Correlation of serum homocysteine and cystatin C levels with prognosis in heart failure with preserved ejection fraction patients.

OBJECTIVE: This study investigated the relationship of serum homocysteine (Hcy) and cystatin C (Cys C) levels with the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: A total of 178 patients with HFpEF who were admitted to our hospital between December 2019 and November 2020 were included. Patients were grouped based on their serum Hcy and Cys C levels: high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level. Cardiac function, ventricular remodeling indices, and prognosis were compared among patients in these groups. Additionally, the predictive value of serum Hcy and Cys C levels for adverse cardiovascular events in HFpEF patients was analyzed. RESULTS: Patients' mean age in the high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level groups was 69.21 ± 4.17,67.74 ± 4.28,69.95 ± 4.98, and 67.06 ± 4.13 years old, respectively. The high Hcy level group exhibited a lower proportion of class II cardiac function according to the New York Heart Association (NYHA) classification and a higher proportion of class IV cardiac function than the normal Hcy level group, with statistically significant differences. Similarly, the high Cys C level group had a lower proportion of class II cardiac function and a higher proportion of class IV cardiac function compared with the normal Cys C level group, with statistically significant differences. Left ventricular end-diastolic internal diameter (LVEDD), left ventricular end-systolic internal diameter (LVESD), and left ventricular mass index (LVMI) were significantly higher in both the high Hcy level and high Cys C level groups compared with the normal group, with statistically significant differences. The rates of all-cause mortality and class I endpoint events were significantly higher in the high Hcy level and high Cys C level groups than in the normal group. Multifactorial logistic regression analysis demonstrated that adverse cardiovascular events were significantly associated with cardiac function class, LVEDD, LVESD, LVMI, Hcy, and Cys C in patients with HFpEF. The area under the curve (AUC) values for Hcy and Cys C, determined using receiver operating characteristic (ROC) curve analysis, were 0.778 (optimal critical value, 25.38) and 0.681 (optimal critical value, 1.56), respectively, for predicting adverse cardiovascular events. Both Hcy and Cys C serum levels were positively correlated with LVEDD, LVESD, LVMI, and NYHA classification. CONCLUSION: Serum levels of Hcy and Cys C were closely associated with cardiac function, ventricular remodeling indices, and prognosis in patients with HFpEF. These levels may serve as valuable indices for assessing HFpEF patients' health status and prognosis, providing important insights into their potential role as biomarkers for HFpEF management and prognosis.

STAT3 inhibitor Stattic Exhibits the Synergistic Effect with FGFRs Inhibitor Erdafitinib in FGFR1-positive Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC), a subset of non-small cell lung cancer (NSCLC), accounts for about 30% of all lung cancers (LC) and exhibits a dismal response to current therapeutic protocols. Existed studies have indicated that aberrations in fibroblast growth factor receptors (FGFRs) play a pivotal role in the progression of LUSC, rendering them as attractive targets for therapeutic intervention in this cancer type. This study found that Erdafitinib (Erda), a novel pan-FGF receptor tyrosine kinase inhibitor (TKI), exerted a cytotoxic effect on LUSC cells. However, STAT3, the downstream target of FGFRs, remained still activated despite Erdafitinib treatment. Then, a STAT3 inhibitor, Stattic (Sta), was concurrently used with Erdafitinib, and the combined treatment demonstrated a synergistic efficacy in both in vitro and in vivo models of LUSC when compared to that of the treatment of the Erdafitinib or Stattic alone. Further molecular studies showed that such an effect of Erdafitinib and Stattic was associated with their concurrently inhibitory effect on FGFR1 and STAT3 signaling in LUSC cells. Therefore, the findings of this study indicated that the concurrent use of Erdafitinib and Stattic is a promising therapeutic approach for the treatment of FGFR1-positive LUSC.

Combination of radiotherapy and PD-L1 blockade induces abscopal responses in EGFR-mutated lung cancer through activating CD8+ T cells.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+T cells was lower in EGFR-mutated NSCLC. In addition, CD8+T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.

