Early vascular healing after neXt-generation drug-eluting stent implantation in Patients with non-ST elevation acute Coronary syndrome: a randomized optical coherence Tomography imaging study (EXPECT).

Early vascular healing after drug-eluting stent (DES) implantation is associated with better outcomes and lower incidence of in-stent thrombosis. To examine vascular healing response in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) guided by optical coherence tomography (OCT) versus angiography alone. Sixty patients were randomized 1:1:1 to OCT-guided PCI with 3-month OCT follow-up (O3 group, n = 20), angiography-guided PCI with 3-month OCT follow-up (A3 group, n = 20), or angiography-guided PCI with 6-month OCT follow-up (A6 group, n = 20). The primary endpoint was the proportion of covered struts at 3- or 6-month follow-up. The proportion of covered struts in the O3 group was significantly higher than in the A3 group (95.2% vs. 92.3%, p < 0.001), but lower than in the A6 group (95.2% vs. 97.4%, p < 0.001). The O3 group had a lower proportion of incomplete strut apposition (ISA) than the A3 group (0.46% vs. 0.76%, p = 0.006), and higher than the A6 group (0.46% vs. 0.27%, p = 0.018) at follow-up. The optimal cut-off value of ISA after implantation of DES for predicting stent coverage at 3 and 6-month follow-up was 200 µm and 308 µm, respectively. Only one patient experienced target lesion revascularization in the A3 group during a 3-year clinical follow-up. In patients with NSTE-ACS undergoing PCI with DES, OCT guidance achieved higher strut coverage compared with angiography guidance at 3-month follow-up. However, the difference in the strut coverage between the OCT-guided group and the angiography-guided group at 6 months indicates that the degree of endothelialization may be more time-dependent instead of invasive device guidance.

Role of ACSL4 in modulating farnesoid X receptor expression and M2 macrophage polarization in HBV-induced hepatocellular carcinoma.

The intricate relationship between bile acid (BA) metabolism, M2 macrophage polarization, and hepatitis B virus-hepatocellular carcinoma (HBV-HCC) necessitates a thorough investigation of ACSL4's (acyl-CoA synthetase long-chain family member 4) role. This study combines advanced bioinformatics and experimental methods to elucidate ACSL4's significance in HBV-HCC development. Using bioinformatics, we identified differentially expressed genes in HBV-HCC. STRING and gene set enrichment analysis analyses were employed to pinpoint critical genes and pathways. Immunoinfiltration analysis, along with in vitro and in vivo experiments, assessed M2 macrophage polarization and related factors. ACSL4 emerged as a pivotal gene influencing HBV-HCC. In HBV-HCC liver tissues, ACSL4 exhibited upregulation, along with increased levels of M2 macrophage markers and BA. Silencing ACSL4 led to heightened farnesoid X receptor (FXR) expression, reduced BA levels, and hindered M2 macrophage polarization, thereby improving HBV-HCC conditions. This study underscores ACSL4's significant role in HBV-HCC progression. ACSL4 modulates BA-mediated M2 macrophage polarization and FXR expression, shedding light on potential therapeutic targets and novel insights into HBV-HCC pathogenesis.

Populus trichocarpa EXPA6 Facilitates Radial and Longitudinal Transport of Na+ under Salt Stress.

Expansins are cell wall (CW) proteins that mediate the CW loosening and regulate salt tolerance in a positive or negative way. However, the role of Populus trichocarpa expansin A6 (PtEXPA6) in salt tolerance and the relevance to cell wall loosening is still unclear in poplars. PtEXPA6 gene was transferred into the hybrid species, Populus alba × P. tremula var. glandulosa (84K) and Populus tremula × P. alba INRA '717-1B4' (717-1B4). Under salt stress, the stem growth, gas exchange, chlorophyll fluorescence, activity and transcription of antioxidant enzymes, Na+ content, and Na+ flux of root xylem and petiole vascular bundle were investigated in wild-type and transgenic poplars. The correlation analysis and principal component analysis (PCA) were used to analyze the correlations among the characteristics and principal components. Our results show that the transcription of PtEXPA6 was downregulated upon a prolonged duration of salt stress (48 h) after a transient increase induced by NaCl (100 mM). The PtEXPA6-transgenic poplars of 84K and 717-1B4 showed a greater reduction (42-65%) in stem height and diameter growth after 15 days of NaCl treatment compared with wild-type (WT) poplars (11-41%). The Na+ accumulation in roots, stems, and leaves was 14-83% higher in the transgenic lines than in the WT. The Na+ buildup in the transgenic poplars affects photosynthesis; the activity of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and the transcription of PODa2, SOD [Cu-Zn], and CAT1. Transient flux kinetics showed that the Na+ efflux of root xylem and leaf petiole vascular bundle were 1.9-3.5-fold greater in the PtEXPA6-transgenic poplars than in the WT poplars. PtEXPA6 overexpression increased root contractility and extensibility by 33% and 32%, indicating that PtEXPA6 increased the CW loosening in the transgenic poplars of 84K and 717-1B4. Noteworthily, the PtEXPA6-promoted CW loosening was shown to facilitate Na+ efflux of root xylem and petiole vascular bundle in the transgenic poplars. We conclude that the overexpression of PtEXPA6 leads to CW loosening that facilitates the radial translocation of Na+ into the root xylem and the subsequent Na+ translocation from roots to leaves, resulting in an excessive Na+ accumulation and consequently, reducing salt tolerance in transgenic poplars. Therefore, the downregulation of PtEXPA6 in NaCl-treated Populus trichocarpa favors the maintenance of ionic and reactive oxygen species (ROS) homeostasis under long-term salt stress.

