IL-17 induces NSCLC cell migration and invasion by elevating MMP19 gene transcription and expression through the interaction of p300-dependent STAT3-K631 acetylation and its Y705-phosphorylation.

The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer (NSCLC). Although researchers have disclosed that interleukin 17 (IL-17) can increase matrix metalloproteinases (MMPs) induction causing NSCLC cell metastasis, the underlying mechanism remains unclear. In the study, we found that IL-17 receptor A (IL-17RA), p300, p-STAT3, Ack-STAT3, and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17. p300, STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3, Ack-STAT3 and MMP19 level as well as the cell migration and invasion. Mechanism investigation revealed that STAT3 and p300 bound to the same region (-544 to -389 nt) of MMP19 promoter, and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity, p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17. Meanwhile, p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact, synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion. Besides, the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300, STAT3 or MMP19 gene plus IL-17 treatment, the nodule number, and MMP19, Ack-STAT3, or p-STAT3 production in the lung metastatic nodules were all alleviated. Collectively, these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation, which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.

Novel non-invasive method for urine mapping: Deep-learning-enabled SERS spectroscopy for the rapid differential detection of kidney allograft injury.

The kidney allograft has been under continuous attack from diverse injuries since the very beginning of organ procurement, leading to a gradual decline in function, chronic fibrosis, and allograft loss. It is vital to routinely and precisely monitor the risk of injuries after renal transplantation, which is difficult to achieve because the traditional laboratory tests lack sensitivity and specificity, and graft biopsies are invasive with the risk of many complications and time-consuming. Herein, a novel method for the diagnosis of graft injury is demonstrated, using deep learning-assisted surface-enhanced Raman spectroscopy (SERS) of the urine analysis. Specifically, we developed a hybrid SERS substrate composed of gold and silver with high sensitivity to the urine composition under test, eliminating the need for labels, which makes measurements easy to perform and meanwhile results in extremely abundant and complex Raman vibrational bands. Deep learning algorithms were then developed to improve the interpretation of the SERS spectral fingerprints. The deep learning model was trained with SERS signals of urine samples of recipients with different injury types including delayed graft function (DGF), calcineurin-inhibitor toxicity (CNIT), T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and BK virus nephropathy (BKVN), which explored the features of these types and achieved the injury differentiation with an overall accuracy of 93.03%. The results highlight the potential of combining label-free SERS spectroscopy with deep learning as a method for liquid biopsy of kidney allograft injuries, which can provide great potential to diagnose and evaluate allograft injuries, and thus extend the life of kidney allografts.

Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay.

Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan-Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

Development of a nomogram for predicting survival in clinical T1N0M1 lung adenocarcinoma: a population-based study.

OBJECTIVE: This study aimed to establish a prognostic model for clinical T1N0M1 (cT1N0M1) lung adenocarcinoma patients to evaluate the prognosis of patients in terms of overall survival (OS) rate and cancer-specific survival (CSS) rate. METHODS: Data of patients with metastatic lung adenocarcinoma from 2010 to 2016 were collected from the Surveillance, Epidemiology and End Results database. Multivariate Cox regression analysis was conducted to identify relevant prognostic factors and used to develop nomograms. The receiver operating characteristic (ROC) curve and calibration curve are used to evaluate the predictive ability of the nomograms. RESULTS: A total of 45610 patients were finally included in this study. The OS and CSS nomograms were constructed by same clinical indicators such as age (<60 years or ≥60 years), sex (female or male), race (white, black, or others), surgery, radiation, chemotherapy, and the number of metastatic sites, based on the results of statistical Cox analysis. From the perspective of OS and CSS, surgery contributed the most to the prognosis. The ROC curve analysis showed that the survival nomograms could accurately predict OS and CSS. According to the points obtained from the nomograms, survival was estimated by the Kaplan-Meier method, then cT1N0M1 patients were divided into three groups: low-risk group, intermediate-risk group, and high-risk group, and the OS ( P  < 0.001) and CSS ( P  < 0.001) were significantly different among the three groups. CONCLUSION: The nomograms and risk stratification model provide a convenient and reliable tool for individualized evaluation and clinical decision-making of patients with cT1N0M1 lung adenocarcinoma.

Curcumin inhibits the development of colorectal cancer via regulating the USP4/LAMP3 pathway.

