Au/Doc/Quer@PDA/A10-3.2 Nanoparticles for targeted treatment of docetaxel-resistant prostate cancer.

Docetaxel (Doc), as a first-line chemotherapy drug for prostate cancer (PC), often loses its therapeutic efficacy due to acquired resistance and lack of targeting specificity. Therefore, there is a need to develop a novel drug that can overcome Doc resistance and enhance its targeting ability to inhibit PC progression. In this study, we prepared Au/Doc/Quer@PDA/A10-3.2 nanoparticles (NPs) composite drug by encapsulating Doc and quercetin (Quer) within polydopamine (PDA)-coated Au NPs and further modifying them with RNA oligonucleotide aptamer A10-3.2. A10-3.2 was used for specific targeting of prostate-specific membrane antigen (PSMA)-positive PC cells (LNCaP). Quer was employed to reverse the resistance of Doc-resistant cell line (LNCaP/R) to Doc. Physical characterization using ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful preparation of Au/Doc/Quer@PDA/A10-3.2 NPs. Fluorescence imaging and flow cytometry experiments demonstrated the targeting ability of Au/Doc/Quer@PDA/A10-3.2 NPs towards PSMA-positive LNCaP/R cells. Cell proliferation, apoptosis, invasion, and migration experiments revealed that Quer reversed the resistance of LNCaP/R cells to Doc. Immunoblotting experiments further confirmed the mechanism behind sensitization of chemotherapy by Quer. Finally, we evaluated the therapeutic efficacy of Au/Doc/Quer@PDA/A10-3.2 NPs in a mouse model of PC. In conclusion, this study synthesized and validated a novel nano-composite drug (Au/Doc/Quer@PDA/A10-3.2 NPs) for combating Doc-resistant PC, which could potentially be applied in clinical treatment of PC.

Sex-dependent association of serum uric acid levels with amyloid accumulation among amyloid-positive older adults.

We aimed to examine the potential effect of sex on the longitudinal association of baseline serum uric acid levels with brain amyloid accumulation over time among older adults with and without abnormal amyloid. At baseline, the study sample comprised 499 older adults, including 276 men and 223 women. Linear mixed-effects regression models were fitted to estimate the individual slopes of change in brain amyloid accumulation [as measured by AV45 standardized uptake value ratio (SUVR)] over time. At baseline, we did not observe a relationship between serum uric acid levels and brain amyloid deposition in women or men regardless of amyloid status. Among amyloid negative subjects, women and men did not differ in the relationship between baseline serum uric acid and the annual change in amyloid accumulation in subjects with normal amyloid levels. In amyloid positive women, serum uric acid levels were not associated with the annual change in amyloid accumulation (unstandardized ß = 0.0005, SE = 0.0006, p value = 0.4179). However, in amyloid positive men, serum uric acid levels were negatively associated with the annual change in amyloid accumulation (unstandardized ß = -0.0015, SE = 0.0005, p value = 0.0048). These findings support a potential sex-specific effect on the relationship between serum uric acid levels and amyloid accumulation among amyloid positive older adults.

Expression and prognosis analysis of integrin subunit α3 (ITGA3) in papillary thyroid cancer.

Integrin subunit α3 (ITGA3) is a member of the integrin family and interacts with extracellular matrix proteins. However, there have been few reports regarding the role of ITGA3 in papillary thyroid cancer. The expression levels of ITGA3 were firstly analyzed by bioinformatics tools and in vitro experiments, followed by evaluating its prognostic significance in papillary thyroid cancer patients using Kaplan-Meier, receiver operating characteristic, and Cox regression analyses. Then, cBioportal and GSCA databases were applied to evaluate genetic alterations of ITGA3. Functional enrichment analysis was conducted and the upstream miRNAs of ITGA3 were determined. The results showed that the ITGA3 mRNA and protein levels were higher in the papillary thyroid cancer group than those in the normal group (all P < 0.05). Moreover, ITGA3 performed well in distinguishing the recurrence-free survival (RFS) status and served as an independent prognostic factor of papillary thyroid cancer patients (P < 0.01). Besides, significant relations between ITGA3 and genetic alterations were observed (FDR <0.01). Functional enrichment analysis indicated ECM-receptor interaction and cell adhesion molecules were the shared regulatory pathways. Moreover, ITGA3 might be the target gene of hsa-miR-3129, hsa-miR-181d, hsa-miR-181b, hsa-miR-199a, and hsa-miR-199b. Of note, the ITGA3 mRNA level was reduced after has-miR-199b-3p/5p was overexpressed. In conclusion, ITGA3 could be a reliable biomarker and have potential value in predicting the RFS status of papillary thyroid cancer patients.