Therapeutic effects of Buzhong Yiqi decoction in patients with spleen and stomach qi deficiency after routine surgery and chemotherapy for colorectal cancer.

BACKGROUND: According to the theory of traditional Chinese medicine (TCM), the spleen and stomach are the basis of acquired nature and the source of qi and blood biochemistry. After surgery and chemotherapy, patients with colorectal cancer often develop spleen and stomach qi deficiency syndrome, leading to decreased immune function. Buzhong Yiqi decoction, a classic TCM prescription, has the effect of tonifying middle-jiao and invigorating qi, boosting Yang, and suppressing immune-related inflammation. Moreover, it is widely used in the treatment of spleen and stomach qi deficiency syndrome. AIM: To investigate the effect of Buzhong Yiqi decoction on spleen and stomach qi deficiency in patients with colorectal cancer. METHODS: One hundred patients with colorectal cancer who underwent preoperative chemotherapy and laparoscopy at The First TCM Hospital of Changde from January 2022 to October 2023 were retrospectively analyzed. The patients were divided equally into control and observation groups. Both groups underwent conventional rehabilitation surgery, and the observation group was supplemented with Buzhong Yiqi decoction. SPSS 26.0 was used for statistical analyses. The χ 2 test was used for univariate analysis; independent sample t-tests were used in all cases. RESULTS: No significant differences were observed preoperatively in the general characteristics of the two groups. Fourteen days post-surgery, the abdominal distension, emaciation, loose stool, loss of appetite, and vomiting scores were significantly lower in the observation group than in the control group (P < 0.05). Immune function and interleukin (IL)-10 levels in the observation group were significantly higher than those of the control group, whereas IL-6, tumor necrosis factor-α, and C-reactive protein levels, tumor biological indexes, and adverse reactions in the observation group were significantly lower than those of the control group (P < 0.05). One month after surgery, the patients' quality of life in the observation group was significantly higher than that of the patients in the control group (P < 0.05). CONCLUSION: Buzhong Yiqi decoction can regulate inflammatory responses and metabolic processes by enhancing immune function, thereby promoting overall immune nutrition and restoring the body's balance.

Bacteroides uniformis Ameliorates Carbohydrate and Lipid Metabolism Disorders in Diabetic Mice by Regulating Bile Acid Metabolism via the Gut-Liver Axis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. METHODS: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). RESULTS: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product-vaccarin (VAC)-that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. CONCLUSIONS: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.

The diagnostic value of 68Ga-NOTA-MAL-Cys-MZHER2:342 PET/CT imaging for HER2-positive lung adenocarcinoma.

Background: The human epidermal growth factor receptor 2 gene (HER2) has been identified as a potential therapeutic target in lung adenocarcinoma (LUAD). Non-invasive positron emission tomography (PET) imaging provides a reliable strategy for in vivo determination of HER2 expression through whole-body detection of abnormalities. The PET tracer 68Ga-NOTA-MAL-Cys-MZHER2:342 has shown promising results for HER2-positive breast and gastric cancers. This study aims to evaluate the performance of 68Ga-NOTA-MAL-Cys-MZHER2:342 in vitro and in vivo models and in clinical patients with HER2-positive LUAD. Methods: NOTA-MAL-Cys-MZHER2:342 was synthesized and labeled with 68Ga. Cell uptake, cell binding ability, and stability studies of 68Ga-NOTA-MAL-Cys-MZHER2:342 were assessed both in the Calu-3 lung cancer (LC) cell line and normal mice. In vivo assessment in tumor-bearing mice was conducted using microPET imaging and biodistribution experiments. Additionally, preliminary PET/CT imaging analysis was performed on HER2-positive LC patients. Results: 68Ga-NOTA-MAL-Cys-MZHER2:342 was prepared with a radiochemical purity (RCP) exceeding 95%. The tracer demonstrated high cell uptake in HER2-overexpressing Calu-3 cells, with an IC50 of 158.9, an adequate 1.73 nM. Good stability was exhibited both in vitro and in vivo. MicroPET imaging of Calu-3-bearing mice revealed high tumor uptake and notable tumor-to-background ratios. Positive outcomes were also observed in two HER2-positive LUAD patients. Conclusion: 68Ga-NOTA-MAL-Cys-MZHER2:342 demonstrated satisfactory stability, sensitivity, and specificity. These findings suggest that 68Ga-NOTA-MAL-Cys-MZHER2:342 PET/CT imaging provides a novel tool for non-invasive visual assessment of HER2 expression in LUAD patients.

