Pan-cancer analysis predict that FAT1 is a therapeutic target and immunotherapy biomarker for multiple cancer types including non-small cell lung cancer.

FAT1, a substantial transmembrane protein, plays a pivotal role in cellular adhesion and cell signaling. Numerous studies have documented frequent alterations in FAT1 across various cancer types, with its aberrant expression being linked to unfavorable survival rates and tumor progression. In the present investigation, we employed bioinformatic analyses, as well as in vitro and in vivo experiments to elucidate the functional significance of FAT1 in pan-cancer, with a primary focus on lung cancer. Our findings unveiled FAT1 overexpression in diverse cancer types, including lung cancer, concomitant with its association with an unfavorable prognosis. Furthermore, FAT1 is intricately involved in immune-related pathways and demonstrates a strong correlation with the expression of immune checkpoint genes. The suppression of FAT1 in lung cancer cells results in reduced cell proliferation, migration, and invasion. These collective findings suggest that FAT1 has potential utility both as a biomarker and as a therapeutic target for lung cancer.

ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer.

Purpose: Lung cancer is a major cause of morbidity and mortality globally, necessitating the identification of predictive markers for effective immunotherapy. Mutations in SWI/SNF chromatin remodeling complex genes were reported sensitized human tumors to immune checkpoint inhibitors (ICIs), but the underlying mechanisms are unclear. This study aims to investigate the association between SWI/SNF gene ARID1B mutation and ICI response in non-small cell lung cancer (NSCLC) patients, to explore the functional consequences of ARID1B mutation on DNA damage response, immune microenvironment, and cGAS-STING pathway activation. Methods: TCGA LUAD, LUSC, and AACR GENIE data are analyzed to assess ARID1B mutation status in NSCLC patients. Prognostic analysis evaluates the effect of ARID1B mutation on patient outcomes. In vitro experiments carried to investigate the consequences of ARID1B knockdown on DNA damage response and repair. The immune microenvironment is assessed based on ARID1B expression, and the relationship between ARID1B and the cGAS-STING pathway is explored. Results: ARID1B mutation frequency is 5.7% in TCGA databases and 4.4% in the AACR GENIE project. NSCLC patients with ARID1B mutation showed improved overall and progression-free survival following ICIs treatment. ARID1B knockdown in lung cancer cell lines enhances DNA damage, impairs DNA repair, alters chromatin accessibility, and activates the cGAS-STING pathway. ARID1B deficiency is associated with immune suppression, indicated by reduced immune scores, decreased immune cell infiltration, and negative correlations with immune-related cell types and functions. Conclusion: ARID1B mutation may predict improved response to ICIs in NSCLC patients. ARID1B mutation leads to impaired DNA damage response and repair, altered chromatin accessibility, and cGAS-STING pathway activation. These findings provide insights into ARID1B's biology and therapeutic implications in lung cancer, highlighting its potential as a target for precision medicine and immunotherapy. Further validation and clinical studies are warranted.

Genomic analysis of hypoxia and mitophagy related genes with prognosis and characterization of the immune microenvironment in LUAD.

Background: Lung adenocarcinoma (LUAD) stands as a prominent subtype within the realm of non-small cell lung cancer and constitutes a primary contributor to cancer-related mortality on a global scale. Notably, hypoxia, a prevalent attribute within solid tumor environments, and mitophagy, a selective manifestation of autophagy dedicated to the removal of damaged mitochondria, have risen to prominence as pivotal factors influencing the initiation and advancement of tumorigenesis. Methods: This investigation harnessed publicly accessible genomic datasets encompassing LUAD patients to delineate genes linked to hypoxia and mitophagy, termed hereafter as hypoxia and mitophagy-related genes (HMRGs). Large-scale repositories furnished both gene expression profiles and clinical particulars. The expression profiles of HMRGs were meticulously scrutinized across 1,093 LUAD specimens, leveraging resources such as The Cancer Genome Atlas and Gene Expression Omnibus datasets. A methodical exploration of HMRG patterns within LUAD led to the discernment of two distinct molecular subtypes. Moreover, a discernible correlation emerged between the subtypes and their respective clinical attributes. A risk scoring system was formulated to prognosticate overall survival (OS) and therapeutic responsiveness in LUAD patients. Subsequently, the reliability of this scoring system was authenticated, and a nomogram was adopted to refine the clinical utility range of the risk score. The proliferation and migration impacts of KRT8 on LUAD cells were evaluated through cck8 assays, edu assays, and transwell assays, the results were further validated in vivo. Results: Elevated risk scores were indicative of unfavorable OS probabilities. Furthermore, these risk scores exhibited associations with immune checkpoints and chemotherapeutic drug sensitivity. Collectively, our exhaustive analysis of HMRGs in LUAD patients unveiled their conceivable participation in configuring the multifaceted tumor microenvironment, encompassing clinicopathological attributes and prognosis. A sequence of experiments illuminated the pro-proliferative and pro-migratory attributes of KRT8 in vitro and vivo, thus underscoring its carcinogenic potential. Conclusions: In this study, we have unearthed innovative gene signatures tethered to HMRGs, which harbor prognostic implications concerning patient outcomes. These insights hold potential for steering the development of targeted therapeutic modalities tailored for LUAD.