In this study, we aimed to explore the effects of curcumin on the progression of colorectal cancer and its underlying mechanisms involved. Cell proliferation, apoptosis and invasion were determined through CCK-8 assay, colony formation assay, EdU assay, flow cytometry, and transwell invasion assay, respectively. The protein expression of Bax, MMP2, USP4 and LAMP3 was measured using western blot. Pearson correlation coefficient was used to evaluate the relationship between USP4 and LAMP3. Co-IP was also conducted to determine the interaction between USP4 and LAMP3. Xenograft tumor model was established to explore the role of curcumin in colorectal cancer in vivo. IHC was utilized to measure the expression of Bax, MMP2, USP4 and LAMP3 in tumor tissues from mice. Curcumin significantly accelerated cell apoptosis, and inhibited cell proliferation and invasion in LoVo and HCT-116 cells. LAMP3 was augmented in colorectal cancer tissues and cells, and curcumin could reduce the expression of LAMP3. Curcumin decreased LAMP3 expression to exhibit the inhibition role in the progression of colorectal cancer. USP4 interacted with LAMP3, and positively regulated LAMP3 expression in colorectal cancer cells. LAMP3 overexpression could reverse the suppressive effects of USP4 knockdown on the development of colorectal cancer. Curcumin downregulated USP4 to impeded the progression of colorectal cancer via repressing LAMP3 expression. In addition, curcumin obviously restrained tumor growth in mice through downregulating USP4 and LAMP3 expression. These data indicated that curcumin exert the anti-tumor effects on the development of colorectal cancer through modulating the USP4/LAMP3 pathway.

Value of ultrasound and magnetic resonance imaging combined with tumor markers in the diagnosis of ovarian tumors.

BACKGROUND: Compare the diagnostic performance of ultrasound (US), magnetic resonance imaging (MRI), and serum tumor markers alone or in combination for detecting ovarian tumors. AIM: To investigate the diagnostic value of US, MRI combined with tumor markers in ovarian tumors. METHODS: The data of 110 patients with ovarian tumors, confirmed by surgery and pathology, were collected in our hospital from February 2018 to May 2023. The dataset included 60 cases of benign tumors and 50 cases of malignant tumors. Prior to surgery, all patients underwent preoperative US and MRI examinations, as well as serum tumor marker tests [carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4)]. The aim of the study was to compare the diagnostic performance of these three methods individually and in combination for ovarian tumors. RESULTS: This study found statistically significant differences in the ultrasonic imaging characteristics between benign and malignant tumors. These differences include echo characteristics, presence or absence of a capsule, blood flow resistance index, clear tumor shape, and blood flow signal display rate (P < 0.05). The apparent diffusion coefficient values of the solid and cystic parts in benign tumors were found to be higher compared to malignant tumors (P < 0.05). Additionally, the time-intensity curve image features of benign and malignant tumors showed significant statistical differences (P < 0.05). The levels of serum CA125 and HE4 in benign tumors were lower than those in malignant tumors (P < 0.05). The combined use of US, MRI, and tumor markers in the diagnosis of ovarian tumors demonstrates higher accuracy, sensitivity, and specificity compared to using each method individually (P < 0.05). CONCLUSION: US, MRI, and tumor markers each have their own advantages and disadvantages when it comes to diagnosing ovarian tumors. However, by combining these three methods, we can significantly enhance the accuracy of ovarian tumor diagnosis, enabling early detection and identification of the tumor's nature, and providing valuable guidance for clinical treatment.

Universal DNA-Based Sensing Toolbox for Programming Cell Functions.

By recombining natural cell signaling systems and further reprogramming cell functions, use of genetically engineered cells and bacteria as therapies is an innovative emerging concept. However, the inherent properties and structures of the natural signal sensing and response pathways constrain further development. We present a universal DNA-based sensing toolbox on the cell surface to endow new signal sensing abilities for cells, control cell states, and reprogram multiple cell functions. The sensing toolbox contains a triangular-prismatic-shaped DNA origami framework and a sensing core anchored inside the internal confined space to enhance the specificity and efficacy of the toolbox. As a proof of principle, the sensing toolbox uses the customizable sensing core with signal sensing switches and converters to recognize unconventional signal inputs, deliver functional components to cells, and then control cell responses, including specific tumor cell death, immune cell disinhibition and adhesion, and bacterial expression. This work expands the diversity of cell sensing signals and reprograms biological functions by constructing nanomechanical-natural hybrid cells, providing new strategies for engineering cells and bacteria in diagnosis and treatment applications.

Stomata variation in the process of polyploidization in Chinese chive (Allium tuberosum).

