PD-L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real-world evidence.

BACKGROUND: Numerous studies have demonstrated that brain metastases patients may benefit from intracranial radiotherapy combined with immune checkpoint inhibitors (ICIs). However, it is unclear whether this treatment is effective for patients with small cell lung cancer brain metastases (SCLC-BMs). METHODS: We conducted a retrospective study by analyzing medical records of patients with SCLC-BMs from January 1, 2017 to June 1, 2022. Data related to median overall survival (mOS), median progression-free survival (mPFS), and intracranial progression-free survival (iPFS) were analyzed. RESULTS: A total of 109 patients were enrolled, of which 60 received WBRT and 49 received WBRT-ICI. Compared to the WBRT alone cohort, the WBRT-ICI cohort showed longer mOS (20.4 months vs. 29.3 months, p = 0.021), mPFS (7.9 months vs. 15.1 months, p < 0.001), and iPFS (8.3 months vs. 16.5 months, p < 0.001). Furthermore, WBRT-ICI cohort had a better response rate for both BMs. (p = 0.035) and extracranial diseases (p < 0.001) compared to those receiving WBRT alone. Notably, the use of WBRT before ICI was associated with longer mOS compared to the use of WBRT after ICI (23.3 months for the ICI-WBRT group vs. 34.8 months for the WBRT-ICI group, p = 0.020). CONCLUSION: Our results indicated that WBRT combined with immunotherapy improved survival in SCLC-BMs patients compared to WBRT monotherapy. Administering WBRT prior to ICI treatment is associated with improved survival outcomes compared to WBRT following ICI treatment, for patients with SCLC-BMs. These findings highlight the significance of conducting further prospective researches on combination strategies of intracranial radiotherapy and ICI in SCLC-BMs patients.

Newly identified peptide Nigrocin-OA27 inhibits UVB induced melanin production via the MITF/TYR pathway.

Melasma is a common skin disease induced by an increase in the content of melanin in the skin, which also causes serious physical and mental harm to patients. In this research, a novel peptide (Nigrocin-OA27) from Odorrana andersonii is shown to exert a whitening effect on C57 mice pigmentation model. The peptide also demonstrated non-toxic and antioxidant capacity, and can significantly reduce melanin content in B16 cells. Topical application effectively delivered Nigrocin-OA27 to skin's epidermal and dermal layers and exhibited significant preventive and whitening effects on the UVB-induced ear pigmentation model in C57 mice. The whitening mechanism of Nigrocin-OA27 may be related to reduced levels of the microphthalmia-associated transcription factor and the key enzyme for melanogenesis-tyrosinase (TYR). Nigrocin-OA27 also inhibited the catalytic activity by adhering to the active core of TYR, thereby reducing melanin formation and deposition. In conclusion, Nigrocin-OA27 may be a potentially effective external agent to treat melasma by inhibiting aberrant skin melanin synthesis.

Comprehensive analysis of atherosclerotic plaques reveals crucial genes and molecular mechanisms associated with plaque progression and rupture.

Background: Plaque rupture and acute atherothrombosis, resulting from continued progression of atherosclerotic plaques (APs), are major contributors to acute clinical events such as stroke or myocardial infarction. This article aimed to explore the gene signatures and potential molecular mechanisms in the progression and instability of APs and to identify novel biomarkers and interventional targets for AP rupture. Methods: The microarray data were downloaded from the Gene Expression Omnibus (GEO) database and grouped into discovery and validation cohorts. In the discovery cohort, Weighted Gene Co-Expression Network Analysis was performed for finding co-expression modules, and the Metascape database was used to perform functional enrichment analysis. Differential Expression Genes analysis subsequently was performed in the validation cohort for verification of the obtained results. Common genes were introduced into Metascape database for protein-protein interaction and functional enrichment analysis. We constructed the miRNAs-mRNAs network with the hub genes. Moreover, gene expression profiles of peripheral blood mononuclear cells (PBMCs) from peripheral blood of patients with plaque rupture were analyzed by high-throughput sequencing, and the diagnostic power of hub genes was verified by receiver operating characteristic (ROC) analysis. Results: In the discovery cohort, the brown module in GSE28829 and the turquoise module in GSE163154 were the most significant co-expression modules. Functional enrichment analysis of shared genes suggested that "Neutrophil degranulation" was the most significantly enriched pathway. These conclusions were also demonstrated by the validation cohort. A total of 16 hub genes were identified. The miRNA-mRNA network revealed that hsa-miR-665 and hsa-miR-512-3p might regulate the "Neutrophil degranulation" pathway through PLAU and SIRPA, which might play a significant role in AP progression and instability. Five hub genes, including PLAUR, FCER1G, PLAU, ITGB2, and SLC2A5, showed significantly increased expression in PBMCs from patients with plaque rupture compared with controls. ROC analysis finally identified three hub genes PLAUR, FCER1G, and PLAU that could effectively distinguish patients with APs rupture from controls. Conclusions: The present study demonstrated that the "neutrophil degranulation" signaling pathways and identified novel mRNA and miRNA candidates are closely associated with plaque progression and instability. The hub genes FCER1G, PLAUR, and PLAU may serve as biomarkers for the prospective prediction of AP rupture.