Seven preoperative factors have strong predictive value for postoperative pneumonia in patients undergoing thoracoscopic lung cancer surgery.

Background: Postoperative pneumonia (POP) is a hospital acquired pneumonia that occurs >48 hours after tracheal intubation. The diagnosis of POP should be based on clinical and radiological findings within 30 days after surgery. It is a common complication after thoracoscopic surgery for lung cancer patients. However, the specific impact of preoperative comorbidities on the incidence of POP remains unclear. This study aimed to analyze the preoperative data of patients with lung cancer to help surgeons predict the risk of incidence of POP after thoracoscopic lung resection. Methods: This study is a prospective study that included patients with lung cancer who were scheduled for thoracoscopic surgery in 1 year. All cases came from two medical centers. Preoperative demographic information, tumor information, preoperative comorbidities, quality of life scores, and incidence of POP were collected. Variables were screened by univariate analysis and multivariate regression. Finally, a prediction model was constructed. A total of 53 preoperative factors were included as candidate predictors. The binary outcome variable was defined as the presence or absence of POP. The incidence of POP was the primary outcome variable. The predictive performance of the model was verified internally through 1,000 iterations of bootstrap resampling. Results: A total of 1,229 patients with lung cancer who underwent thoracoscopic surgery were enrolled. In addition, 196 cases (15.95%) had POP; 1,025 (83.40%) patients had comorbid conditions. The total number of comorbidity diagnosed in all samples was 2,929. The prediction model suggested that patients with advanced age, high body mass index (BMI), smoking, poor physical condition, respiratory diseases, diabetes, and neurological diseases were more likely to develop POP. The area under the curve (AUC) and Brier scores were 0.851 and 0.091, respectively. The expected and observed results were in strong agreement, according to the likelihood of POP calibration curve. Conclusions: The constructed model is capable of evaluating the probability of POP occurrence in patients with lung cancer. Seven preoperative factors in patients with lung cancer were found to be associated with increased probability of having pneumonia after thoracoscopic lung resection. This model can help predict the incidence of POP after surgery.

Apatinib added when NSCLC patients get slow progression with EGFR-TKI: A prospective, single-arm study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) acquired resistance was an inevitably events in NSCLC treatment. AIMS: Intending to overcome the acquired resistance of EGFR-TKI. MATERIALS & METHODS: A clinical trial was, we enrolled 12 patients who were slowly progressing on first-generation EGFR-TKI, and added apatinib when the patients got slow progression. RESULTS: Seven patients were included in the efficacy analysis. The median PFS2 of apatinib combined with EGFR-TKI was 8.2 months (95% CI, 7.3 m-NA), and the total PFS reached 20.9 months (95% CI, 17.3 m-NA) when plus PFS1. All the adverse events were manageable. The median PFS was significantly longer for circulating tumor DNA (ctDNA)-cleared patients (8.4 months; 95% CI, 8.2-NA) than for those ctDNA not cleared (7.1 months; 95% CI, 6.9-NA) (p = 0.0082). DISCUSSION: The addition of apatinib did improve the duration of first-generation EGFR-TKI use, and the duration was better than the first-line use of third-generation EGFR-TKI. CONCLUSION: The addition of apatinib when the patients got slow progression after initial EGFR-TKI therapy may be a good treatment option and the side effects are controllable. It is possible to monitor treatment efficacy using ctDNA.

Adaptive Dynamic Analysis of MEMS Gyroscope Random Noise Based on PID-DAVAR.