Erdafitinib promotes ferroptosis in human uveal melanoma by inducing ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling axis.

Uveal melanoma (UM) is a rare yet lethal primary intraocular malignancy affecting adults. Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that FGFR1 expression was increased in UM tumor tissues and was linked to aggressive behavior and a poor prognosis. This study assessed the anti-tumor effects of Erdafitinib, a selective pan-FGFR inhibitor, in both in vitro and in vivo UM models. Erdafitinib exhibited a robust anti-cancer activity in UM through inducing ferroptosis in the FGFR1-dependent manner. Transcriptomic data revealed that Erdafitinib mediated its anti-cancer effects via modulating the ferritinophagy/lysosome biogenesis. Subsequent research revealed that Erdafitinib exerted its effects by reducing the expression of FGFR1 and inhibiting the activity of mTORC1 in UM cells. Concurrently, it enhanced the dephosphorylation, nuclear translocation, and transcriptional activity of TFEB. The aggregation of TFEB in nucleus triggered FTH1-dependent ferritinophagy, leading to lysosomal activation and iron overload. Conversely, the overexpression of FGFR1 served to mitigate the effects of Erdafitinib on ferritinophagy, lysosome biogenesis, and the activation of the mTORC1/TFEB signaling pathway. In vivo experiments have convincingly shown that Erdafitinib markedly curtails tumor growth in an UM xenograft mouse model, an effect that is closely correlated with a decrease in FGFR1 expression levels. The present study is the first to demonstrate that Erdafitinib powerfully induces ferroptosis in UM by orchestrating the ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling. Consequently, Erdafitinib emerges as a strong candidate for clinical trial investigation, and FGFR1 emerges as a novel and promising therapeutic target in the treatment of UM.

PANoptosis: a novel target for cardiovascular diseases.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

Ultrasensitive detection of uveal melanoma using [18F]AlF-NOTA-PRGD2 PET imaging.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and early detection is critical to improve the clinical outcome of this disease. In this study, the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 (an investigational medicinal product) positron emission tomography (PET) imaging in UM xenografts and UM patients were evaluated. The cell uptake, cell binding ability and in vitro stability of [18F]AlF-NOTA-PRGD2 were evaluated in 92-1 UM cell line. MicroPET imaging and biodistribution study of [18F]AlF-NOTA-PRGD2 were conducted in 92-1 UM xenografts. Then, UM patients were further recruited for evaluating the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 PET imaging (approval no. NCT02441972 in clinicaltrials.gov). In addition, comparison of [18F]AlF-NOTA-PRGD2 and 18F-labelled fluorodeoxyglucose ([18F]FDG) PET imaging in UM xenografts and UM patients were conducted. RESULTS: The in vitro data showed that [18F]AlF-NOTA-PRGD2 had a high cell uptake, cell binding ability and in vitro stability in 92-1 UM cell line. The in vivo data indicated that 92-1 UM tumors were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer in the subcutaneous and ocular primary UM xenografts model at 60 min post-injection. And the tumor uptake of the tracer was 2.55 ± 0.44%ID/g and 1.73 ± 0.15%ID/g at these two tissue locations respectively, at 7 days after animal model construction. The clinical data showed that tumors in UM patients were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer at 60 min post-injection. In addition, [18F]AlF-NOTA-PRGD2 tracer showed higher sensitivity and specificity for PET imaging in UM xenografts and UM patients compared to [18F]FDG tracer. CONCLUSION: [18F]AlF-NOTA-PRGD2 PET imaging may be a more preferred approach in the diagnosis of primary UM compared to [18F]FDG PET imaging. Additionally, due to the high tumor-to-background ratio, [18F]AlF-NOTA-PRGD2 PET imaging seems also to be applicable for the diagnosis of UM patients with liver metastasis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02441972, Registered 1 January 2012, https://clinicaltrials.gov/study/NCT02441972 .