Peptide OM-LV20 protects astrocytes against oxidative stress via the 'PAC1R/JNK/TPH1' axis.

Stroke can lead to severe nerve injury and debilitation, resulting in considerable social and economic burdens. Due to the high complexity of post-injury repair mechanisms, drugs approved for use in stroke are extremely scarce, and thus, the discovery of new antistroke drugs and targets is critical. Tryptophan hydroxylase 1 (TPH1) is involved in a variety of mental and neurobehavioral processes, but its effects on stroke have not yet been reported. Here, we used primary astrocyte culture, quantitative real-time PCR, double immunofluorescence assay, lentiviral infection, cell viability analysis, Western blotting, and other biochemical experiments to explore the protective mechanism of peptide OM-LV20, which previously exhibited neuroprotective effects in rats after ischemic stroke via a mechanism that may involve TPH1. First, we showed that TPH1 was expressed in rat astrocytes. Next, we determined that OM-LV20 impacted expression changes of TPH1 in CTX-TNA2 cells and exhibited a protective effect on the decrease in cell viability and catalase (CAT) levels induced by hydrogen peroxide. Importantly, we also found that TPH1 expression induced by OM-LV20 may be related to the level of change in the pituitary adenylate cyclase-activating peptide type 1 receptor (PAC1R) and to the JNK signaling pathways, thereby exerting a protective effect on astrocytes against oxidative stress. The protective effects of OM-LV20 likely occur via the 'PAC1R/JNK/TPH1' axis, thus highlighting TPH1 as a novel antistroke drug target.

Development and Validation of a DeepSurv Nomogram to Predict Survival Outcomes and Guide Personalized Adjuvant Chemotherapy in Non-Small Cell Lung Cancer.

Objective: To develop and validate a DeepSurv nomogram based on radiomic features extracted from computed tomography images and clinicopathological factors, to predict the overall survival and guide individualized adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC). Patients and Methods: This retrospective study involved 976 consecutive patients with NSCLC (training cohort, n=683; validation cohort, n=293). DeepSurv was constructed based on 1,227 radiomic features, and the risk score was calculated for each patient as the output. A clinical multivariate Cox regression model was built with clinicopathological factors to determine the independent risk factors. Finally, a DeepSurv nomogram was constructed by integrating the risk score and independent clinicopathological factors. The discrimination capability, calibration, and clinical usefulness of the nomogram performance were assessed using concordance index evaluation, the Greenwood-Nam-D'Agostino test, and decision curve analysis, respectively. The treatment strategy was analyzed using a Kaplan-Meier curve and log-rank test for the high- and low-risk groups. Results: The DeepSurv nomogram yielded a significantly better concordance index (training cohort, 0.821; validation cohort 0.768) with goodness-of-fit (P<0.05). The risk score, age, thyroid transcription factor-1, Ki-67, and disease stage were the independent risk factors for NSCLC.The Greenwood-Nam-D'Agostino test showed good calibration performance (P=0.39). Both high- and low-risk patients did not benefit from adjuvant chemotherapy, and chemotherapy in low-risk groups may lead to a poorer prognosis. Conclusions: The DeepSurv nomogram, which is based on the risk score and independent risk factors, had good predictive performance for survival outcome. Further, it could be used to guide personalized adjuvant chemotherapy in patients with NSCLC.

Induction of Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury in Mice.

Acute myocardial infarction is a common cardiovascular disease with high mortality. Myocardial reperfusion injury can counteract the beneficial effects of heart reflow and induce secondary myocardial injury. A simple and reproducible model of myocardial infarction and myocardial ischemia-reperfusion injury is a good tool for researchers. Here, a customizable method to create a myocardial infarction (MI) model and MIRI by precision ligation of the left anterior descending coronary artery (LAD) through micromanipulation is described. Accurate and reproducible ligature positioning of the LAD helps obtain consistent results for heart injury. ST-segment changes can help to identify model accuracy. The serum level of cardiac troponin T (cTnT) is used to assess the myocardial injury, cardiac ultrasound is employed to evaluate the myocardial systolic function, and Evans-Blue/triphenyl tetrazolium chloride staining is used to measure infarct size. In general, this protocol reduces procedure duration, ensures controllable infarct size, and improves mouse survival.