Analysis and identification of ferroptosis-related diagnostic markers in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune, inflammatory joint disease. There is growing evidence that ferroptosis is involved in the pathogenesis of RA. This study aimed to search for diagnostic markers of ferroptosis in RA and to analyse the potential mechanisms and clinical value. MATERIALS AND METHODS: RA-associated datasets were used from the publicly available GEO database. Three methods of machine learning were applied to screen biomarkers. The diagnostic efficacy of the results was also verified by receiver operating characteristic (ROC) curve, external dataset, qRT-PCR and Western blot. Enrichment analysis was performed in this process, while protein-protein interaction (PPI) analysis and immune infiltration correlation analysis were performed using biomarkers, and competing endogenous RNA (ceRNA) networks were constructed to search for prospective therapeutic targets. RESULTS: MMP13 and GABARAPL1 can be used as ferroptosis diagnostic genes in RA. The ROC curve and PPI result demonstrated that MMP13 and GABARAPL1 had an excellent diagnostic value. The results of signature genes in the external dataset, qRT-PCR and Western blot further confirm our findings. The enrichment analysis showed that p53, MAPK and NOD-like receptor signalling pathways may be involved in the process of ferroptosis in RA. In addition, two ferroptosis diagnostic genes in RA participate in the occurrence of ferroptosis in RA via oxidative stress, metabolism and immune response. Immune infiltration analysis showed that RA extensively infiltrated B cells, T cells, macrophages and other immune cells. Persistent immune activation may be an essential reason for the progression of ferroptosis in RA. We also obtained five potential therapeutic agents for RA and some long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulating ferroptosis diagnostic genes. CONCLUSIONS: Our study suggests that MMP13 and GABARAPL1, which are closely linked with oxidative stress and immunological modulation, can be used as ferroptosis-related potential diagnostic markers in RA and provide new clues regarding the diagnostic and therapeutic targets of ferroptosis in RA.

Diagnostic significance of EyeMAX in diagnosing patients with tumor in the terminal end of the common bile duct.

A biliary stricture is an abnormal narrowing in the ductal drainage system of the liver. There are many etiologies of biliary stricture, the most common and ominous of which is malignancy, either primary or metastatic.It is difficult to obtain pathological tissue of the terminal end of the common bile duct. A 72-year-old woman, complained of abdominal pain for 2 months, underwent cholecystectomy for acute cholecystitis 11 years ago. Abdominal CT and MRI examination revealed soft tissue occupation (12*8 mm) in the duodenal papillary area, and endoscopic ultrasonography revealed a hypoechoic lesion (11.1*10.7 mm) in the ampulla. We performed ERCP, and intraoperative biliary cell brushing on the patient, but no positive pathological results were obtained. We further performed novel 9F digital single operator cholangioscopy system (DSOC) (eyeMAX, Micro-Tech, Nanjing, China) and observed intraoperative hyperemia and edema of the mucosa in the terminal end of the common bile duct, presenting fish-like changes with mucous attachment and clear lesion boundaries. The pathological results suggested cholangiocarcinoma.

Collagen hydrogel-driven pyroptosis suppression and combined microfracture technique delay osteoarthritis progression.

