Search Results (3,930)

Background: Uric acid levels are linked to cardiovascular outcomes and mortality, especially in chronic kidney disease (CKD). However, their impact across varying kidney function remains unclear. Methods: We conducted a retrospective cohort study using the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) database from a single center. Adult patients with at least one serum uric acid measurement between 2002 and 2021 were included and categorized by estimated glomerular filtration rate (eGFR): normal kidney function (≥90 mL/min/1.73 m²), mild dysfunction (60–89 mL/min/1.73 m²), moderate dysfunction (30–59 mL/min/1.73 m²), and advanced dysfunction (<30 mL/min/1.73 m²). The primary outcome was all-cause mortality with secondary outcomes being myocardial infarction (MI) and heart failure (HF). Results: A total of 242,793 participants were analyzed. Uric acid levels showed a U-shaped association with all-cause mortality in advanced kidney dysfunction, where both low (<3 mg/dL) and high (>10 mg/dL) levels increased mortality risk. In mild kidney dysfunction, lower uric acid levels were linked to better survival. HF risk increased linearly with higher uric acid, particularly in normal kidney function, while no significant association was found between uric acid and MI in any group. Conclusions: Uric acid levels are associated with mortality in a U-shaped pattern for advanced kidney dysfunction, while lower levels appear protective in mild dysfunction. These findings suggest the need for personalized uric acid management in CKD patients based on their kidney function. Full article

A 71-year-old male ex-smoker presented in October 2021 to our department with a brain and bone metastatic adenocarcinoma NSCLC. PDL1, ROS, EGFR, and ALK were negative. He underwent stereotactic radiotherapy for brain metastases. In November 2021, he started a chemotherapy (CHT) regimen with cisplatin (75 mg/m² every 21 days) and pemetrexed (500 mg/m² every 21 days), and ICI with Atezolizumab (1200 mg every 21 days). In July 2022, RT to the lung tumor and mediastinal nodal was performed with a total dose of 45 Gy in 15 fractions. He continued with immunotherapy until December 2022, when a grade 3–4 toxicity from immunotherapy was observed (hypothyroidism, psoriasis, and cystitis). He achieved a complete clinical response to the therapy. To date, the patient is alive, with a complete metabolic response, without treatment at 37 months from diagnosis. Full article

Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, p = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included KRAS Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in TP53 (90.7%), APC (87.0%), and non-V600E BRAF mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants. Full article

Background: The accurate assessment of the glomerular filtration rate (GFR) in potential living kidney donors (PLKDs) is essential for successful transplantation and safeguarding kidney donation practice. Scintigraphy-measured GFR (mGFR) is widely regarded as the clinical reference standard. Various estimated GFR (eGFR) equations, such as the Modification of Diet in Renal Disease (MDRD), Cockcroft–Gault (CG), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, have been developed; however, none have been specifically validated for Vietnamese PLKDs. This study aimed to evaluate the accuracy of eGFR formulas compared to mGFR in PLKDs. Methods: This convenience retrospective study analyzed 189 PLKDs at Cho Ray Hospital in Vietnam from January 2014 to December 2020. The eGFR was calculated using various formulas and compared to the mGFR assessed using ^99mTechnetium-diethylenetriaminepentaacetic acid. Bias, accuracy, and Bland–Altman plots were used to assess the significance of the eGFR values. Results: The median mGFR was 94.20 mL/min/1.73 m² (interquartile range [IQR]: 88.40–100.50). The eGFR values were as follows: 77.52 mL/min/1.73 m² (IQR: 70.50–86.33) for CG; 76.14 mL/min/1.73 m² (IQR: 68.05–83.37) for MDRD; 106.80 ± 15.24 mL/min/1.73 m² for CKD-EPI cystatin C 2012; 96.44 ± 13.40 mL/min/1.73 m² for CKD-EPI creatinine cystatin C 2012; 88.74 ± 13.27 mL/min/1.73 m² for CKD-EPI creatinine 2021; and 101.32 ± 12.82 mL/min/1.73 m² for CKD-EPI creatinine cystatin C 2021. Among these formulas, the CKD-EPI creatinine cystatin C 2012 (P30 = 98.96%) and 2021 (P30 = 97.92%) showed the best consistency with the mGFR, owing to their high accuracy, low bias, and narrow limits of agreement in the Bland–Altman plots. Conclusions: The CKD-EPI equations based on creatinine and cystatin C are reliable tools for donor screening. Full article