A novel DNA methylation signature revealed GDF6 and RCC1 as potential prognostic biomarkers correlated with cell proliferation in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) accounts for the majority (80%-90%) of renal cell carcinoma (RCC) patients at the time of diagnosis, and approximately 15% of ccRCC patients will develop distant metastasis or recurrence during their lifetime. Increasing number of studies have revealed that the aberrant DNA methylations is closely correlated with the tumorigenesis in ccRCC. RESULTS: In this study, we utilized a LASSO (least absolute shrinkage and selection operator) model to identify a combination of 13 probes-based DNA methylation signature that associated with the progression-free survival (PFS) of ccRCC patients. First, differentially methylated regions (CpGs) related to PFS and phenotypes were identified. Next, prognostic DNA methylation probes were selected from the differentially methylated probes (DMPs) and calculated risk scores to stratify patients with ccRCC. The performance of this signature was validated in an independent testing set using various analyses, including Kaplan-Meier analysis for PFS and receiver operating characteristic (ROC) curve analysis. Based on our 13-DNA methylation probes signature, ccRCC patients were successfully stratified into high- and low-risk groups. Combining DNA methylation signature with clinical variables such as T stage, M stage and tumor grade could further improve the accuracy of prediction. Moreover, we highlight two molecular biomarkers (RCC1 and GDF6) corresponding to our probes. Invitro experiments showed that knockdown of RCC1 or GDF6 in ccRCC cell lines reduced cell proliferation, which indicated that both biomarkers are associated with tumorigenesis. CONCLUSIONS: The 13-probes-based DNA methylation signature has the potential to serve as an independent tool for survival outcome improvement and treatment strategy selection for ccRCC patients. In addition, our findings suggest that RCC1 and GDF6 may serve as promising markers for ccRCC.

The effect of nutritional biochemical indexes on the hospitalization outcome of COVID-19.

Aims to investigate the relationship between nutritional biochemical indexes and hospitalization outcomes of COVID-19 patients, 132 continuous patients with COVID-19 from December 2022 to January 2023 in Lishui hospital were retrospectively analyzed, and the nutritional biochemical indexes in peripheral blood, such as total protein, albumin, calcium, phosphorus, and magnesium, were detected. Meanwhile, the levels of several cytokines and PBMC subtypes (CD4, CD3, CD8, NK and B cells) were detected too. The Spearman correlation analysis, one-way ANOVA and multivariate logit regression were conducted. Results suggested that the levels of total protein and albumin were significantly decreased in patients with poor outcomes, and the levels of calcium, phosphorus, and magnesium were significantly correlated with hospitalization outcomes. COVID-19 patients with diabetes had higher levels of IL-6 and IFN-γ than those patients without diabetes. The levels of IL-2, IFN-γ, IL-6 and Il-10 in the dead patients were significantly higher than those in the recovery and worse patients. Total protein and albumin were significantly positively correlated with levels of NK and B, CD4, CD8, CD3 lymphocytes. The levels of CD4, CD8 and CD3 lymphocytes were significantly decreased in dead patients than other patients. Multivariate logit regression analysis suggests that lymphocyte number, albumin and IL-6 are independent risk factors to evaluate the hospitalization outcome. In summary, nutritional biochemical indexes were significantly corelated with cytokines and PBMC subsets, and had an impact on the severity of COVID-19 patients. Improvement of low protein malnutrition is broad-spectrum and basic strategy to improve the hospitalization outcome of COVID-19.

The Value of Combined Detection of Serum PSA, MALAT1 and TMPRSS2-ETV1 in Evaluating the Progress and Prognosis of Prostate Cancer.

OBJECTIVE: To explore the prognostic value of combined detection of serum prostate specific antigen (PSA), lung cancer metastasis-associated transcript 1 (MALAT1), transmembrane serine protease 2 (TMPRSS2), and erythropoietin-specific transforming gene variant 1 (ETV1) in prostate cancer. METHODS: Ninety patients with prostate cancer who were treated in hospital were divided into two groups according to tumor node metastasis stage: Stage I-II group (n = 34) and stage III-IV group (n = 56). The serum levels of PSA, MALAT1, and TMPRSS2-ETV1 were detected in both groups and correlated with prostate cancer status to determine their value as indicators of disease progression and prognosis. RESULTS: Age, body mass index (BMI), and Gleason score differed significantly between the study group and the control group (p < 0.05). The expression levels of serum PSA and MALAT1 were higher in group III-IV than in group I-II, and the positive expression rate of TMPRSS2-ETV1 was significantly higher in group III-IV than in the control group (p < 0.05). Pearson's correlation analysis showed that serum PSA, MALAT1, and TMPRSS2-ETV1 were significantly correlated with prostate cancer (p < 0.05). Differences in PSA levels correlated with differences in age, BMI, type of pathology, and Gleason score, whereas differences in serum MALAT1 levels correlated with differences in age, BMI, and type of pathology. Gleason scores differed significantly between patients with positive and negative TMPRSS2-ETV1 indicators (p < 0.05). Multivariate logistic regression analysis showed that serum PSA, MALAT1, and TMPRSS2-ETV1 were independent risk factors affecting the prognosis of prostate cancer (p < 0.05). The areas under the curve (AUCs) of serum PSA, MALAT1, and TMPRSS2-ETV1 as prognostic predictors in prostate cancer were 0.692, 0.731, and 0.709, respectively, whereas the AUC of the combination was 0.819. Assessment of disease progression using the combination of indicators had a significantly higher prognostic value than single indicators (p < 0.05). CONCLUSIONS: Serum levels of PSA, MALAT1, and TMPRSS2-ETV1 were abnormal in patients with prostate cancer, and the combined detection of these factors provided a reference for assessing disease progression and predicting the prognosis of prostate cancer.