Bortezomib alleviates myocardial ischemia reperfusion injury via enhancing of Nrf2/HO-1 signaling pathway.

Bortezomib is a classical proteasome inhibitor and previous researches have reported its roles of anti-oxidation and anti-inflammatory functions in various diseases. However, the role of Bortezomib in myocardial ischemia reperfusion injury (MIRI) is unclear. Thus, our research seeks to reveal the protective effects of Bortezomib pretreatment in the mice model of MIRI. First, by the optimization of Bortezomib concentration and pretreatment timepoints, we found that 0.5 mg/kg Bortezomib pretreatment 2 h before MIRI significantly attenuated pathological damage and neutrophil infiltration. Then we found that pretreatment with Bortezomib obviously increased myocardial systolic function ((left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)) and decreased infarct size, as well as serum Troponin T levels. Meanwhile, Bortezomib pretreatment also remarkably augmented oxidative stress related protein levels of Superoxide dismutase [Cu-Zn] (SOD1), Catalase (CAT) and Glutathione (GSH), while reactive oxygen species (ROS) contents and Malonaldehyde (MDA) protein level were significantly reduced. Mechanistically, Bortezomib pretreatment significantly promoted nuclear translocation of transcriptional factor nuclear factor erythroid 2-related factor 2(Nrf2) and Heme Oxygenase 1(HO-1) expression. Interestingly, co-treatment with ML-385, a new type and selective Nrf2 inhibitor, counteracted antioxidative effects induced by Bortezomib pretreatment. In conclusion, Bortezomib pretreatment mitigates MIRI by inhibiting oxidative damage which is regulated by Nrf2/HO-1 signaling pathway.

Dynamic wavefront measurement with a point diffraction interferometer based on birefringence polarization beam splitting.

In this study, we proposed a point diffraction interferometer based on birefringence polarization beam splitting (BPBS-PDI) for transmission wavefront measurements. Using the polarization beam splitting property of birefringent crystals and a specially designed calcite crystal as a polarization beam splitter, two beams of linearly polarized light with orthogonal polarization directions and a small angular separation can be obtained to produce the reference and test beams with perpendicular polarization directions through a pinhole point diffraction plate. By introducing spatial synchronization phase-shifting technology, influencing factors such as environmental vibrations on the measurement results, are reduced. Subsequently, the birefringent crystal and system error calibration methods were studied. Finally, a BPBS-PDI experimental device was set up to obtain the wavefront distribution of the lens to be tested. The experimental results are consistent with those of the ZYGO interferometer, indicating that the BPBS-PDI wavefront measurement method can be used to measure a lens transmission wavefront with high accuracy.

Type 2 innate lymphoid cells regulation by regulatory T cells attenuates atherosclerosis.

Regulatory T cells (Tregs) have been shown to attenuate the development and progression of atherosclerosis; however, the exact mechanism is still unclear. In our study, Tregs were adoptively transferred into ApoE-/- mice, and type 2 innate lymphoid cells (ILC2s) were expanded by the IL-2/Jes6-1 complex or depleted by anti-CD90.2 mAb in ApoE-/-Rag1-/- mice to study their effects on atherosclerosis. Then, Tregs were cocultured with ILC2s in vitro to analyze ILC2s number and IL-13 production. In vivo, ApoE-/-Rag1-/- mice were treated with activated Tregs with or without anti-CD90.2 mAb to explore whether Tregs reduced atherosclerosis through ILC2s. Finally, neutralizing antibodies and Transwell assay were used to investigate how Tregs regulate ILC2s. Our results show that both Tregs and ILC2s reduce atherosclerosis lesions and macrophage infiltration. Moreover, Tregs effectively expanded the number of ILC2s and increased their production of IL-13 in vivo and in vitro. Furthermore, the reductions in plaque size and macrophage infiltration by Tregs were partly reversed by anti-CD90.2 mAb. Mechanistically, our data reveal that IL-10, TGF-ß and cell-cell contacts are required for Tregs-ILC2s regulation. These results show that Tregs may play a partial protective role against atherosclerosis by expanding the number of ILC2s and consequently increasing IL-13 production.