Clinical prediction of insufficient vaults after implantable collamer lens implantation.

AIM: To determine the factors related to preoperative ocular characters that are predictive of insufficient vault (<250 µm) after implantable collamer lens (ICL V4c; STAAR Surgical) implantation. METHODS: The participants underwent ICL surgery and were divided into the low (<250 µm) and normal (250-1000 µm) vault groups based on the postoperative vault at 3mo. The preoperative biometric parameters and clinical outcomes were compared between the two groups. The relationship between the 3-month vault values and preoperative ocular parameters were evaluated by Generalized estimating equations. RESULTS: Sixteen (23 eyes) and 36 patients (63 eyes) were in the low and normal vault groups, respectively. All implantation procedures were uneventful with no cataract formation in the early postoperative period. The sulcus-to-sulcus lens rise (STSL) and iris ciliary angle (ICA) were correlated with vault at 3mo after surgery. Every 0.1 mm increase in STSL was associated with 38.9 µm decrease in the postoperative 3-month vault. A rise of 1 degree in ICA is associated with a reduction of 4 µm in vault. CONCLUSION: Eyes with a narrow ciliary sulcus are associated with a higher rate of low vault after ICL implantation, suggesting a need for adjustments to the ICL size in these patients. Evaluating the characteristics of the ciliary sulcus contributes valuable information to predict low vault after surgery.

The RAE1-STOP1-GL2-RHD6 module regulates the ALMT1-dependent aluminum resistance in Arabidopsis.

Aluminum (Al) toxicity is one of the major constraints for crop production in acid soils, Al-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-dependent malate exudation from roots is essential for Al resistance in Arabidopsis, in which the C2H2-type transcription factor SENSITIVE TO PROTONRHIZOTOXICITY1 (STOP1) play a critical role. In this study, we reveal that the RAE1-GL2-STOP1-RHD6 protein module regulated the ALMT1-mediated Al resistance. GL2, STOP1 and RHD6 directly target the promoter of ALMT1 to suppress or activate its transcriptional expression, respectively, and mutually influence their action on the promoter of ALMT1 by forming a protein complex. STOP1 mediates the expression of RHD6 and RHD6-regulated root growth inhibition, while GL2 and STOP1 suppress each other's expression at the transcriptional and translational level and regulate Al-inhibited root growth. F-box protein RAE1 degrades RHD6 via the 26S proteasome, leading to suppressed activity of the ALMT1 promoter. RHD6 inhibits the transcriptional expression of RAE1 by directly targeting its promoter. Unlike RHD6, RAE1 promotes the GL2 expression at the protein level and GL2 activates the expression of RAE1 at the transcriptional level by directly targeting its promoter. The study provides insights into the transcriptional regulation of ALMT1, revealing its significance in Al resistance and highlighting the crucial role of the STOP1-associated regulatory networks.

PET imaging for the early evaluation of ocular inflammation in diabetic rats by using [18F]-DPA-714.

Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([18F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [18F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [18F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [18F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM.

Exploring predictive markers for liver failure post-hepatectomy in hepatocellular carcinoma patients.