BACKGROUND: Stomatal variation, including guard cell (GC) density, size and chloroplast number, is often used to differentiate polyploids from diploids. However, few works have focused on stomatal variation with respect to polyploidization, especially for consecutively different ploidy levels within a plant species. For example, Allium tuberosum, which is mainly a tetraploid (2n = 4x = 32), is also found at other ploidy levels which have not been widely studied yet. RESULTS: We recently found cultivars with different ploidy levels, including those that are diploid (2n = 2x = 16), triploid (2n = 3x = 24), pseudopentaploid (2n = 34-42, mostly 40) and pseudohexaploid (2n = 44-50, mostly 48). GCs were evaluated for their density, size (length and width) and chloroplast number. There was no correspondence between ploidy level and stomatal density, in which anisopolyploids (approximately 57 and 53 stomata/mm2 in triploid and pseudopentaploid, respectively) had a higher stomatal density than isopolyploids (approximately 36, 43, and 44 stomata/mm2 in diploid, tetraploid and pseudohexaploid, respectively). There was a positive relationship between ploidy level and GC chloroplast number (approximately 44, 45, 51, 72 and 90 in diploid to pseudohexaploid, respectively). GC length and width also increased with ploidy level. However, the length increased approximately 1.22 times faster than the width during polyploidization. CONCLUSIONS: This study shows that GC size increased with increasing DNA content, but the rate of increase differed between length and width. In the process of polyploidization, plants evolved longer and narrower stomata with more chloroplasts in the GCs.

A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway.

BACKGROUND: The NOD-, LRR- and pyrin domain­containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1ß, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan-Meier survival curves, and Cox regression analysis. RESULTS: In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan-Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis. CONCLUSIONS: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target. TRIAL REGISTRATION: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910).

The emerging roles of SUMOylation in the tumor microenvironment and therapeutic implications.

Tumor initiation, progression, and response to therapies depend to a great extent on interactions between malignant cells and the tumor microenvironment (TME), which denotes the cancerous/non-cancerous cells, cytokines, chemokines, and various other factors around tumors. Cancer cells as well as stroma cells can not only obtain adaption to the TME but also sculpt their microenvironment through a series of signaling pathways. The post-translational modification (PTM) of eukaryotic cells by small ubiquitin-related modifier (SUMO) proteins is now recognized as a key flexible pathway. Proteins involved in tumorigenesis guiding several biological processes including chromatin organization, DNA repair, transcription, protein trafficking, and signal conduction rely on SUMOylation. The purpose of this review is to explore the role that SUMOylation plays in the TME formation and reprogramming, emphasize the importance of targeting SUMOylation to intervene in the TME and discuss the potential of SUMOylation inhibitors (SUMOi) in ameliorating tumor prognosis.

Neuroprotection of isookanin against MPTP-induced cell death of SH-SY5Y cells via BCL2/BAX and PI3K/AKT pathways.

BACKGROUND AND PURPOSE: Isookanin, an important antioxidant component in Coreopsis tinctoria Nutt., has shown remarkable hypolipidemic, hypoglycemic, and hypotensive effects. However, the neuroprotective effect of isookanin has not been reported yet. Here, the neuroprotective effects and relevant molecular mechanisms of isookanin are explored for the first time. METHODS: The SH-SY5Y cells were exposed to neurotoxic H2O2, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and Aß25-35, respectively. Cell viability and apoptosis were evaluated by MTT, lactate dehydrogenase (LDH), and TUNEL assays. Intercellular ROS and mitochondrial membrane potential were assessed by DCFH-DA and JC-1 assay. Western blot and qRT-PCR were used to explore the perturbed signaling at the gene and protein levels. Molecular docking analysis and in vitro assay were further applied to confirm potential target. RESULTS: Among the three in vitro models, isookanin showed the best neuroprotection against MPTP-induced damage. Isookanin attenuated the levels of LDH, intracellular ROS, and mitochondrial membrane potential. Isookanin upregulated phosphorylation of AKT and PI3K, and increased BCL2/BAX ratio. Isookanin possessed a powerful affinity toward AKT. Besides, the protective effects of isookanin disappeared when cells were co-treated with an AKT inhibitor (AZD5363). CONCLUSION: Isookanin regulated BCL2/BAX and PI3K/AKT pathways to reduce mitochondrial damage and cellular apoptosis. Isookanin may be a new protector for neurodegenerative diseases.

NUCKS1 promotes the progression of colorectal cancer via activating PI3K/AKT/mTOR signaling pathway.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.

LINC00659 cooperated with ALKBH5 to accelerate gastric cancer progression by stabilising JAK1 mRNA in an m6 A-YTHDF2-dependent manner.