Combined effects of interleukin-1ß and cyclic stretching on metalloproteinase expression in corneal fibroblasts in vitro.

BACKGROUND: Corneal tensile strain increases if the cornea becomes thin or if intraocular pressure increases. However, the effects of mechanical stress on extracellular matrix (ECM) remodelling in the corneal repair process and the corneal anomalies are unknown. METHODS: In this study, the combined effects of interleukin-1ß (IL-1ß) on matrix metalloproteinases (MMPs) in corneal fibroblasts under cyclic stretching were investigated in vitro. Cultured rabbit corneal fibroblasts were subjected to 5, 10 or 15 % cyclic equibiaxial stretching at 0.1 Hz for 36 h in the presence of IL-1ß. Conditioned medium was harvested for the analysis of MMP2 and MMP9 protein production using the gelatin zymography and western blot techniques. RESULTS AND CONCLUSIONS: Cyclic equibiaxial stretching changed the cell morphology by increasing the contractility of F-actin fibres. IL-1ß alone induced the expression of MMP9 and increased the production of MMP2, and 5 % stretching alone decreased the production of MMP2, which indicates that a low stretching magnitude can reduce ECM degradation. In the presence of IL-1ß, 5 and 10 % stretching increased the production of MMP2, whereas 15 % stretching increased the production of MMP9. These results indicate that MMP expression is enhanced by cyclic mechanical stimulation in the presence of IL-1ß, which is expected to contribute to corneal ECM degradation, leading to the development of post-refractive surgery keratectasia.

Induction of matrix metalloproteinase-1 by tumor necrosis factor-α is mediated by interleukin-6 in cultured fibroblasts of keratoconus.

Inflammatory molecules and matrix metalloproteinase (MMPs) have been found over-expressed in the tear film of patients with keratoconus. However, the mechanistic link between inflammatory molecules and MMPs in the pathogenesis of keratoconus remains still elusive. Therefore, we investigated the effect of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) on MMP-1 expression and used IL-6 antibody (IL-6 Ab) to examine the role of IL-6 on TNF-α mediated regulation of MMP-1 in fibroblasts of normal cornea and keratoconus. Real-time polymerase chain reaction, Enzyme-linked immunosorbent assay, and Western blot data demonstrated that MMP-1 and IL-6 were expressed in fibroblasts of normal cornea and keratoconus. Levels of MMP-1 and IL-6 were significantly higher in keratoconus than normal cornea. TNF-α treatment led to a significant increase in IL-6 levels. IL-6 treatment induced MMP-1 synthesis in normal cornea and keratoconus. TNF-α increased MMP-1 expression in a dose- and time-dependent manner and this response was completely inhibited by the IL-6 Ab. In conclusion, these results indicate that fibroblasts of keratoconus shows increased levels of IL-6 and MMP-1 gene and protein expression and IL-6 mediates the TNF-α-induced MMP-1 expression.

Expression of MMP-2, MT1-MMP, and TIMP-2 by cultured rabbit corneal fibroblasts under mechanical stretch.

Refractive surgery not only leads to tissue injury but also evokes mechanical stress increase of the cornea. How the mechanical stress affects the corneal matrix remodeling, specifically, matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases; TIMPs) is not well understood. In this study, cultured rabbit corneal fibroblasts in vitro were subjected to regimen of 5%, 10%, or 15% equibiaxial stretch at 0.1 Hz for 3 or 24 h. MMP-2 protein level was measured by gelatin zymography and Western blotting. MMP-2, membrane type 1 MMP (MT1-MMP), and TIMP-2 mRNA levels were quantified by real-time quantitative PCR. Extracellular regulated protein kinase (ERK) phosphorylation protein levels were assessed by Western blotting. Our results showed that a 15% stretch resulted in increases in MMP-2 protein, MMP-2 mRNA, and MT1-MMP mRNA levels, but a decrease in TIMP-2 mRNA level. However, a 5% stretch caused decreases in MMP-2 protein and mRNA level, but an increase in TIMP-2 mRNA level, and no change in MT1-MMP mRNA level. A 15% stretch also caused a significant increase in ERK1/2 phosphorylation. Inhibition of the mitogenactivated protein kinase (MEK) pathway with PD98059 attenuated stretch-induced increase in MMP-2 production and ERK activity. These results suggest that small-magnitude stretching may promote corneal matrix synthetic events, whereas large-magnitude stretching promotes corneal matrix degradation by changing the balance between MMPs and TIMPs in corneal fibroblasts. Large-magnitude stretch-induced increase in pro-MMP-2 production was in an ERK-dependent manner.