FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. Here, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in PDAC patients. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of ITGB5 mRNA and activated FAK signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32-eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32-eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible PDAC patients for treatment with defactinib.

Normal spinopelvic parameters and correlation analysis in 217 asymptomatic children.

BACKGROUND: Understanding spinal sagittal balance is crucial for assessing and treating spinal deformities in pediatric populations. OBJECTIVE: The aim of the present observational study is to examine the parameters of sagittal alignment of the regional spine and spinopelvic region in asymptomatic pediatric populations and the characteristics of these parameters with age and sex. METHODS: We enrolled 217 participants, consisting of 112 males (51.6%) and 105 females (48.4%), aged between 4 and 15 years, with an average age of 12.19 years. Pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, thoracic kyphosis, T1 slope, C7 slope, cervical sagittal vertical axis, and C2-7 Cobb angle were measured. Three spine surgeons conducted radiographic measurements utilizing the PACS software. The measurement reliability was assessed through ICCs. RESULTS: Our results show significant age-related changes in pelvic tilt and cervical sagittal vertical axis, with notable gender differences in pelvic tilt, lumbar lordosis, and thoracic kyphosis. Girls have larger PT, boys have larger cSVA. PI, PT, and cSVA also differ among different age groups. Correlation analysis shows that a series of relationships that align with adult population patterns between pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, and thoracic kyphosis. CONCLUSION: Significant variations in PT and cSVA across diverse age cohorts highlights notable disparities in the distribution of PT and cSVA values within the pediatric population. Gender-based differences in PT, LL, and TK and correlation in spinopelvic parameter could enhances our understanding of compensatory mechanisms.

Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.

Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. In addition, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A, demonstrating potent and specific inhibition of YAP1/TAZ-TEAD-mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

Dynamic radiological features predict pathological response after neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immunochemotherapy (NICT) plus esophagectomy has emerged as a promising treatment option for locally advanced esophageal squamous cell carcinoma (LA-ESCC). Pathologic complete response (pCR) is a key indicator associated with great efficacy and overall survival (OS). However, there are insufficient indicators for the reliable assessment of pCR. METHODS: 192 patients with LA-ESCC treated with NICT from December 2019 to October 2023 were recruited. According to pCR status, patients were categorized into pCR group (22.92%) and non-pCR group (77.08%). Radiological features of pretreatment and preoperative CT images were extracted. Logistic and COX regressions were trained to predict pathological response and prognosis, respectively. RESULTS: Four of the selected radiological features were combined to construct an ESCC preoperative imaging score (ECPI-Score). Logistic models revealed independent associations of ECPI-Score and vascular sign with pCR, with AUC of 0.918 in the training set and 0.862 in the validation set, respectively. After grouping by ECPI-Score, a higher proportion of pCR was observed among the high-ECPI group and negative vascular sign. Kaplan Meier analysis demonstrated that recurrence-free survival (RFS) with negative vascular sign was significantly better than those with positive (P = 0.038), but not for OS (P = 0.310). CONCLUSIONS: This study demonstrates dynamic radiological features are independent predictors of pCR for LA-ESCC treated with NICT. It will guide clinicians to make accurate treatment plans.

Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation.

Ferroptosis, a novel form of iron-dependent non-apoptotic cell death, plays an active role in the pathogenesis of diverse diseases, including cancer. However, the mechanism through which ferroptosis is regulated in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, our study, via combining bioinformatic analysis with experimental validation, showed that ferroptosis is inhibited in PDAC. Genome-wide sequencing further revealed that the ferroptosis activator imidazole ketone erastin (IKE) induced upregulation of the E3 ubiquitin ligase RBCK1 in PDAC cells at the transcriptional or translational level. RBCK1 depletion or knockdown rendered PDAC cells more vulnerable to IKE-induced ferroptotic death in vitro. In a mouse xenograft model, genetic depletion of RBCK1 increased the killing effects of ferroptosis inducer on PDAC cells. Mechanistically, RBCK1 interacts with and polyubiquitylates mitofusin 2 (MFN2), a key regulator of mitochondrial dynamics, to facilitate its proteasomal degradation under ferroptotic stress, leading to decreased mitochondrial reactive oxygen species (ROS) production and lipid peroxidation. These findings not only provide new insights into the defense mechanisms of PDAC cells against ferroptotic death but also indicate that targeting the RBCK1-MFN2 axis may be a promising option for treating patients with PDAC.