Establishment of a sensitive UPLC-MS/MS method to quantify safinamide in rat plasma.

A fast, simple, and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established for the quantification of safinamide in rat plasma. Plasma samples were treated with acetonitrile for protein precipitation, and diazepam was used as an internal standard (IS). The analytes were separated on an Acquity UPLC C18 (2.1 mm × 50 mm, 1.7 µm) chromatographic column with gradient elution using a mobile phase (0.1% formic acid-acetonitrile). Then, the eluates were detected by electrospray ionization (ESI) in positive ion mode. The analytes were quantified by multiple reaction monitoring (MRM) using the transition m/z 303.3→215.0 of safinamide and m/z 285.0→154.0 of IS. Safinamide had good linearity in the concentration range of 1.0-2000 ng/mL, and the lower limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precision and accuracy of safinamide were less than 7.63%, while the average recovery rate was 92.98%-100.29%. The method was validated to be stable and had low noise, short chromatographic run time, wide linear range, small sample volumes, low sample injection volumes, and high sensitivity. Therefore, it can be used in pharmacokinetics and preclinical and clinical studies.

Activation of cGAS-STING Signal to Inhibit the Proliferation of Bladder Cancer: The Immune Effect of Cisplatin.

Cisplatin is commonly used in neoadjuvant, adjuvant, and systemic therapy for advanced bladder cancer, but its immune-related mechanism is still unclear. Exploration of the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer. We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and explored the important function of these immune effects in the bladder cancer microenvironment in a mice tumor model. We found cisplatin induced immune response in bladder cancer by RNA sequencing and validated that cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8+ T cells and dendritic cells in a transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING. Our findings indicated a cisplatin-related immune effect in bladder cancer, and cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.

A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years.

Background and Objective: Glucocorticoids, secreted from the adrenal gland, are commonly used in the treatment of castration-resistant prostate cancer (CRPC) because of their anti-inflammatory and anti-toxic effects. However, glucocorticoids have been reported to have the opposite effects within the course of treatment. Many studies have shown that glucocorticoid receptors (GRs) are involved in the establishment of a dominant population of androgen-independent malignant cells, which may result in CRPC. In this review, we summarized the mechanisms of GRs in CRPC and the clinical application of glucocorticoids based on the present evidence. Methods: We summarized the isoforms of GRs and the mechanisms involved in CRPC. An updated literature search was performed from the ClinicalTrials database, the National Center for Biotechnology Information database and European Union Drug Regulating Authorities Clinical Trials database. The focus was on the timeframe from 2017 to 2022. At least one primary or secondary outcome [prostate-specific antigen (PSA) response rate, progression-free survival (PFS) or overall survival (OS) and median time to PSA progression] according to studies should be included. Key Content and Findings: The molecular structures and applications of the isoforms of GR have been intensively researched in the past 60 years. In recent years, researchers have pointed out that GRs may be involved in the development of CRPC via genomic and non-genomic effects. Clinical trials in the past 5 years have focused on the efficacy of drugs regarding CRPC. The use of glucocorticoids during treatments of CRPC follows the guidelines (e.g., NCCN Guidelines®, guidelines of CSCO, etc.). Based on the collected data, prednisone appears to be the most widely used steroid hormone, followed by dexamethasone. Comparisons of the PSA response rate and the median time to PSA progression revealed that the efficacy of the 2 hormones is similar; however, further research on the effect of steroid hormone in CRPC is still required. Conclusions: Various GR isoforms may play an important part in the development of CRPC, whose mechanism remains unclear. Most clinical trials have focused on the use of prednisone in the last 5 years. The efficacy of prednisone and dexamethasone is similar.

Aspirin using was associated with slower cognitive decline in patients with Alzheimer's disease.