The pathogenesis of osteoarthritis (OA), a disease causing severe medical burden and joint deformities, remains unclear. Chondrocyte death and osteochondral injury caused are the main pathological changes in OA. Thus, inhibiting chondrocyte death and repairing defective osteochondral are two important challenges in the treatment of OA. In this study, we found morphological changes consistent with cell pyroptosis in OA cartilage tissues. To inhibit chondrocyte pyroptosis and delay the progression of OA, we proposed to use decellularized extracellular matrix (dECM) and gelatin methacrylate (GelMA) to form a composite hydrogel GelMA/dECM. Regarding osteochondral defect repair, our proposed treatment strategy was hydrogel combined with microfracture (MF) surgery. MF established a biological link between the osteochondral defect and the bone-marrow cavity, prompting the recruitment of bone-marrow mesenchymal stem cells (BMSCs) to the osteochondral defect site, and the retained biopeptides in the hydrogel regulate the polarization of the BMSCs into hyaline cartilage, accelerating the repair of the defect. In vitro/vivo experiments and RNA sequencing analyses demonstrated that GelMA/dECM inhibited the occurrence of chondrocyte pyroptosis and delayed OA disease progression. Hydrogel also recruited numerous of BMSCs and contributed to chondrogenic differentiation, accelerating the in situ repair of defective osteochondral combined with MF. Collectively, GelMA/dECM composite hydrogel inhibited cartilage pyroptosis and reduced the pathway of chondrocyte death. Moreover, the hydrogel combined with microfracture technique could accelerate the repair of osteochondral defects. This is a groundbreaking attempt by tissue engineering, cell biology, and clinical medicine.

GPRASP2 deficiency contributes to apoptosis in the spiral ganglion cells via the AMPK/DRP1 signaling pathway.

G protein-coupled receptor-associated sorting protein 2 (GPRASP2) deficiency has been implicated in immunological inflammation, cancers, and neurological disorders. Our previous work revealed that the pathogenic mutation in GPRASP2 was responsible for X-linked recessive syndromic hearing loss (SHL). Given the specific high expression of GPRASP2 in the spiral ganglion, GPRASP2 likely contributes to the maintenance and functionality of neurons, potentially playing a role in synaptic transmission. The impact of GPRASP2 deficiency on spiral ganglion cells (SGCs) and their underlying pathogenic mechanisms will be investigated in this study. The primary culture of SGCs obtained from mouse cochleae was treated with Gprasp2-targeting short hairpin RNA (Gprasp2-shRNA) via lentivirus infection. The results showed that GPRASP2 deficiency enhanced SGCs apoptosis and decreased cell viability. Meanwhile, a significant abnormality of mitochondrial morphology and decreased membrane potential were observed in GPRASP2-deficient SGCs. These effects could be mitigated by treatment with the mitochondrial division inhibitor 1 (Mdivi-1). In addition to enhancing SGCs apoptosis and decreasing cell viability, GPRASP2 deficiency also inhibited the development of SGCs in mouse cochlear explant culture. Our study further revealed that this deficiency resulted in increased phosphorylation of AMPK and activation of the AMPK/DRP1 pathway, promoting SGCs apoptosis. These findings provide insight into the pathogenic mechanisms by which GPRASP2 deficiency is implicated in auditory dysfunction.

Ligation-assisted endoscopic submucosal resection following unroofing technique for small esophageal subepithelial lesions originating from the muscularis propria.

BACKGROUND: The majority of esophageal subepithelial lesions originating from the muscularis propria (SEL-MPs) are benign in nature, although a subset may exhibit malignant characteristics. Conventional endoscopic resection techniques are time-consuming and lack efficacy for small SEL-MPs. AIM: To evaluate the efficacy and safety of ligation-assisted endoscopic submucosal resection (ESMR-L) following unroofing technique for small esophageal SEL-MPs. METHODS: From January 2021 to September 2023, 17 patients diagnosed with esophageal SEL-MPs underwent ESMR-L following unroofing technique at the endoscopy center of Shenzhen People's Hospital. Details of clinicopathological characteristics and clinical outcomes were collected and analyzed. RESULTS: The mean age of the patients was 50.12 ± 12.65 years. The mean size of the tumors was 7.47 ± 2.83 mm and all cases achieved en bloc resection successfully. The average operation time was 12.2 minutes without any complications. Histopathology identified 2 Lesions (11.8%) as gastrointestinal stromal tumors at very low risk, 12 Lesions (70.6%) as leiomyoma and 3 Lesions (17.6%) as smooth muscle proliferation. No recurrence was found during the mean follow-up duration of 14.18 ± 9.62 months. CONCLUSION: ESMR-L following roofing technique is an effective and safe technique for management of esophageal SEL-MPs smaller than 20 mm, but it cannot ensure en bloc resection and may require further treatment.