BACKGROUND: N6-methyladenosine (m6 A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m6 A in noncoding RNAs makes a difference, and the aberrant expression of m6 A-associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known. METHODS: The quantitative real-time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP-seq), RIP and RNA pull-down assays were performed to examine the influence of LINC00659 on the ALKBH5-JAK1 interaction. RESULTS: ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m6 A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m6 A-YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC. CONCLUSION: ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m6 A-YTHDF2-dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

Clinical Efficacy and Safety of Foldable Capsular Vitreous Body Implant Surgery in 22 Cases of Silicone Oil-dependent Eyes.

OBJECTIVE: This study aimed to evaluate the clinical efficacy and safety of foldable capsular vitreous body (FCVB) implant surgery in silicone oil-dependent eyes. METHODS: A total of 22 participants with silicone oil-dependent eyes who received treatment with FCVB implant surgery between January 2019 and June 2020 were included in this retrospective study. The intraocular pressure (IOP), best-corrected visual acuity (BCVA), demographic data, and any recorded complications were evaluated. RESULTS: The postoperative IOP (12.73±4.20 mmHg) was significantly improved (P=0.03) compared to the preoperative IOP (10.23±3.69 mmHg) (the main endpoint). There was no significant difference (P=0.33) in the final BCVA preoperation and 3rd month postoperation (the secondary endpoint). The most common postoperative complication was hyphema. Other common postoperative complications included corneal opacity, a shallow anterior chamber, and a low IOP. CONCLUSION: FCVB implant surgery is a safe and effective method for treating silicone oil-dependent eyes; however, attention should be paid to the prevention and timely treatment of complications.

Safety, efficacy, and pharmacokinetics of SH-1028 in EGFR T790M-positive advanced non-small cell lung cancer patients: A dose-escalation phase 1 study.

BACKGROUND: SH-1028 is a new third-generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M-mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time. METHODS: Patients with EGFR T790M mutation, locally advanced non-small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH-1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc. RESULTS: Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH-1028. A total of 95.0% (19 of 20) of patients reported treatment-related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41-99.37) and 75.0% (95% CI, 19.41-99.37), respectively. The overall ORR was 40% (95% CI, 19.12-63.95), and DCR was 70.0% (95% CI, 45.72-88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily. CONCLUSIONS: SH-1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily. PLAIN LANGUAGE SUMMARY: Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer. First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation.

LOC101929709 promotes gastric cancer progression by aiding LIN28B to stabilize c-MYC mRNA.

BACKGROUND: LIN28B plays a critical role in the Warburg effect. However, its underlying mechanism remains elusive. Recently, it has been reported that LIN28B could collaborate with IGF2BP3, which can bind to m6A-modified c-MYC transcripts. Therefore, this study investigated if LIN28B recognises methylated c-MYC mRNA to promote the Warburg effect in gastric cancer. METHODS: Effects of LIN28B on gastric cancer were confirmed in vitro and in vivo. On the basis of bioinformatics analysis, the association between LIN28B and c-MYC mRNA was shown using RNA immunoprecipitation (RIP) and luciferase reporter assays. The role of m6A was identified by RNA pull-down assays. We further performed RIP-seq to search for long non-coding RNAs (lncRNAs) participating in the LIN28B binding process. Chromatin immunoprecipitation was used to show the impact of c-MYC on transcription of LIN28B and lncRNAs. RESULTS: LIN28B was identified to stabilize c-MYC mRNA by recognizing m6A. Furthermore, the interaction between c-MYC mRNA and LIN28B is speculated to be supported by LOC101929709, which binds to both LIN28B and IGF2BP3. Functional experiments revealed that LOC101929709 promotes the proliferation, migration and glycolysis of gastric cancer. Mechanistically, LOC101929709 enriched in the cytoplasm helps LIN28B stabilize c-MYC mRNA. Moreover, c-MYC promoted the transcription of both LOC101929709 and LIN28B. Additionally, LOC101929709 also activated the PI3K/AKT pathway. CONCLUSIONS: The c-MYC/LOC101929709/LIN28B axis promotes aerobic glycolysis and tumour progression. Thus, LOC101929709 can be a novel potential target for gastric cancer treatment.

Nano-Biohybrid DNA Engager That Reprograms the T-Cell Receptor.