Neuro-stimulating effect of Citri Reticulata Pericarpium Viride essential oil through regulating Glu/NMDAR on olfactory bulb to improve anxiety-like behavior.

ETHNOPHARMACOLOGICAL RELEVANCE: Citri Reticulata Pericarpium Viride (also known Qing-Pi or QP) is a plant in the Rutaceae family, QP is a traditional Qi-regulating medicine in Chinese medicine that is compatible with other Chinese medicine components and has extensive clinical practice in treating anxiety and depression. Reports on the pharmacological effects of QP have demonstrated its neuroprotective effects and antioxidant capacities. Numerous pharmacological benefits of QP are attributed to its antioxidant abilities. Anxiety disorders are a broadly defined category of mental illnesses. Oxidative stress and an imbalance in the antioxidant defense system are typical pathological features of these disorders. AIM OF THE STUDY: The aim of this study was to evaluate the effects of QP essential oil on anxiety using animal models and investigate the underlying neurobiological mechanisms. MATERIALS AND METHODS: This study aimed to develop an animal model of anxiety using chronic restraint stress and investigate the effects of inhalation of Citri Reticulata Pericarpium Viride essential oil on anxiety-like behavior, olfactory function, and olfactory bulb neurogenesis in mice with anxiety. RESULTS: The results showed that long-term chronic restraint stimulation caused a decrease in olfactory function, significant anxiety-like behavior, and a notable reduction in the number of neurons in the olfactory bulb. However, inhalation of Citri Reticulata Pericarpium Viride essential oil reversed these effects, improving the olfactory function, neuro-stimulating effect, alleviating anxiety-like behavior, and regulating theta (4-12Hz) oscillation in the hippocampus DG area. These effects were associated with changes in the expression levels of glutamate receptor NMDAR and NeuN in olfactory bulb. CONCLUSIONS: The study revealed that mice with anxiety induced by chronic restraint stress exhibited significant olfactory dysfunction, providing strong evidence for the causal relationship between anxiety disorders and olfactory dysfunction. Moreover, QP essential oil has the potential to be developed as a therapeutic drug for anxiety disorders, in addition to its role as a complementary anxiolytic.

Highly sensitive optical fiber pressure sensor based on the FPI and Vernier effect via femtosecond laser plane-by-plane writing technology.

In this paper, a highly sensitive pressure sensor based on fiber-optic Fabry-Perot interferometers (FPIs) and the Vernier effect (VE) is proposed and experimentally demonstrated. We employ a closed capillary-based F P I s for the sensing cavity, and an F P I r created through femtosecond laser refractive index modulation for the reference cavity, which remains impervious to pressure changes. Connecting these two FPIs in series produces a VE-based cascaded sensor with a clear spectral envelope. The femtosecond laser micromachining technique provides precise control over the length of F P I r and facilitates adjustments to the VE's amplification degree. Experimental results reveal significant pressure sensitivities of -795.96p m/M P a and -3219.91p m/M P a, respectively, representing a 20-fold and 80-fold improvement compared to F P I s (-39.80p m/M P a). This type of sensor has good sensitivity amplification and, due to its all-fiber structure, can be a promising candidate for high-temperature and high-pressure sensing, especially in harsh environments.

Association between Life's Essential 8 score and high-sensitivity C-reactive protein: A cross-sectional study from NHANES 2015-2018.