Background/Objectives: Post-transplant diabetes mellitus (PTDM) and prediabetes (PreDM) are common after renal transplantation and increase the risk of cardiovascular events and mortality. Compared to immediate-release tacrolimus (IR-Tac), the LCPT formulation, with delayed absorption, offers higher bioavailability and a smoother time–concentration curve, potentially reducing beta-cell stress. Methods: This randomized pilot trial compared de novo immunosuppression with IR-Tac (twice daily) and LCPT (once daily). At-risk recipients (age ≥ 60 years or 18–59 years with metabolic syndrome) were enrolled and followed for 3 months. The primary and secondary outcomes were the incidence of PTDM and PreDM, respectively. Results: 27 patients were randomized to IR-Tac and 25 to LCPT. The incidence of PTDM was comparable between groups [IR Tac: 18.5% (95% CI: 8.2–36.7%) vs. LCPT: 24% (95% CI: 11.5–43.4%); p = 0.7]. Although not statistically significant, the LCPT group exhibited a trend toward a reduction in PreDM incidence [IR-Tac: 40.7% (95% CI: 25–59%) vs. LCPT: 20% (95% CI: 9–39%); p = 0.1]. A sensitivity analysis showed similar results, with no significant differences in cumulative corticosteroid doses or baseline body mass index (BMI) between groups. The LCPT group showed a trend toward higher tacrolimus exposure at the end of the study [trough levels: IR-Tac group 8.3 (6.9–9.2) vs. LCPT group 9.4 (7.4–11.4) ng/mL; p = 0.05)], as well as fewer acute rejection episodes (none vs. three). Delayed graft function was more common in the IR-Tac group (37% vs. 8%; p = 0.01), and the eGFR was lower. Adverse events were comparable between groups. Conclusions: The potential biological activity of LCPT in preventing glucose metabolic alterations in at-risk patients warrants further investigation. Full article

Background: Despite the prevalence of impaired renal function in acute heart failure (AHF) patients, the intricate relationship between glomerular, tubular, and metabolic renal function remains unexplored. We aimed to investigate the co-occurrence of glomerular, tubular, and metabolic renal dysfunction in AHF and their impact on prognosis. Methods: eGFR, spot urine sodium, and HCO³⁻ were measured in 243 patients hospitalized for AHF. The population was stratified by the 4-point renal dysfunction score and linked with outcomes. Results: Glomerular dysfunction exhibited an elevated risk of death (HR of 2.04; 95% CI [1.24–3.36]; p = 0.006), combined risk of death, and HF rehospitalization (HR of 2.03; 95% CI [1.34–3.05]; p = 0.005). Similarly, tubular dysfunction correlated with a higher death risk (HR of 1.72; 95% CI [1.04–2.82]; p = 0.03) and a higher combined risk (HR of 1.82; 95% CI [1.21–2.74]; p = 0.004). While renal metabolic dysfunction was linked to increased death risk (HR of 1.82; 95% CI [1.07–3.11]; p = 0.028), it was not associated with composite risk (HR of 1.37; 95% CI [0.88–2.15]; p = 0.174). Multivariate analysis revealed a direct association between the renal dysfunction score and death risk (HR of 1.92 per 1 point; 95% CI [1.47–2.52]; p < 0.0001) and the combined risk of death and HF rehospitalization (HR of 1.78 per 1 point; 95% CI [1.43–2.22]; p < 0.0001). Conclusions: Renal dysfunction is common, with varied overlaps. Glomerular, tubular, and metabolic dysfunctions predict adverse outcomes in AHF. The established renal score may aid patient stratification and prognosis. Full article

