion, Paneth cell dysfunction, and ileal microbiome alteration. Moreover, AIM2 deficiency in mice or antibiotic microbial depletion attenuates chemotherapy‐augmented antitumor responses to anti‐PD1 therapy. Collectively, these findings provide mechanistic insights into how chemotherapy‐induced genomic stress is transduced to gut microbiome change and support the rationale of applying low‐dose chemotherapy as a promising adjuvant strategy in cancer immunotherapy with minimal toxicity.

Millimeter Wave (mm-wave) technology is a prerequisite to ensure ubiquitous wireless communication, given the rapid growth of the Internet of Things (IoT) infrastructure that integrates emerging technologies such as virtual reality (VR), artificial intelligence (AI), etc. However, to ensure the future growth and acceptance of this technology, a highly efficient mm-wave compatible transceiver hardware is essential to be developed. A low noise amplifier (LNA) is one of the modules that directly influences the performance of an IoT transceiver. Numerous approaches have thus far been deployed in LNA design, such as differential cascode topology, active inductor, embedded input balun, transformer-based feedback, current reuse, stacked structure, and body biasing, to standardize various parameters e.g. die area, gain, noise figure, linearity, and power efficiency. Although complementary metal–oxide–semiconductor (CMOS) technology-based current LNA architectures in the mm-wave range suffer from substrate losses and device parasitic, it is regarded as a competitive solution for THz communication due to its inherent benefits of low-cost integrity, which promotes CMOS LNA design as an emerging research topic. This review presents several CMOS LNA architectures and perceives the adjustments of circuit topologies to ratify LNA structures in mm-wave applications. Furthermore, various state-of-the-art LNA design features are compared to envision CMOS LNA design directions and identify apposite circuit techniques suitable for the imminent 6G communication protocol. Therefore, this review will serve as a comparative study and reference for the future LNA design for the mm-wave sensor transceiver applications.

BackgroundPulmonary vein isolation with wide antral ablation leads to better clinical outcomes for the treatment of atrial fibrillation, but the isolation lesion is invisible in conventional cryoballoon ablation. In this study, we aim to investigate the efficacy of the wide pulmonary vein isolation technique that includes the intervenous carina region, guided by high-density mapping, compared with pulmonary vein isolation alone without the mapping system.MethodsWe conducted a propensity score–matched comparison of 74 patients who underwent a wide cryoballoon ablation guided by high-density mapping (mapping group) and 74 controls who underwent conventional cryoballoon ablation in the same period (no-mapping group). The primary outcome was a clinical recurrence of documented atrial arrhythmias for >30 s during the 1-year follow-up.ResultsOf 74 patients in the mapping group, residual local potential in the pulmonary vein antrum was found in 30 (40.5%) patients, and additional cryothermal applications were performed to achieve a wide pulmonary vein isolation. Compared with the no-mapping group, the use of the mapping system in the mapping group was associated with a longer fluoroscopic time (26.97 ± 8.07 min vs. 23.76 ± 8.36 min, P = 0.023) and greater fluoroscopic exposure [339 (IQR181–586) mGy vs. 224 (IQR133–409) mGy, P = 0.012]. However, no significant differences between the two groups were found in terms of procedural duration and left atrial dwell time (104.10 ± 18.76 min vs. 102.45 ± 21.01 min, P = 0.619; 83.52 ± 17.01 min vs. 79.59 ± 17.96 min, P = 0.177). The rate of 12-month freedom from clinical atrial arrhythmia recurrence was 85.1% in the mapping group and 70.3% in the no-mapping group (log-rank P = 0.029).ConclusionVoltage and pulmonary vein potential mapping after cryoballoon pulmonary vein isolation can identify residual potential in the pulmonary vein antrum, and additional cryoablation guided by mapping leads to improved freedom from atrial arrhythmias compared with conventional pulmonary vein isolation without the mapping system.Clinical Trial Registration NumberChiCTR2200064383.