As a MEMS gyroscope is susceptible to environmental interference, its performance is degraded due to random noise. Accurate and rapid analysis of random noise of MEMS gyroscope is of great significance to improve the gyroscope's performance. A PID-DAVAR adaptive algorithm is designed by combining the PID principle with DAVAR. It can adaptively adjust the length of the truncation window according to the dynamic characteristics of the gyroscope's output signal. When the output signal fluctuates drastically, the length of the truncation window becomes smaller, and the mutation characteristics of the intercepted signal are analyzed detailed and thoroughly. When the output signal fluctuates steadily, the length of the truncation window becomes larger, and the intercepted signals are analyzed swiftly and roughly. The variable length of the truncation window ensures the confidence of the variance and shortens the data processing time without losing the signal characteristics. Experimental and simulation results show that the PID-DAVAR adaptive algorithm can shorten the data processing time by 50%. The tracking error of the noise coefficients of angular random walk, bias instability, and rate random walk is about 10% on average, and the minimum error is about 4%. It can accurately and promptly present the dynamic characteristics of the MEMS gyroscope's random noise. The PID-DAVAR adaptive algorithm not only satisfies the requirement of variance confidence but also has a good signal-tracking ability.

Weak Capacitance Detection Circuit of Micro-Hemispherical Gyroscope Based on Common-Mode Feedback Fusion Modulation and Demodulation.

As an effective capacitance signal produced by a micro-hemisphere gyro is usually below the pF level, and the capacitance reading process is susceptible to parasitic capacitance and environmental noise, it is highly difficult to acquire an effective capacitance signal. Reducing and suppressing noise in the gyro capacitance detection circuit is a key means to improve the performance of detecting the weak capacitance generated by MEMS gyros. In this paper, we propose a novel capacitance detection circuit, where three different means are utilized to achieve noise reduction. Firstly, the input common-mode feedback is applied to the circuit to solve the input common-mode voltage drift caused by both parasitic capacitance and gain capacitance. Secondly, a low-noise, high-gain amplifier is used to reduce the equivalent input noise. Thirdly, the modulator-demodulator and filter are introduced to the proposed circuit to effectively mitigate the side effects of noise; thus, the accuracy of capacitance detection can be further improved. The experimental results show that with the input voltage of 6 V, the newly designed circuit produces an output dynamic range of 102 dB and the output voltage noise of 5.69 nV/√Hz, achieving a sensitivity of 12.53 V/pF.

Design and Optimization of Hemispherical Resonators Based on PSO-BP and NSGA-II.

Although one of the poster children of high-performance MEMS (Micro Electro Mechanical Systems) gyroscopes, the MEMS hemispherical resonator gyroscope (HRG) is faced with the barrier of technical and process limits, which makes it unable to form a resonator with the best structure. How to obtain the best resonator under specific technical and process limits is a significant topic for us. In this paper, the optimization of a MEMS polysilicon hemispherical resonator, designed by patterns based on PSO-BP and NSGA-II, was introduced. Firstly, the geometric parameters that significantly contribute to the performance of the resonator were determined via a thermoelastic model and process characteristics. Variety regulation between its performance parameters and geometric characteristics was discovered preliminarily using finite element simulation under a specified range. Then, the mapping between performance parameters and structure parameters was determined and stored in the BP neural network, which was optimized via PSO. Finally, the structure parameters in a specific numerical range corresponding to the best performance were obtained via the selection, heredity, and variation of NSGAII. Additionally, it was demonstrated using commercial finite element soft analysis that the output of the NSGAII, which corresponded to the Q factor of 42,454 and frequency difference of 8539, was a better structure for the resonator (generated by polysilicon under this process within a selected range) than the original. Instead of experimental processing, this study provides an effective and economical alternative for the design and optimization of high-performance HRGs under specific technical and process limits.

Whole-exome sequencing in primary pulmonary synovial sarcoma misdiagnosed as mesothelioma: A case report and literature review.

Synovial sarcoma is a highly malignant tumor that accounts for 10% of all soft tissue sarcomas. Primary pulmonary synovial sarcoma (PPSS) is extremely rare, and its prognosis is poor. A diagnosis is usually established after other primary lung malignancies or metastatic extrathoracic sarcomas have been excluded. Therefore, it is often misdiagnosed. In this study, we report the case of a 38-year-old woman who was misdiagnosed as having pleural mesothelioma and finally endured surgery to remove the tumor. The tumor showed SYT-SSX fusion transcripts and was diagnosed as PPSS after combining histopathological and immunohistochemical analyses. Finally, we determined some biomarkers through whole-exome sequencing (WES) to improve the diagnosis and treatment strategies.