Five phenolic Schiff bases (7–11) incorporating a fragment of methanesulfonamide were synthesized and evaluated for their efficacy as antitumor agents. Compounds 7 and 8 demonstrated the most potent antitumor action, with a positive cytotoxic effect (PCE) of 54/59 and 59/59 and a mean growth percentage (MG%) of 67.3% and 19.5%, respectively, compared with imatinib (PCE = 20/59 and MG% = 92.6%). The PCE values for derivatives 9–11 were 3/59, 4/59, and 4/59, respectively, indicating poor antitumor effect. Compound 8 exhibited the most significant efficacy, suppressing cell proliferation by an average of 50% at a dosage of 0.501 µM, in comparison with the reference drugs sorafenib (2.33 µM), gefitinib (2.10 µM), erlotinib (7.68 µM), and celecoxib (17.5 µM). Compounds 7 and 8 had substantial inhibitory effects on the human epidermal growth factor receptor 2 (HER2), with IC₅₀ values of 0.183 μM and 0.464 μM, respectively. Furthermore, they exhibited significant inhibition of the epidermal growth factor receptor (EGFR), with IC₅₀ values of 0.752 μM and 0.166 μM, respectively. Compound 8 exhibited the highest COX-2 inhibition (IC₅₀ = 12.76 μM). We performed molecular docking dynamic experiments to examine the precise interaction and structural prerequisites for the anticancer activity of derivatives 7 and 8 by targeting EGFR and HER2. Full article

Objectives: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial–mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods: We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results: The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions: Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation. Full article

Unresectable stage III non-small-cell lung cancer (NSCLC) remains a clinical challenge, due to the need for optimal local and systemic control. The management of unresectable Stage III NSCLC has evolved with advancements in radiation therapy (RT), systemic therapies, and immunotherapy. For patients with locally advanced NSCLC who are not surgical candidates, concurrent chemoradiotherapy (CRT) has modest survival outcomes, due to both local progression and distant metastasis. Efforts to enhance outcomes have led to dose-escalation trials, advances in modern RT techniques such as intensity-modulated RT (IMRT) and proton beam therapy (PBT), and the integration of adaptive RT to optimize target coverage while sparing organs at risk. Concurrent and consolidative immunotherapy, particularly with PD-L1 inhibitors, has shown promise, as evidenced by the PACIFIC trial, which demonstrated improved progression-free survival (PFS) and overall survival (OS) with durvalumab following CRT. Ongoing trials are now investigating novel immunotherapy combinations and targeted therapies in this setting, including dual checkpoint inhibition, DNA repair inhibitors, and molecularly targeted agents like osimertinib for EGFR-mutated NSCLC. Emerging biomarkers, such as circulating tumor DNA and radiomics, offer potential for personalizing treatment and predicting outcomes. Additionally, PBT and MR-guided adaptive RT have shown the potential to reduce toxicities while maintaining efficacy. Integrating these novel approaches may offer opportunities for optimizing treatment responses and minimizing adverse effects in this challenging patient population. Further investigation into patient stratification, biomarker-driven therapy, and refined therapeutic combinations is essential to improve long-term outcomes in unresectable Stage III NSCLC. This narrative review explores the current management strategies for unresectable Stage III NSCLC, from a radiation oncology perspective. Full article