Impact of steel slag, gypsum, and coal gangue on microbial immobilization of metal(loid)s in non-ferrous mine waste dumps.

Non-ferrous mine waste dumps globally generate soil pollution characterized by low pH and high metal(loid)s content. In this study, the steel slag (SS), gypsum (G), and coal gangue (CG) combined with functional bacteria consortium (FB23) were used for immobilizing metal(loid)s in the soil. The result shown that FB23 can effectively decrease As, Pb, and Zn concentrations within 10 d in an aqueous medium experiment. In a 310-day field column experiment, solid waste including SS, G, and CG combined with FB23 decreased As, Cd, Cu, and Pb concentrations in the aqueous phase. Optimized treatment was obtained by combining FB23 with 1% SS, 1% G, and 1.5% CG. Furthermore, the application of solid waste (SS, G, and CG) increased the top 20 functional bacterial consortium (FB23) abundance at the genus level from 1% to 21% over 50 days in the soil waste dump. Moreover, dissolved organic carbon (DOC) and pH were identified as the main factors influencing the reduction in bioavailable As, Cd, Cu, and Pb in the combination remediation. Additionally, the reduction of Fe and sulfur S was crucial for decreasing the mobilization of the metal(loid)s. This study provides valuable insights into the remediation of metal contamination on a larger scale.

[Effect of Three Foliar Inhibitors on Accumulation of Cd and As in Rice Grains].

This study investigated the impact of single and combined applications of three foliar inhibitors on the accumulation of cadmium （Cd） and arsenic （As） in rice grains. Two rice varieties, Songyazao 1 （for early rice） and Wuxiang Youyue （for late rice）, were selected for this experiment. We established nine treatments using a pot experiment method, including a control （CK） treated with no foliar inhibitor and three individual foliar inhibitors： cysteine （L-Cys）, potassium sulfide （K2S）, and dipotassium hydrogen phosphate （K2HPO4）. We then combined the applications of two foliar inhibitors： L-Cys with low/high concentrations of K2S, L-Cys with low/high concentrations of K2HPO4, and K2S with a low concentration of K2HPO4. The results showed that the single and combined applications of foliar inhibitors reduced Cd and As concentrations in rice grains. The Cd content in brown rice treated with L-Cys and K2S/K2HPO4 was reduced below the standard limit for food safety of 0.20 mg·kg-1. Compared to the CK, the content of inorganic arsenic （IAs） in early and late rice decreased by 4.68%-56.75% and 2.84%-16.91%, respectively. Foliar inhibitors applied individually or in combinations facilitated the transport of Cd and As from the stem to the leaf while inhibiting their transport from the leaf to the rice grain. This resulted in the sequestration of Cd and As within the leaf cell wall, ultimately reducing the content of these elements in rice grains. Among the combination treatments, the application of L-Cys and high-concentration K2S achieved the best results. The Cd content in early and late rice decreased by 37.64% and 26.37%, respectively, falling below 0.20 mg·kg-1. The IAs content in early and late rice was reduced to 0.10 mg·kg-1 （below 0.20 mg·kg-1） and 0.24 mg·kg-1, respectively. This study provides a valuable theoretical foundation and empirical data to support the achievement of safe rice production practices.

Depression and Anxiety among Migrant Older Adults during the COVID-19 Pandemic in China: Network Analysis of Continuous Cross-Sectional Data.

Many Chinese migrant older adults are more prone to mental health problems due to their "migrant" status. During the COVID-19 pandemic, restrictions on their mobility exacerbated these conditions. Mental health is a crucial dimension of healthy aging. Network analysis offers a novel method for exploring interactions between mental health problems at the symptom level. This study employs network analysis to examine the interactions between comorbid depressive and anxiety symptoms across different stages of the COVID-19 pandemic. Surveys were conducted from September 2019 to January 2020 (T1), September 2020 to January 2021 (T2), and September 2021 onwards (T3). Depression and anxiety symptoms were measured by the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Expected Influence (EI) and Bridge Expected Influence (Bridge EI) were used to identify central and bridge symptoms in the network. Network stability and accuracy tests were performed. Among the Chinese migrant older adults, the anxiety prevalence was 18.50% at T1, 21.11% at T2, and 9.38% at T3. The prevalence of depression was 26.95% at T1, 55.44% at T2, and 60.24% at T3. The primary central symptoms included 'Afraid something will happen' (A2), 'Irritability' (A6), 'Panic' (A7), 'Feeling of worthlessness' (D6), 'Anhedonia' (D1), and 'Feeling of fear' (A5). The major bridge symptoms included 'Feeling of fear' (A5), 'Panic' (A7), 'Irritability' (A6), 'Fatigue' (D4), 'Anhedonia' (D1), and 'Depressed or sad mood' (D2). Differences in network structure were observed across the periods. The network analysis further revealed the evolving relationships between central and bridge symptoms over time, highlighting the importance of targeted intervention strategies for central and bridge symptoms of comorbid depression and anxiety at different periods.

Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers.

A previous study using Thermostable Group II Intron Reverse Transcriptase sequencing (TGIRT-seq) found human plasma contains short (≤300 nt) structured full-length excised linear intron (FLEXI) RNAs with potential to serve as blood-based biomarkers. Here, TGIRT-seq identified >9,000 different FLEXI RNAs in human cell lines, including relatively abundant FLEXIs with cell-type-specific expression patterns. Analysis of public CLIP-seq datasets identified 126 RNA-binding proteins (RBPs) that have binding sites within the region corresponding to the FLEXI or overlapping FLEXI splice sites in pre-mRNAs, including 53 RBPs with binding sites for ≥30 different FLEXIs. These included splicing factors, transcription factors, a chromatin remodeling protein, cellular growth regulators, and proteins with cytoplasmic functions. Analysis of ENCODE datasets identified subsets of these RBPs whose knockdown impacted FLEXI host gene mRNA levels or proximate alternative splicing, indicating functional interactions. Hierarchical clustering identified six subsets of RBPs whose FLEXI binding sites were co-enriched in six subsets of functionally related host genes: AGO1-4 and DICER, including but not limited to agotrons or mirtron pre-miRNAs; DKC1, NOLC1, SMNDC1, and AATF (Apoptosis Antagonizing Transcription Factor), including but not limited to snoRNA-encoding FLEXIs; two subsets of alternative splicing factors; and two subsets that included RBPs with cytoplasmic functions (e.g., LARP4, PABPC4, METAP2, and ZNF622) together with regulatory proteins. Cell fractionation experiments showed cytoplasmic enrichment of FLEXI RNAs with binding sites for RBPs with cytoplasmic functions. The subsets of host genes encoding FLEXIs with binding sites for different subsets of RBPs were co-enriched with non-FLEXI other short and long introns with binding sites for the same RBPs, suggesting overarching mechanisms for coordinately regulating expression of functionally related genes. Our findings identify FLEXIs as a previously unrecognized large class of cellular RNAs and provide a comprehensive roadmap for further analyzing their biological functions and the relationship of their RBPs to cellular regulatory mechanisms.

Irinotecan hydrochloride liposome HR070803 in combination with 5-fluorouracil and leucovorin in locally advanced or metastatic pancreatic ductal adenocarcinoma following prior gemcitabine-based therapy (PAN-HEROIC-1): a phase 3 trial.

Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1-8.4] versus 5.0 months [95% CI 4.3-6.0]; HR 0.63 [95% CI 0.48-0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.

Hepatic and extrahepatic metabolic modulation in hbv-related decompensated cirrhosis and acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.

Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.

Simultaneous measurement of methane, propane and isobutane using a compact mid-infrared photoacoustic spectrophone.

Hydrocarbon gas sensing is a challenging task using laser absorption spectroscopy due to the complex and broad structure of absorption lines. This application requires quick, accurate and highly sensitive detection of hydrocarbon gases concentrations. In this paper, a compact photoacoustic spectrophone was developed to simultaneously measure methane, propane and isobutane. This spectrophone uses wavelength modulation spectroscopy (WMS) with a single acoustic resonator and a single DFB laser emitting at 3368 nm, which greatly reduces the system complexity without using time-division multiplexing technology for multi-gas sensing. Due to the complex and broadband absorption of hydrocarbon gases, a novel signal processing method based on multilinear regression with Ridge regression (MLR-RG) is proposed to reduce the measurement error caused by the nonlinearity of spectra signal. For single gas measurement, the detection limits of methane, propane, and isobutane are determined to be 828 ppb, 419 ppb, and 619 ppb (SNR = 1, integration time = 20 s), respectively. For simultaneous multi-gas sensing in a gaseous mixture, the detection limits of propane and isobutane are determined to be 7 ppb, 68 ppb with an integration time of 860 s, 460 s, respectively. The measurement accuracy of propane and isobutane using MLR-RG is higher than that of ordinary least squares regression and partial least squares regression by 75% and 60%, respectively. The proposed algorithm based on MLR-RG provides a promising approach to process the broad overlapping absorption spectra for accurately retrieving hydrocarbon gases concentrations.