Neoadjuvant camrelizumab and chemotherapy in patients with resectable stage IIIA squamous non-small-cell lung cancer: Clinical experience of three cases.

Neoadjuvant immunochemotherapy has attracted much attention as a treatment for locally advanced non-small-cell lung cancer. However, there is scarce evidence of the safety and efficacy of camrelizumab as neoadjuvant in lung cancer. Here, we present three patients who were diagnosed with IIIA squamous non-small-cell lung cancer from September to December in 2020 and received two cycles of neoadjuvant camrelizumab plus nab-paclitaxel and nedaplatin, followed by surgical resection. All three patients had a reduction in the tumor size on CT image and not delayed planned surgery. We did not observe grade 3 or 4 adverse events. Two of the three patients achieved a major pathological response (MPR), including one complete tumor regression of the primary lung tumor. Multiplex fluorescent immunohistochemistry revealed that CD8+ T cells, FoxP3+ regulatory T cells, and PD-L1 expression on immune cells in the surgical specimen were much higher than in the pretreatment biopsy sample in patients with MPR. This was not observed in the patient without MPR. Camrelizumab plus chemotherapy could potentially be a neoadjuvant regimen for resectable IIIA squamous non-small-cell lung cancer, with a high MPR proportion, and did not compromise surgical procedure. Our findings should be validated in a future randomized clinical trial.

Survival Benefits for Pulmonary Adenocarcinoma With Malignant Pleural Effusion After Thoracoscopic Surgical Treatment: A Real-World Study.

Objectives: Malignant cells in the pleural fluid or pleural metastasis are classified as stage IV non-small cell lung cancer. Radical surgery is generally considered not suitable for such patients. The aim of our study was to discuss the effectiveness of video-assisted thoracoscopic surgery (VATS) in such patients. Methods: A retrospective analysis of the clinical records of 195 patients was performed. These patients were all diagnosed with locally advanced pulmonary adenocarcinomas with malignant pleural effusion (MPE, M1a) but no distant organ metastasis. The 195 patients included 96 patients who underwent VATS plus chemotherapy and 99 patients who received thoracic drainage plus chemotherapy. The baseline characteristics of the patients included age, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) score, and number of chemotherapy cycles (2-4 cycles or >4 cycles); we also analyzed clinical characteristics including the specific surgical options of the VATS group. Results: In multivariate analysis, when compared to the thoracic drainage group, the VATS group remained significantly associated with the overall survival [HR=0.480 (95%CI 0.301-0.765)]; when compared to the lobectomy, the sub-lobectomy and the palliative surgery, remained significantly associated with the overall survival [HR=0.637 (95%CI 0.409-0.993) and HR=0.548 (95%CI 0.435-0.832), respectively]. The median survival time (MST) of patients who underwent VATS (n = 96, 49.2%) was 25 months (95% CI 22.373-27.627) whereas the patients who received thoracic drainage (n = 99, 50.8%) was 11 months (95% CI 9.978-12.022). For patients who underwent VATS, the MST of patients who received a lobectomy (n = 50, 52.1%) was 27 months (95% CI 22.432-31.568), the MST of patients who received a sub-lobectomy plus pleurodesis (n = 26, 27.1%) was 27 months (95% CI 19.157-34.843), and the MST of patients who received only pleurodesis (n = 20, 20.8%) was 12 months (95% CI 7.617-16.383). Conclusion: For pulmonary adenocarcinomas with MPE, receiving a lobectomy or sub-lobectomy plus pleurodesis with VATS was associated with improved survival compared with patients who only received thoracic drainage and chemotherapy. Our results and previously published data may justify the use of VATS for treating pulmonary adenocarcinomas with MPE.

To Explore the Effects of Acupuncture and Medical Treatment at Different Times on the Gastrointestinal Reaction and White Blood Cell Count of Patients with Lung Cancer Chemotherapy.