BACKGROUND: Earlier studies showed a negative correlation between life's simple 7 (LS7) and high-sensitivity C-reactive protein (hs-CRP), but no association has been found between life's essential 8 (LE8), an improved version of LS7, and hs-CRP. HYPOTHESIS: This study investigated the association between LE8 and hs-CRP utilizing data from the National Health and Nutritional Examination Survey. METHODS: A total of 7229 adults were incorporated in our study. LE8 was scored according to American Heart Association guidelines, and LE8 was divided into health behaviors and health factors. Serum samples of the participants were used to measure hs-CRP. To investigate the association between LE8 and hs-CRP, weighted linear regression, and restricted cubic spline were utilized. RESULTS: Among 7229 participants, the average age was 48.03 ± 16.88 years, 3689 (51.2%) were females and the median hs-CRP was 1.92 (0.81-4.49) mg/L. In adjusted weighted linear regression, a negative correlation was observed between the LE8 score and hs-CRP. Compared with the low LE8 score, the moderate LE8 score ß was -0.533 (-0.646 to -0.420), and the high LE8 score ß was -1.237 (-1.376 to -1.097). Health behaviors and health factors were also negatively associated with hs-CRP. In stratified analyses, the negative correlation between LE8 and hs-CRP remained consistent across subgroups. CONCLUSION: There was a negative correlation between LE8 as well as its sub-indicator scores and hs-CRP. Maintaining a positive LE8 score may be conducive to lowering the level of hs-CRP.

Effects of Levosimendan on Diaphragmatic Dysfunction in Patients with Sepsis.

OBJECTIVE: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. METHODS: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBT) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 minutes, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The pre- and post-administration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). RESULTS: Forty-four patients were enrolled in the study. We found that post-administration of levosimendan, the patients' tidal volume (GCSMV) increased, while the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO2) decreased when compared to the pre-administration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively), and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant (P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the post-administration levels of DE, TFdi, and D-RSBI as compared to the pre-administration period (P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning (P = 0.545). CONCLUSION: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

131I Induced In Vivo Proteolysis by Photoswitchable azoPROTAC Reinforces Internal Radiotherapy.

Photopharmacology, incorporating photoswitches such as azobenezes into drugs, is an emerging therapeutic method to realize spatiotemporal control of pharmacological activity by light. However, most photoswitchable molecules are triggered by UV light with limited tissue penetration, which greatly restricts the in vivo application. Here, this study proves that 131I can trigger the trans-cis photoisomerization of a reported azobenezen incorporating PROTACs (azoPROTAC). With the presence of 50 µCi mL-1 131I, the azoPROTAC can effectively down-regulate BRD4 and c-Myc levels in 4T1 cells at a similar level as it does under light irradiation (405 nm, 60 mW cm-2). What's more, the degradation of BRD4 can further benefit the 131I-based radiotherapy. The in vivo experiment proves that intratumoral co-adminstration of 131I (300 µCi) and azoPROTC (25 mg kg-1) via hydrogel not only successfully induce protein degradation in 4T1 tumor bearing-mice but also efficiently inhibit tumor growth with enhanced radiotherapeutic effect and anti-tumor immunological effect. This is the first time that a radioisotope is successfully used as a trigger in photopharmacology in a mouse model. It believes that this study will benefit photopharmacology in deep tissue.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Electronic structure and optical properties of nitrogen-doped antimonene under biaxial strain: first-principles study.