The luteolin in Schisandra chinensis [Schisandraceae Schisandra (Turcz.) Baill.] were extracted by ultrasonic extraction assisted by an ionic liquid–enzyme composite system, and the content of luteolins was determined using high-performance liquid chromatography (HPLC). This process was initially conducted through a one-factor experiment and a Box–Behnken combinatorial design of response surface method. The extraction process was optimized, and the results demonstrated that the optimal extraction conditions were 13.31% enzyme addition, 0.53 mol/L ionic liquid concentration, 173.47 min ultrasonic shaking, and 0.2266 mg/g, which was 4.88 times higher than that of the traditional reflux extraction. Secondly, the antioxidant function of luteolins was studied based on network pharmacology. For the study of the antioxidant mechanism of luteolin, the herb group identification database, SwissTargetPrediction on luteolins target prediction, and GeneCards database to achieve the antioxidant target were used. For the analysis of the intersection of the target protein interactions, GO bioanalysis and KEGG signaling pathway enrichment analysis were used. There were 57 overlapping targets of luteolin and antioxidants, including AKT1, MMP9, ESR1, EGFR, and SRC. GO function and KEGG pathway enrichment analysis showed that luteolin antioxidants were related to zoerythromycin metabolic process, adriamycin metabolic process, negative regulation of apoptotic process, endocrine resistance and oxidoreductase. The key targets in the pathways, such as luteolin AKT1 and MMP9, exert antioxidant effects. The antioxidant activity of luteolins was investigated by determining the scavenging ability of luteolins against two types of free radicals: 2,2-bipyridine-bis(3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt (ABTS+) free radicals and 1,1-diphenyl-2-trinitrophenylhydrazine free radicals (DPPH-). The results of the antioxidant test demonstrated that the ABTS radical scavenging rate was 87.26%, and the DPPH radical scavenging rate was 93.85% when the quality concentration of Schisandra luteolins was 0.1 mg/g, indicating the potential of this natural antioxidant. This method of extracting Schisandra chinensis luteolins is highly productive, environmentally friendly, and practical, and it facilitates the development and utilization of industrial Schisandra chinensis. Full article

Background/Objectives: Here, we report on the synthesis and biological evaluation of a novel peptide–drug conjugate, P6-SN38, which consists of the EGFR-specific short cyclic peptide, P6, and the Topo I inhibitor SN38, which is a bioactive metabolite of the anticancer drug irinotecan. Methods: SN38 is attached to the peptide at position 20 of the E ring’s tertiary hydroxyl group via a mono-succinate linker. Results: The developed peptide–drug conjugate (PDC) exhibited sub-micromolar anticancer activity on EGFR-positive (EGFR+) cell lines but no effect on EGFR-negative (EGFR−) cells. In vivo studies have shown that this PDC specifically accumulates in EGFR+ non-small cell lung cancer (NSCLC) xenografts and presents superior anticancer activity compared to the EGFR-specific antibody cetuximab (Erbitux^TM) and free SN38. The 10 mg/kg dose of P6-SN38 in a side-by-side EGFR+/EGFR− xenograft shows eradication of the EGFR+ tumor with good tolerance, but no inhibition of tumor growth of the EGFR− counterpart. Conclusions: The PDC examined in this study was proven to be highly efficient for NSCLC, broadening its utilization for targeted cancer therapy in EGFR overexpressed cancers. Full article

Background and Objectives: Uric acid (UA) and the markers of mineral bone metabolism and inflammation are commonly altered in patients with chronic kidney disease (CKD) and are associated with the risk of cardiovascular complications and death. Studies point to a link between high serum UA and mineral bone homeostasis and inflammation, but controversy remains. The aim of this study was to evaluate the relationship between UA levels and mineral bone metabolism and inflammation biomarkers in a sample of Mexican patients with CKD 3a–5. Materials and Methods: This cross-sectional study included 146 Mexican patients with CKD 3a–5. In addition, 25 healthy subjects were included in the study with the aim of generating reference data for comparisons. Metabolic parameters including UA serum concentrations, mineral bone metabolism (parathormone (PTH), fibroblast growth factor 23 (FGF23), calcium, and phosphate), and inflammation (interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)) biomarkers were measured in all of the samples and compared as a function of the estimated glomerular function rate (eGFR) or UA levels. Results: Intact PTH, FGF23, and cytokines were higher in advanced CKD stages. Patients with hyperuricemia had significantly higher values of FGF23 and TNF-α compared with those without hyperuricemia. The eGFR was found to be significantly and negatively correlated with all markers. Uric acid was significantly correlated with phosphate, iPTH, FGF23, and TNF-α, whereas iPTH was significantly correlated with FGF23, TNF-α, and FGF23. Finally, a multivariate analysis confirmed the relationship of eGFR with all the tested biomarkers, as well as other relationships of iPTH with UA and TNF-α and of FGF23 with UA and TNF-α. Conclusions: This study supports the relationship between uric acid and levels of mineral bone metabolism and inflammation biomarkers in patients with CKD at middle to advanced stages. In the follow-up of patients with CKD, monitoring and controlling UA levels through nutritional or pharmacological interventions could help in the prevention of alterations related to mineral bone metabolism. Full article