Objective: To explore and analyze the effects of acupuncture and medical treatment at different times on the gastrointestinal reaction and leukocyte count of patients with lung cancer undergoing chemotherapy. Methods: Select 224 lung cancer chemotherapy patients admitted to our hospital and randomly divide them into three groups: control group (n = 76), study 1 group (n = 78), and study 2 group (n = 70). The control group was treated with tropisetron hydrochloride for 30 minutes before chemotherapy. Study 1 group was given tropisetron hydrochloride and acupuncture combination therapy 30 minutes before chemotherapy. Study 2 group was given tropisetron hydrochloride treatment 30 min before chemotherapy and acupuncture treatment 30 min after chemotherapy. Collect patients' general information and compare the three groups of white blood cell count, G-CSF, GM-CSF levels, quality of life and KPS score, platelets, neutrophils, hemoglobin levels, TCM symptom scores, and the degree of digestive tract reaction. Results: The data of the control group and study groups 1 and 2 are comparable in gender, age, pathological type, etc. (P > 0.05). Before treatment, the white blood cell counts of the three groups were not significantly different (P > 0.05), significantly reduced after treatment, but the difference between the groups was not statistically significant (P > 0.05). The levels of G-CSF and GM-CSF in the three groups were not substantially different before treatment (P > 0.05). The levels of G-CSF and GM-CSF were considerably lowered in all three groups, although the drop in the study group was more significant (P > 0.05) when compared to that in the control group. Before treatment, the quality of life and KPS score of the three groups were not statistically different (P > 0.05). The three groups' quality of life and KPS scores fell after treatment, with the study 1 group experiencing the greatest reduction, followed by the study 2 group and the control group. The levels of platelets, neutrophils, and hemoglobin in all three groups declined dramatically, with the most noticeable reduction in the control group, followed by study 2 and study 1. The difference between the three groups was statistically significant (P < 0.05). The TCM symptom scores of the three groups showed an upward trend, but compared with those of the study 1 group and study 2 group, the TCM symptom scores of the control group increased significantly and the difference between the three groups was statistically significant (P < 0.05). The effective rates of the control group, study group 1, and study group 2 were 42.11%, 82.05%, and 62.86%, respectively; compared with that of the control group, the treatment efficiency of study groups 1 and 2 was higher and the difference between the three groups was statistically significant (P < 0.05). Conclusion: Tropisetron hydrochloride is an effective treatment for patients with lung cancer before chemotherapy, which can effectively improve the side effects of nausea and vomiting caused by chemotherapy, reduce the white blood cell count, and improve the quality of life of patients; it plays an important role in the improvement of prognosis.

Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca2+/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart. METHODS: A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALB/c nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin. RESULTS: Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both I/R- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALB/c nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury. CONCLUSIONS: Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac I/R injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.

[A Case Report and Literature Review of Pulmonary Wegener' Granulomatosis].

Wegener' granulomatosis is an autoimmune diseases, often involving the lung and kidney, has a high mortality rate in nontreatment patients. The low incidence and nonspecific features, often lead to misdiagnosis and delayed treatment. This paper reported the diagnosis and treatment of a 55-year-old female patient with primary Wegener' granuloma of the lung diagnosed by percutaneous lung biopsy of pulmonary nodules, and reviews the relevant literature.
.

A large-scale, multicentered trial evaluating the sensitivity and specificity of digital PCR versus ARMS-PCR for detecting ctDNA-based EGFR p.T790M in non-small-cell lung cancer patients.

BACKGROUND: Developing liquid biopsy technology with higher sensitivity and specificity especially for low-frequency mutations remains crucial. This study demonstrated superior performance of the newly developed digital PCR (dPCR) kit for ctDNA-based EGFR p.T790M detection in metastatic non-small-cell lung cancer (NSCLC) against ARMS-PCR. METHODS: This large-scale, multi-centered diagnostic study recruited 1,045 patients including 1,029 patients diagnosed with advanced NSCLC and 16 patients with specific samples between April 1st 2018 and November 30th 2019. EGFR p.T790M in plasma samples from mNSCLC patients were tested using dPCR with ADx-ARMS PCR and Cobas® EGFR Mutation Test V2 as comparator assays to confirm cut-off value for dPCR and evaluate its performance against ARMS-PCR-based assays. Efficacy was evaluated for patients with EGFR p.T790M detected by dPCR or ARMS-PCR, who underwent Osimertinib treatment. RESULTS: The sensitivity, specificity, and concordance of dPCR against ADx-ARMS PCR was 98.15%, 88.66% and 90.16%, respectively for 1,026 plasma samples. Additional 9.26% patients were detected positive by dPCR. The majority of those samples had a mutation allele frequency between 0.1% and 1%. In 45 paired tissue and plasma samples, the sensitivity improved from 30.77% to 53.85% by dPCR with the specificity over 90%. The response of Osimertinib in 74 EGFR p.T790M-positive patients detected by dPCR, including 26 determined as negative by ARMS-PCR, were evaluated to have an ORR of 44.59% and a DCR of 90.54%. CONCLUSIONS: dPCR is a sensitive and accurate tool for ctDNA-based EGFR p.T790M detection due to its significantly improved sensitivity without compromising specificity, and dPCR is equivalent to ARMS-PCR as a companion diagnostic tool while benefiting more patients under Osimertinib treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR2100043147.