Although engineered T cells with transgenic chimeric antigen receptors (CARs) have made a breakthrough in cancer therapeutics, this approach still faces many challenges in the specificity, efficacy, and self-safety of genetic engineering. Here, we developed a nano-biohybrid DNA engager-reprogrammed T-cell receptor (EN-TCR) system to improve the specificity and efficacy, mitigate the excessive activation, and shield against risks from transgenesis, thus achieving a diversiform and precise control of the T-cell response. Utilizing modular assembly, the EN-TCR system can graft different specificities on T cells via antibody assembly. Besides, the designability of DNA hybridization enables precise target recognition by the library of multiantigen cell recognition circuits and allows gradual tuning of the T-cell activation level by the signaling switch and independent control over different types of T cells. Furthermore, we demonstrated the effectiveness of the system in tumor models. Together, this study provides a nongenetic T-cell engineering strategy to overcome major hindrances in T-cell therapy and may be extended to a general and convenient cell engineering strategy.

Expression analysis of irisin during different development stages of skeletal muscle in mice.

BACKGROUND: As a newly discovered muscle factor secreted by skeletal muscle cells, irisin is a polypeptide fragment formed from hydrolysis of fibronectin type Ⅲ domain-containing protein 5 (FNDC5). Irisin can promote beigeing of white adipose tissue (WAT) and regulate glucose and lipid metabolisms. However, the functions of irisin in skeletal muscle development remain largely unknown. In order to characterize the expression of irisin, this study investigated the expression of irisin precursor FNDC5 in myoblasts and skeletal muscles during different developmental stages of SPF mice. RESULTS: The Western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence assay results showed that FNDC5 was expressed in all the developmental stages of myoblasts and gastrocnemius, but its expression differed at different stages. FNDC5 protein exhibited the highest expression in gastrocnemius of sexually mature mice, followed by elderly mice and adolescent mice, and it displayed the lowest expression in pups. Additionally, FNDC5 protein was mainly expressed in cytoplasm, and it had the highest expression in primary myoblasts, followed by the myotubes with the lowest expression in C2C12 myogenic cells. CONCLUSIONS: Overall, FNDC5 was mainly expressed in cytoplasm and extracellular matrix with different expression levels at different developmental stages of skeletal muscle cells and tissues in mice. This study will provide new strategies for promoting skeletal muscle development and treating muscle- and metabolism-related disease by using irisin.

Gut microbiota: A new insight into lung diseases.

The human gut microbiota is a complex ecosystem involved in the metabolism, immunity, and health of the host. The microbiome plays a key role in the development of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of host-microbe symbiosis. Lung diseases are usually accompanied by dysbiosis of the intestinal flora and an immune-inflammatory response. The intestinal flora and its metabolites are directly or indirectly involved in the immune regulation of the host in lung disease. However, the exact mechanism of action of the gut-lung axis crosstalk remains unclear. This review is aimed to summarize the latest advances in gut microbiota and their metabolites in typical lung diseases, such as pulmonary hypertension, COPD, and lung cancer. Especially COVID-19, a problem troubling the world, is also discussed in it. Moreover, it is concentrated on the action mechanisms between the identified gut microbiota or their metabolites and the specific lung diseases, and on the link among the gut microbiota, its metabolites, and immune regulation, which could be used as a breakthrough to find new mechanisms and targets for some diseases without specific therapeutic drugs in clinic. It is also discussed a new therapeutic tool "drug-bacterial interaction" and the potential of therapeutic applications in clinic. This review would provide a clear direction for future research on gut microbiota and lung diseases, and propose a new therapeutic strategy targeting "drug-bacterial interaction" in clinic.

Ischemia and reperfusion injury combined with cisplatin induces immunogenic cell death in lung cancer cells.

A first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), cisplatin (CDDP), fails to induce immunogenic cell death (ICD) because it fails to induce calreticulin (CRT) exposure on the cell surface. We investigated the potential of ischemia and reperfusion injury (I/R) combined with CDDP to induce ICD in lung cancer cells. The in vitro model of I/R, oxygen-glucose deprivation and reperfusion (OGD/R), effectively induced CRT exposure, ATP secretion, high mobility group box 1 (HMGB1) release and eIF2α phosphorylation in both Lewis lung carcinoma (LLC) and A549 cells when combined with CDDP. By using a vaccine assay and coculture with bone marrow-derived dendritic cells (BMDCs), we showed that OGD/R restored the immunogenicity of CDDP by phosphorylating eIF2α and demonstrated that OGD/R + CDDP (O + C) is an ICD inducer. Using the inguinal tumor model, we found that I/R significantly enhanced the tumor-killing effect of CDDP and Mitomycin C, and this effect relied on adaptive antitumor immunity. Consistently, I + C altered the ratio of interferon-gamma-secreting T lymphocytes, thus overcoming the immunosuppressive effect induced by CDDP. In conclusion, our research presents a new combination strategy and indicates that I/R is a potential anticancer immunogenic modality when combined with nonimmunogenic chemotherapy.