This letter to the editor addresses the study titled "Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma" by Kuang et al in the World Journal of Gastrointestinal Surgery. The study acknowledges the comprehensive patient data analysis while suggesting that there is a need for further discussion on the clinical applicability of these markers across diverse patient populations. This letter recommends prospective studies for validation and considers the influence of confounding factors. This finding underscores the significance of this study in improving hepatocellular carcinoma management.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Laryngopharyngeal reflux disease: Updated examination of mechanisms, pathophysiology, treatment, and association with gastroesophageal reflux disease.

Laryngopharyngeal reflux disease (LPRD) is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus. LPRD commonly presents with sym-ptoms such as hoarseness, cough, sore throat, a feeling of throat obstruction, excessive throat mucus. This complex condition is thought to involve both reflux and reflex mechanisms, but a clear understanding of its molecular mechanisms is still lacking. Currently, there is no standardized diagnosis or treatment protocol. Therapeutic strategies for LPRD mainly include lifestyle modifications, proton pump inhibitors and endoscopic surgery. This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms, patho-physiology and treatment of LPRD. We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.

A prognostic model of idiopathic pulmonary fibrosis constructed based on macrophage and mitochondria-related genes.

BACKGROUND: Studies have shown that mitochondrial function and macrophages may play a role in the development of idiopathic pulmonary fibrosis (IPF). However, the understanding of the interactions and specific mechanisms between mitochondrial function and macrophages in pulmonary fibrosis is still very limited. METHODS: To construct a prognostic model for IPF based on Macrophage- related genes (MaRGs) and Mitochondria-related genes (MitoRGs), differential analysis was performed to achieve differentially expressed genes (DEGs) between IPF and Control groups in the GSE28042 dataset. Then, MitoRGs, MaRGs and DEGs were overlapped to screen out the signature genes. The univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm were implemented to achieve key genes. Furthermore, the independent prognostic analysis was employed. The ingenuity pathway analysis (IPA) was employed to further understand the molecular mechanisms of key genes.Next, the immune infiltration analysis was implemented to identify differential immune cells between two risk subgroups. RESULTS: There were 4791 DEGs between IPF and Control groups. Furthermore, 26 signature genes were achieved by the intersection processing. Three key genes including ALDH2, MCL1, and BCL2A1 were achieved, and the risk model based on the key genes was created. In addition, a nomogram for survival forecasting of IPF patients was created based on riskScore, Age, and Gender, and we found that key genes were associated with classical pathways including 'Apoptosis Signaling', 'PI3K/AKT Signaling', and so on. Next, two differential immune cells including Monocytes and CD8 T cells were identified between two risk subgroups. Moreover, we found that MIR29B2CHG and hsa-mir-1-3p could regulate the expression of ALDH2. CONCLUSION: We achieved 3 key genes including ALDH2, MCL1,, and BCL2A1 associated with IPF, providing a new theoretical basis for clinical treatment of IPF.

Associations of residential greenness exposure and ambient air pollutants with newly-diagnosed drug-resistant tuberculosis cases.