We aimed to examine whether the use of aspirin is associated with change in cognitive performance over time, and whether this association is modified by the cognitive stages. This study included a total of 1866 subjects, including 509 subjects with normal cognition (NC), 985 subjects with mild cognitive impairment (MCI), and 372 patients with Alzheimer's disease (AD). In each group, we further categorized our subjects into two groups based on their aspirin using conditions: Aspirin users and non-aspirin users. Mini-Mental State Examination (MMSE) was the cognitive outcome. Linear mixed models were conducted to examine the longitudinal relationship between the use of aspirin and cognitive performance in each diagnostic group. In the cross-sectional analysis, there were no significant differences in MMSE scores between non-aspirin users and aspirin users in subjects with NC, subjects with MCI or patients with AD. In the longitudinal analysis, we detected an association of the baseline use of aspirin with cognitive decline (MMSE) over time in patients with AD, but not in the NC group or MCI group. Specifically, in AD patients, the use of aspirin at baseline was associated with slower cognitive decline over time. Our data may support an association between the use of aspirin and slower cognitive decline, while this association may be dependent on the clinical stages.

Transcriptionomic Study on Apoptosis of SKOV-3 Cells Induced by Phycoerythrin from Gracilaria lemaneiformis.

OBJECTIVE: To investigate the effects of Phycoerythrin (PE) on the human ovarian cancer cell line SKOV-3 and its antitumor mechanisms from a transcriptional point of view. METHODS: SKOV-3 cells were exposed to different concentrations of phycoerythrin. The efficiency of this treatment was evaluated through cell growth inhibition, changes in cell morphology, apoptosis and intracellular ROS levels. High throughput sequencing (RNA-seq) was performed to screen Differentially Expressed Genes (DEGs), which was verified using RT-PCR and Western blotting. RESULTS: PE showed a significant inhibitory effect on the growth of SKOV-3 cells in a time- and dose-dependent manner. H&E staining, electron microscopy and flow cytometry revealed that PE induced apoptosis in SKOV-3 cells. Transcriptome analysis showed that 2963 genes were differentially expressed between untreated or PEtreated cells. GO and KEGG pathway analyses identified 16 classical pathways that were enriched. We verified 8 DEGs including, JNK, GADD45A, EDEM2, RAD23, UBQLN, CAPN1, XBP1, and OS9. These results were consistent with the results from transcriptional sequences. CONCLUSION: The inhibitory effect of PE on SKOV-3 cells was a result of interaction with multiple pathways and signaling molecules. Among these, the ROS/JNK/Bcl-2 signaling pathway, upregulation of JNK, GADD45A and RAD23 as well as downregulation of XBP1 and OS9 played a critical role in the PE -induced apoptosis in human ovarian cancer cells.

Association of Plasma Transferrin With Cognitive Decline in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Objective: The objective of this study was to examine whether plasma transferrin levels are associated with longitudinal changes in cognitive performance in older individuals with normal cognition (CN), mild cognitive impairment (MCI), and mild Alzheimer's disease (AD). Methods: At baseline, there were a total of 358 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, including 58 older individuals with CN, 198 older individuals with MCI, and 102 patients with AD. Linear mixed models were utilized to examine the associations of plasma transferrin levels with changes in cognitive performance over time after adjustment of several potential covariates. The Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were used to examine the global cognition of participants. Results: First, no significant differences in the plasma transferrin levels were observed across three diagnostic groups. Second, in the cross-sectional analyses, the baseline plasma transferrin levels were negatively associated with the MMSE scores in the CN group, but not in the MCI or the AD group. Third, in the longitudinal analyses, we found that a higher plasma transferrin was associated with a steeper cognitive decline in the MCI and AD groups, but not in the CN group. Conclusion: Higher plasma transferrin levels were associated with a steeper cognitive decline in participants with MCI and AD.

Embelin Promotes Oncolytic Vaccinia Virus-Mediated Antitumor Immunity Through Disruption of IL-6/STAT3 Signaling in Lymphoma.

OBJECTIVE: Oncolytic virotherapy is a promising alternative to conventional treatment, yet limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy. METHODS: In this study, we found that use of an adjuvant of embelin, a small molecular inhibitor of XIAP, increased the replication of oncolytic vaccinia virus (OVV) by mitigating antiviral innate immunity. Moreover, embelin suppresses constitutive STAT3 phosphorylation and mitigates OVV-induced activation of STAT3 in lymphoma. In the subcutaneous lymphoma model, embelin significantly enhanced the therapeutic efficacy of OVV and prolonged the survival. In addition, embelin significantly increased the OVV-induced infiltration of T cells and NK cells and decreased the number of OVV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. RESULTS: Our results explored the ability of OVV and embelin in combination to enhance lymphoma cell lysis, revealing a beneficial combinatorial effect wherein both lymphoma cell lysis and OVV replication were enhanced both in vitro and in an in vivo murine model system. CONCLUSION: Our findings indicate the utility of embelin as an adjuvant for oncolytic viro-immunotherapy.