Remarkable Uptake of Deoxynivalenol in Stable Metal-Organic Frameworks.

Deoxynivalenol (DON), which is known as one of the most harmful mycotoxins, has contaminated food and feed and attracted concerns worldwide. However, the effective adsorptive removal of DON to ensure food safety still is a challenge, which is ascribed to the poor planarity and larger steric hindrance of DON molecules. Here, a new Zr(IV)-based metal-organic framework, entitled BUT-16 with one-dimensional channels and N-atom-decorated pore surface, is designed, prepared, and utilized for the adsorptive removal of DON. It exhibits excellent adsorption ability with an adsorption capacity of 46 mg/g higher than all reported adsorbents until now and a rapid adsorption rate of 0.031 g mg-1 min-1. DFT calculation and X-ray photoelectron spectroscopy results of the guest-loaded phase suggest that the record-breaking adsorption could be due to the cooperation of hydrogen bonding and Zr···O interaction between DON molecules and BUT-16 host. Most importantly, BUT-16 can effectively adsorb and remove DON in the simulated gastric fluid, but DON adsorbed on BUT-16 is hardly desorbed in the simulated intestinal fluid. The results demonstrate that BUT-16 has great promising application for the control of DON in foods and feeds.

Inonotsuoxide B regulates M1 to M2 macrophage polarization through sirtuin-1/endoplasmic reticulum stress axis.

We explored the effect of tetracyclic triterpenoid inonotsuoxide B (IB) extracts of Inonotus obliquus on M1 to M2 macrophage polarization and its possible underlying mechanism. Lipopolysaccharide (LPS)-activated M1 macrophages exert pro-inflammatory effects and release inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. The model and various groups were treated with different IB concentrations (2.5, 5, and 10 µg/mL) to observe changes in the M1 and M2 phenotypes, gene expression of NAD-dependent deacetylase sirtuin-1 (Sirt1), and endoplasmic reticulum stress (ERS). SIRT1-siRNA and thapsigargin (TG), an ERS agonist, were used to examine the relationship between SIRT1/ERS and the effect of IB on M1 to M2 RAW264.7 macrophage phenotypic changes. We found that IB had no effect on RAW264.7 cell proliferation at 10 µg/mL. Increasing concentrations of IB (2.5, 5, and 10 µg/mL) decreased the number of phenotypic M1 macrophages and, consequently, decreased the release of the inflammatory cytokines, IL-1ß and TNF-α. Furthermore, IB treatment increased the level of phenotypic M2 macrophages, which increased the release of anti-inflammatory cytokines such as arginase (Arg)-1 and found in inflammatory zone 1 (FIZZ1) in a dose-dependent manner. Further, we found that IB increased the expression of SIRT1 and inhibited that of ERS. Inhibition of Sirt1 expression by siRNA significantly increased that of ERS marker genes and IL1ß. Excessive ERS levels inhibited the IB-induced transformation of phenotypic M1 macrophage to the M2 macrophage phenotype. Therefore, IB, an extract of I. obliquus, may regulate macrophage polarization through the SIRT1/ERS signaling pathway.

Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of TRIM72 in Primates.