CONTENT: In this thesis, the role of N atom doping and biaxial strain in modulating the electronic structure and optical properties of antimonene has been deeply investigated using a first-principles approach based on density-functional theory. The results show that N doping significantly reduces the band gap of antimonene and introduces new electronic states, thus affecting its electronic structure. In terms of optical properties, N doping reduces the static permittivity of antimonene and alters its absorption, reflection, and energy loss properties. In addition, biaxial strain further enhanced the modulation effect of these properties. This study not only provides theoretical support for the application of antimonene in the field of high-performance two-dimensional electronic and optoelectronic devices, but also reveals strain and doping as an effective means to modulate the physical properties of two-dimensional materials. METHODS: For the calculations, we used the DFT-based CASTEP software package for the simulation of the electronic structure. In order to more accurately characterize the weak interactions between two-dimensional materials, we specifically introduced the Van der Waals dispersion correction. We have chosen the Perdew-Burke-Ernzerhof (PBE) exchange-correlation generalization under the generalized gradient approximation (GGA) and combined it with the Van der Waals correction term in order to fully consider the electronic structure of antimonene. For the calculation parameter settings, we set the truncation energy to 400 eV to ensure the accuracy of the calculation. Meanwhile, we adopt a 6 × 6 × 1 k-point grid for Brillouin zone sampling to obtain more accurate energy band structure and density of states information. For the convergence settings, the convergence criteria for both the system energy and the interaction force between atoms were set to 1 × 10-5 eV and 0.01 eV/Å, respectively. We selected a 3 × 3 × 1 supercell model with 18 Sb atoms. A vacuum thickness of 18 Å was established in the Z direction, which is sufficient to avoid interactions between the two atomic layers above and below the periodic structure.

Adsorption of Zn atoms by monolayer WS2 doped with different atoms X (X = O, Se, N, P, F, Cl): first principles study.

CONTEXT: The effect of X (X = O, Se, N, P, F, Cl) doping on the adsorption of Zn atoms by WS2 was investigated based on first principles. The electronic structure and optical properties of the adsorbed system after atomic doping were calculated. It is found that the Zn atom adsorbed on the W top (Tw) site has the most stable structure. When an S atom is replaced with an X atom based on the adsorption system, where the adsorption energy decreases after doping of O, P, F, and Cl atoms compared to the undoped system, it means that each system is more stable after doping of these atoms; charge transfer shows that the adsorption system after P-atom doping the system around the Zn atom loses electrons while S-atom gains electrons, which indicates that P-atom doping is favorable for the adsorption of Zn by WS2, N, P-atom is introduced as p-type doping and F, Cl-atom is introduced undoped by n-type doping, and the band gap of the doped system is less than that of the undoped one. With the introduction of different dopant atoms, certain impurity energy levels are introduced into the adsorption system. The prohibited bandwidth around the Fermi energy level reduces the density of states, causing the doped system's density of states to shift to lower energies, among which the shifts of N, P, F, and Cl are more pronounced. The P-doped adsorption system shows a new peak near the energy of - 11 eV. In addition, the study of optical properties showed that the peak reflections of both doped and non-doped systems adsorbing Zn atoms appeared in the ultraviolet region; the absorbance coefficient of the doped system is moved in the lower energy direction and red-shifted after atom doping; in addition, the absorption coefficients and reflectance of the P, Se doped systems are enhanced in the wavelength range of 200-300 nm compared with that before doping, the dielectric function and CBM and VBM positions were also calculated further indicating the potential of Se-doped systems in improving photocatalytic efficiency. METHODS: In this paper, the structure optimization of X (X = O, Se, N, P, F, Cl) doping on WS2 adsorbed Zn atom model is performed based on the CASTEP module in Materials-Studio software under the first principles using GGA and PBE generalized function. The corresponding binding energies, bond lengths, bond angles, charge densities, energy band structures, densities of states, and optical properties were also analyzed. The Monkhorst-Pack particular K-point sampling method is used in the calculations; the K-point grid is 6 × 6 × 1, and the cutoff energy for the plane wave expansion is 500 eV. After geometric optimization, the iterative accuracy converges to a value of less than 1 × 10-5 eV/atom for the total energy of each atom and less than 0.03 eV/Å for all atomic forces. The thickness of the vacuum layer was set to 20 Å to avoid the effect of interlayer interaction forces. In this paper, 27 atoms were used to form a 3 × 3 × 1 supercellular tungsten disulfide system consisting of 18 S atoms and 9 W atoms.