In this study, we investigated the effect and mechanism of Resibufogenin on renal cell carcinoma based on network pharmacology, molecular docking, and in vitro experiments. The results showed that there were 35 cross-targets between Resibufogenin and renal cell carcinoma. GO and KEGG pathway analyses indicated that Resibufogenin inhibited renal cancer cells through the vascular smooth muscle contraction signalling pathway and EGFR tyrosine kinase inhibitor resistance signaling pathway, and MAPK1, PRKCB, and Resibufogenin had strong associative activities. After different concentrations of Resibufogenin were applied to human renal cancer cells, it was found that the IC50 value was 408.2 nM, 10 nM resibufogenin could significantly inhibit cell migration (p < 0.0001), the percentage of apoptosis and necrosis increased dose-dependently, and the expression of genes of MAPK1 and PRKCB in the cells was significantly reduced (p < 0.001) in a dose-dependent manner. The above results indicate that Resibufogenin can inhibit human renal cell carcinoma through multi-targets and multi-methods, which provides a theoretical basis for the application of Resibufogenin in the treatment of renal cell carcinoma and the development of novel drugs in the future. Full article

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used ¹⁰⁹Pd (T_1/2 = 13.7 h) in the form of a ¹⁰⁹Pd/^109mAg in vivo generator as a source of β⁻ particles and Auger electrons in targeted radionuclide therapy for TNBC. ¹⁰⁹Pd, obtained through neutron irradiation of the ¹⁰⁸Pd target, was deposited onto 15 nm gold nanoparticles to form Au@¹⁰⁹Pd core–shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@¹⁰⁹Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β⁻–Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β⁻, conversion, and Auger electrons from the ¹⁰⁹Pd/^109mAg generator, similar to ¹⁶¹Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells. Full article

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a variety of human epithelial tumors, and its aberrant activation plays a pivotal role in promoting tumor growth, invasion, and metastasis. The clinically approved passive EGFR-related therapies have numerous limitations. Seven EGFR-ECD epitope peptides (EG1-7) were selected through bioinformatics epitope prediction tools including NetMHCpan-4.1, NetMHCIIpan-3.2, and IEDB Consensus (v2.18 and v2.22) and fused to the translocation domain of diphtheria toxin (DTT). The A549 tumor model was successfully established in a murine mouse model. The vaccine was formulated by combining the adjuvants Alum and CpG and subsequently assessed for its immunogenicity and anti-tumor efficacy. DTT-EG (3;5;6;7) vaccines elicited specific humoral and cellular immune responses and effectively suppressed tumor growth in both prophylactic and therapeutic mouse tumor models. The selected epitopes EG3 (HGAVRFSNNPALCNV145-159), EG5 (KDSLSINATNIKHFK346-360), EG6 (VKEITGFLLIQAWPE398-412), and EG7 (LCYANTINWKKLFGT469-483) were incorporated into vaccines for active immunization, representing a promising strategy for the treatment of tumors with overexpressed epidermal growth factor receptor (EGFR). The vaccine design and fusion method employed in this study demonstrate a viable approach toward the development of cancer vaccines. Full article