Growing evidence has found the health protective effects of greenness exposure on tuberculosis (TB) and the impact of ambient air pollutants on TB drug-resistance. However, it remains unclear whether residential greenness is also beneficial to reduce TB drug-resistance, and whether air pollution modify the greenness-TB resistance relationship. We enrolled 5006 newly-diagnosed TB patients from Shandong, China, during 2014 to 2021. Normalized Difference Vegetation Index (NDVI) in 250 m and 500 m buffer around individuals' residential zone was used to assess greenness exposure. All patients were divided by quartiles of NDVI250-m and NDVI500-m (from low to high: Q1, Q2, Q3, Q4) respectively. Six logistic regression models (NDVI, NDVI + PM2.5/PM10/SO2/NO2/O3) were used to estimate the association of NDVI and TB drug-resistance when adjusting different air pollutants or not. All models were adjusted for age, gender, body mass index, complications, smoking, drinking, population density, nighttime light index, road density. Compared with participants in NDVI250-m Q1 and NDVI500-m Q1, other groups had lower rates of MDR-TB, PDR-TB, RFP-resistance, SM-resistance, RFP + SM resistance, INH + RFP + EMB + SM resistance. NDVI500-m reduced the risk of multidrug resistant tuberculosis (MDR-TB) and the adjusted odds ratio (aOR, 95% confidence interval, CI) compared with NDVI500-m Q1 were 0.736 (0.547-0.991) in NDVI + PM10 model, 0.733 (0.544-0.986) in NDVI + PM2.5 model, 0.735(0.546-0.99) in NDVI + SO2 model, 0.736 (0.546-0.991) in NDVI + NO2 model, respectively, P < 0.05. NDVI500-m contributed to a decreased risk of streptomycin (SM)-resistance. The aOR of rifampicin (RFP) + SM resistance were 0.132 (NDVI250-m, Q4 vs Q1, 95% CI: 0.03-0.578), 0.199 (NDVI500-m, Q3 vs. Q1, 95% CI: 0.057-0.688) and 0.264 (NDVI500-m, Q4 vs. Q1, 95% CI: 0.087-0.799). The adjusted ORs (Q2 vs. Q1, 95% CI) of isoniazid (INH) + RFP + ethambutol (EMB) + SM resistance in 500 m buffer were 0.276 (0.119-0.639) in NDVI model, 0.279 (0.11-0.705) in NDVI + PM10 model, 0.281 (0.111-0.713) in NDVI + PM2.5 model, 0.279 (0.11-0.709) in NDVI + SO2 model, 0.296 (0.117-0.754) in NDVI + NO2 model, 0.294 (0.116-0.748) in NDVI + O3 model, respectively. The study showed, for the first time, that residential greenness exposure in 500 m buffer is beneficial for reducing newly-diagnosed DR-TB (including PDR-RB, MDR-TB, MR-TB), and ambient air pollutants may partially mediate this association.

Development of novel pyrimidine nucleoside analogs as potential anticancer agents: Synthesis, characterization, and In-vitro evaluation against pancreatic cancer.

The present study proposed modification of 5-FU by conjugation with an acyl chloride and a 5-membered heterocyclic ring to improve its in-vitro cytotoxicity and metabolic stability. XYZ-I-71 and XYZ-I-73 were synthesized by introducing a tetrahydrofuran ring on 5-fluorocytosine (a precursor of 5-FU) and conjugation with octanoyl chloride and lauroyl chloride, respectively. The structure of the synthesized compounds was validated using NMR and micro-elemental analysis. The antiproliferative activity of the analogs was determined against MiaPaCa-2, PANC-1, and BxPC-3 pancreatic cancer cells. The analog's stability in human liver microsomes was quantified by HPLC. We found that the XYZ-I-73 (IC50 3.6 ± 0.4 µM) analog was most effective against MiaPaCa-2 cells compared to XYZ-I-71(IC50 12.3 ± 1.7 µM), GemHCl (IC50 24.2 ± 1.3 µM), Irinotecan (IC50 10.1 ± 1.5 µM) and 5-FU (IC50 13.2 ± 1.1 µM). The antiproliferative effects of this analog in Miapaca-2 cells is evident based on it having a 7-fold,3-fold, and 4-fold increased cytotoxic effect over Gem-HCl, Irinotecan, and 5-FU, respectively. On the other hand, XYZ-I-71 exhibited a 2-fold increased cytotoxic effect over Gem-HCl but a comparable cytotoxic effect to 5-FU and Irinotecan in MiaPaCa-2 cells. A similar trend of higher XYZ-I-73 inhibition was observed in PANC-1 and BxPC-3 cultures. For 48-h MiaPaCa-2 cell migration studies, XYZ-I-73 (5 µM) significantly reduced migration (# of migrated cells, 168 ± 2.9), followed by XYZ-I-71(315±2.1), Gem-HCl (762±3.1) and 5-FU (710 ± 3.2). PARP absorbance studies demonstrated significant inhibition of PARP expression of XYZ-I-73 treated cells compared to 5-FU, GemHCl, and XYZ-I-71. Further, BAX and p53 expressions were significantly increased in cells treated with XYZ-I-73 compared to 5-FU, GemHCl, and XYZ-I-71. In-vitro, metabolic stability studies showed that 80 ± 5.9% of XYZ-I-71 and XYZ-I-73 remained intact after 2 h exposure in liver microsomal solution compared to 5-FU. The XYZ-I-73 analog demonstrated a remarkable cytotoxic effect and improved in-vitro metabolic stability over the selected standard drugs and may have potential anticancer activity against pancreatic cancer.