Enhancing Specific Fluorescence In Situ Hybridization with Quantum Dots for Single-Molecule RNA Imaging in Formalin-Fixed Paraffin-Embedded Tumor Tissues.

Single-molecule fluorescence in situ hybridization (smFISH) represents a promising approach for the quantitative analysis of nucleic acid biomarkers in clinical tissue samples. However, low signal intensity and high background noise are complications that arise from diagnostic pathology when performed with smFISH-based RNA imaging in formalin-fixed paraffin-embedded (FFPE) tissue specimens. Moreover, the associated complex procedures can produce uncertain results and poor image quality. Herein, by combining the high specificity of split DNA probes with the high signal readout of ZnCdSe/ZnS quantum dot (QD) labeling, we introduce QD split-FISH, a high-brightness smFISH technology, to quantify the expression of mRNA in both cell lines and clinical FFPE tissue samples of breast cancer and lung squamous carcinoma. Owing to its high signal-to-noise ratio, QD split-FISH is a fast, inexpensive, and sensitive method for quantifying mRNA expression in FFPE tumor tissues, making it suitable for biomarker imaging and diagnostic pathology.

The NF-κB/NUAK2 signaling axis regulates pancreatic cancer progression by targeting SMAD2/3.

Nuclear factor kappa B (NF-κB) plays a pivotal role in the development of pancreatic cancer, and its phosphorylation has previously been linked to the regulation of NUAK2. However, the regulatory connection between NF-κB and NUAK2, as well as NUAK2's role in pancreatic cancer, remains unclear. In this study, we observed that inhibiting NUAK2 impeded the proliferation, migration, and invasion of pancreatic cancer cells while triggering apoptosis. NUAK2 overexpression partially resisted apoptosis and reversed the inhibitory effects of the NF-κB inhibitor. NF-κB transcriptionally regulated NUAK2 transcription by binding to the promoter region of NUAK2. Mechanistically, NUAK2 knockdown remarkably reduced the expression levels of p-SMAD2/3 and SMAD2/3, resulting in decreased nuclear translocation of SMAD4. In SMAD4-negative cells, NUAK2 knockdown impacted FAK signaling by downregulating SMAD2/3. Moreover, NUAK2 knockdown heightened the sensitivity of pancreatic cancer cells to gemcitabine, suggesting that NUAK2 inhibitors could be a promising strategy for pancreatic cancer treatment.

Disruption of intestinal epithelial permeability in the Co-culture system of Caco-2/HT29-MTX cells exposed individually or simultaneously to acrylamide and ochratoxin A.

Mycotoxins and thermal processing hazards are common contaminants in various foods and cause severe problems in terms of food safety and health. Combined use of acrylamide (AA) and ochratoxin A (OTA) would result in more significant intestinal toxicity than either toxin alone, but the underlying mechanisms behind this poor outcome remain unclear. Herein, we established the co-culture system of Caco-2/HT29-MTX cells for simulating a real intestinal environment that is more sensitive to AA and OTA, and showed that the combination of AA and OTA could up-regulate permeability of the intestine via increasing LY permeabilization, and decreasing TEER, then induce oxidative stress imbalance (GSH, SOD, MDA, and ROS) and inflammatory system disorder (TNF-α, IL-1ß, IL-10, and IL-6), thereby leading a rapid decline in cell viability. Western blot, PAS- and AB-staining revealed that AA and OTA showed a synergistic effect on the intestine mainly through the disruption of tight junctions (TJs) and a mucus layer. Furthermore, based on correlation analysis, oxidative stress was more relevant to the mucus layer and TJs. Therefore, our findings provide a better evaluation model and a potential mechanism for further determining or preventing the combined toxicity caused by AA and OTA.

Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1.

Tumor-resident microbiota in breast cancer promote cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increases the chemosensitivity of breast cancer by impairing BCSCs.