In this study, we designed, formulated, and investigated the potential antitumor activity of a folate receptor (FR)-mediated double-targeted drug delivery system. The system comprised of the FR ligand folic acid (FA), glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly, GFLG), which can be specifically cleaved by cathepsin B, and the anticancer drug mitomycin C (MMC). The antitumor effect of FA-GFLG-MMC was compared to that of MMC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that FA-GFLG-MMC has a significantly higher inhibitory effect on HeLa, SiHa, and PC9 cells (high FR expression) than that on 16HBE and A549 cells (low FR expression). Furthermore, FA-GFLG-MMC inhibited cancer cell proliferation in a dose-dependent manner. Free MMC was toxic to both cancer and normal cells. Apoptosis of the HeLa, SiHa, and PC9 cells was higher than that of the A549 cells; however, the apoptotic effect on 16HBE cells was minimal. Proapoptotic protein bcl-2-associated X-protein (BAX) and antiapoptotic protein BCL-2 play critical roles in cellular defense and apoptotic signal transduction. BAX/BCL-2 ratio is used to determine the intensity of an apoptotic signal and assess whether a cell will survive or undergo apoptosis. BAX and BCL-2 expression in cells treated with 5 μM FA-GFLG-MMC was studied by Western blotting. FA-GFLG-MMC increased the BAX/BCL-2 ratio in HeLa, SiHa, and PC9 cells. The results show that FA-GFLG-MMC can effectively inhibit tumor cell proliferation by inducing apoptosis. Therefore, the system developed can enhance the delivery of anticancer drugs to cancer cells and thereby reduce their toxic effects on normal cells.
To retrospectively analyze the prognostic significance of plasma Epstein-Barr virus (EBV) DNA in 122 patients with diffuse large B cell lymphoma (DLBCL). Plasma EBV DNA positivity was related to advanced disease stage (P=0.030), B symptoms (P=0.004) and elevated serum lactic dehydrogenase (LDH) (P=0.001). Furthermore, univariate analysis indicated that plasma EBV DNA level was associated with worse overall survival (OS) (HR=0.223, 95%CI 0.096-0.518, P<0.001) and worse progression free survival (PFS) (HR=4.417, 95%CI 1.911-10.208, P<0.001), whereas multivariate analysis showed plasma EBV DNA as a probable independent prognostic factor of clinical outcome(HR=0.409, 95%CI 0.166-1.008, P=0.052).回顾性分析122例弥漫大B细胞淋巴瘤(DLBCL)临床资料，探讨血浆EB病毒(EBV)DNA阳性(≥1.0×10(3) copies/ml)与DLBCL预后的关系。结果显示，血浆EBV DNA阳性与Ann Arbor分期高(P＝0.030)、有B症状(P＝0.004)、LDH水平高(P＝0.001)相关。单因素分析显示，血浆EBV DNA阳性是影响DLBCL患者总体生存(HR＝0.223，95%CI 0.096～0.518, P<0.001)及无进展生存(HR＝4.417，95%CI 1.911～10.208, P<0.001)的预后因素；多因素分析显示，血浆EBV DNA可能是DLBCL总体生存的独立预后因素(HR＝0.409, 95%CI 0.166～1.008，P＝0.052)。.
In clinical studies there is still a lot of controversy about the increased anterior and rotational stability between double-bundle (DB) and single-bundle (SB) anterior cruciate ligament (ACL) reconstruction. The aim of this study was to evaluate the clinical results of four-tunnel DB ACL reconstruction.Sixty-four consecutive patients with ACL ruptures from May 2005 to May 2006 were randomly assigned into two groups: 32 cases for SB ACL reconstruction and 32 cases for DB ACL reconstruction. Clinical data, including KT 2000, Biodex test, Lysholm score, Tegner score and IKDC score, were prospectively collected until at least 10 months post-operative.The average values of KT 2000 were (1.47 +/- 1.17) mm and (1.68 +/- 1.14) mm for the SB and DB ACL reconstruction groups at 30 degrees of knee flexion (P > 0.05), and were (1.04 +/- 0.98) mm and (1.13 +/- 0.98) mm at 90 degrees of knee flexion (P > 0.05). There were also no significant differences in Lysholm score, Tegner score, IKDC score and Biodex test scores between the two groups (P > 0.05). The operation time of DB ACL reconstruction was 20 minutes longer than the SB ACL reconstruction (P < 0.05).Double bundle ACL reconstructions have no obvious clinical advantages over single bundle ACL reconstructions.
We systemically evaluated the sensitivity of the hypoxia targeted 2-nitroimidazole-ICG conjugate using piperazine linker in in-vivo tumor models, which showed hypoxia can be targeted with twice higher signal strength than that of untargeted ICG.
Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure. We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy. SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m 2 with urine protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment-emergent adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD 11]; mean eGFR 72 ml/min per 1.73 m 2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo ( n =34) or SC0062 5 mg ( n =33), 10 mg ( n =32), or 20 mg ( n =32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment-emergent adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by two (6%), one (3%), one (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with five (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890.
Abstract Background: Human periodontal ligament stem cells (PDLSCs)-mediated regenerative periodontal therapy is a promising method for periodontitis. Besides, odontogenic stem cells are exposed to hypoxia in both physiological and pathological conditions. The behaviour of stem cells under hypoxia is worth exploring. So far, whether long noncoding RNAs (lncRNAs) can affect the proliferation and cementogenesis of PDLSCs, as well as their specific mechanism, remains to be elucidated. This study investigates lncRNA NEAT1 and its possible regulatory mechanisms of cementogenic differentiation of PDLSCs under hypoxia. Methods: CCK-8 assay, flow cytometry (FCM) and EdU assay was adopted to test the proliferation ability. Osteoblastic/cementogenic differentiation of PDLSCs under hypoxia was detected by western blot assay (WB), quantitative real-time polymerase chain reaction (RT-PCR), alkaline phosphatase (ALP) activity, alcian blue staining (ABS), alizarin red staining (ARS). The relationship between them was proved by dual-luciferase reporter assay and rescue experiments. Results: PDLSCs exhibited a more powerful cementogenic differentiation potential in hypoxic conditions. miR-214-5p may regulate SMAD4, while Lnc NEAT1 acts as a sponge, forming a ceRNA mechanism in which HIF-1α plays an important role. It may act as an enabler, jointly constitute the regulatory axis of Lnc NEAT1/ miR-214-5p/ SMAD4, and affect the cementogenic differentiation of PDLSCs under hypoxia. Conclusions: Our results showed that hypoxia could enhance the cementogenic differentiation potential of PDLSCs in vitro . In addition, we found that Lnc NEAT1 may be a potential target for improving the function of PDLSCs in regenerative periodontiology, and Lnc NEAT1/miR-214-5p/SMAD4 could regulate the cementogenic differentiation ability of PDLSCs under hypoxia.
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