Comparison of 18 F-AlF-NOTA-PRGD2 and 18 F-FDG PET/CT Imaging in a Case of Primary Uveal Melanoma.

ABSTRACT: Uveal melanoma is the most common intraocular malignancy in adults with a high rate of metastasis and mortality. This study presented the PET/CT imaging of 18 F-AlF-NOTA-PRGD2 and 18 F-FDG in a patient with primary uveal melanoma. In addition to fundus photograph and ophthalmic ultrasonography, both 18 F-AlF-NOTA-PRGD2 and 18 F-FDG PET/CT imaging showed increased radioactive uptake in the lesions within the scan area. The tumoral lesions presented significantly higher uptake of 18 F-AlF-NOTA-PRGD2 compared with that of 18 F-FDG.

Plasma-derived from human umbilical cord blood restores ovarian function and improves serum reproductive hormones levels in mice with premature ovarian insufficiency (POI) through cytokines and growth factors.

Premature ovarian insufficiency (POI) patients experience a decline in ovarian function and a reduction in serum reproductive hormones, leading to a significant impact on the outcomes of assisted reproductive technology. Despite the absence of an effective clinical treatment to restore fertility in POI patients, recent research has indicated that cord blood plasma (CBP) derived from human umbilical cord blood (hUCB) may offer therapeutic benefits for various degenerative diseases. The primary aim of this study is to explore approaches for enhancing ovarian function and serum reproductive hormones through the administration of CBP in a murine model. Initially, hUCB was utilized to obtain CBP (CBP), which was subsequently analyzed for cytokine and growth factor profiles in comparison to adult blood plasma (ABP) by use of flow cytometry. Subsequently, POI mouse models were established through the induction of 4-vinylcyclohexene diepoxide, followed by the injection of CBP into the tail. At 7, 14, and 21 days posttreatment, mouse ovaries and blood were collected, and their estrus cycle, body weight, and ovarian weights were evaluated using precise electronic balance. Finally, ovarian morphology and follicle number were assessed through HE staining, while serum levels of anti-Müllerian hormone (AMH), estradiol (E2) and follicle-stimulating hormone (FSH) were determined by ELISA. Our study revealed that individuals with CBP exhibited significantly lower concentrations of proinflammatory cytokines, including IL-ß (p < 0.01) and IL-2 (p < 0.05), while displaying elevated levels of anti-inflammatory cytokines and chemokines, such as IL-2, IL-4, IL-6, IL-8, IL-12P70, IL-17A, IP-10, interferon-γ, and tumor necrosis factor-α (p < 0.01). Furthermore, CBP demonstrated remarkably higher levels of growth factors, including transforming growth factor-ß1, vascular endothelial growth factor, and insulin-like growth factor-1 (p < 0.01) than ABP. Notably, our investigation also revealed that CBP restored the content of serum reproductive hormones, such as AMH, E2, and FSH (p < 0.05), and increased the number of primordial and primary follicles (p < 0.01) and decreased the number of luteal and atretic follicles (p < 0.01) in vivo. Our findings suggested that CBP-secreted cytokines and growth factors could be restored POI ovarian function, enhanced serum reproductive hormones and rescued follicular development in vivo. These findings further support the potential of CBP as a promising strategy in clinical applications for POI related infertility.