Cis-regulatory elements play important roles in tissue-specific gene expression and in the evolution of various phenotypes, and mutations in promoters and enhancers may be responsible for adaptations of species to environments. TRIM72 is a highly conserved protein that is involved in energy metabolism. Its expression in the heart varies considerably in primates, with high levels of expression in Old World monkeys and near absence in hominids. Here, we combine phylogenetic hypothesis testing and experimentation to demonstrate that mutations in promoter are responsible for the differences among primate species in the heart-specific expression of TRIM72. Maximum likelihood estimates of lineage-specific substitution rates under local-clock models show that relative to the evolutionary rate of introns, the rate of promoter was accelerated by 78% in the common ancestor of Old World monkeys, suggesting a role for positive selection in the evolution of the TRIM72 promoter, possibly driven by selective pressure due to changes in cardiac physiology after species divergence. We demonstrate that mutations in the TRIM72 promoter account for the differential myocardial TRIM72 expression of the human and the rhesus macaque. Furthermore, changes in TRIM72 expression alter the expression of genes involved in oxidative phosphorylation, which in turn affects mitochondrial respiration and cardiac energy capacity. On a broader timescale, phylogenetic regression analyses of data from 29 mammalian species show that mammals with high cardiac expression of TRIM72 have high heart rate, suggesting that the expression changes of TRIM72 may be related to differences in the heart physiology of those species.

Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian Leydig cells†.

Leydig cells play a critical role in male reproductive physiology, and their dysfunction is usually associated with male infertility. Melatonin has an important protective and regulatory role in these cells. However, the lack of suitable animal models impedes us from addressing the impact of endogenous melatonin on these cells. In the current study, by using arylalkylamine N-acetyltransferase (AANAT) overexpression transgenic sheep and AANAT knockout mice, we confirmed the regulatory effects of endogenously occurring melatonin on Leydig cells as well as its beneficial effects on male reproductive performance. The results showed that the endogenously elevated melatonin level was correlated with decreased Leydig cell apoptosis, increased testosterone production, and improved quality of sperm in melatonin-enriched transgenic mammals. Signal transduction analysis indicated that melatonin targeted the mitochondrial apoptotic Bax/Bcl2 pathway and thus suppressed Leydig cell apoptosis. In addition, melatonin upregulated the expression of testosterone synthesis-related genes of Steroidogenic Acute Regulatory Protein (StAR), Steroidogenic factor 1 (SF1), and Transcription factor GATA-4 (Gata4) in Leydig cells. This action was primarily mediated by the melatonin nuclear receptor RAR-related orphan receptor alpha (RORα) since blockade of this receptor suppressed the effect of melatonin on testosterone synthesis. All of these actions of melatonin cause Leydig cells to generate more testosterone, which is necessary for spermatogenesis in mammals. In contrast, AANAT knockout animals have dysfunctional Leydig cells and reduced reproductive performance.

Symptom trajectories during chemotherapy in patients with non-small cell lung cancer (NSCLC) and the function of prolonging low dose dexamethasone in promoting enhanced recovery after chemotherapy.

BACKGROUND: Lung cancer, mainly non-small cell lung cancer (NSCLC), is one of the leading causes of death worldwide. Currently, chemotherapy is still the most significant treatment strategy for NSCLC. However, scant attention has been paid in previous studies to those patients who often experience various symptoms and discomfort during chemotherapy treatment cycles. METHODS: This study included 127 NSCLC patients who completed an EORTC QLQ-C30 questionnaire and specifically designed symptom diary. Chi-square test, factor analysis, Pearson correlation coefficient and hierarchical cluster analysis were used to perform multivariate analysis. RESULTS: We identified the top five most-frequent symptoms within the chemotherapy cycle which included fatigue, insomnia, cough and sputum, appetite loss and hypodipsia. These symptoms were at a moderate level on chemotherapy treatment days 3-7, and were then reduced to a stable and lower level in the following two weeks. A statistically significant difference in adverse events (AEs) was found between 54 patients who received dexamethasone (treatment group) and the control group: fatigue (risk ratio [RR]: 1.48; 95% confidence interval [CI]: 1.120-1.961; p = 0.006), insomnia (RR: 1.34; 95% CI: 1.016-1.778; p = 0.038), cough and sputum (RR: 2.00; 95% CI: 1.484-2.695; p < 0.001), appetite loss (RR: 1.28; 95% CI: 0.959-1.696; p = 0.095). In total, 62 patients completed the EORTC QLQ-C30 scale. The functioning scales of the treatment group were higher than the control population within positive effect sizes (ES: 0.1-0.8). Apart from diarrhea scales, most symptom scales were lower than the control group within negative effect sizes (ES: 0.1-0.9). CONCLUSIONS: In this study we identified the top five most frequent post-chemotherapy AEs in a chemotherapy treatment cycle and found that dexamethasone was well tolerated by NSCLC patients who received platinum-based chemotherapy and substantially alleviated the symptom burden and improved the health-related quality of life (HRQOL) of patients.