Contrast-enhanced US to Improve Diagnostic Performance of O-RADS US Risk Stratification System for Malignancy.

Background The Ovarian-Adnexal Reporting and Data System (O-RADS) has limited specificity for malignancy. Contrast-enhanced US can help distinguish malignant from benign lesions, but its added value to O-RADS has not yet been assessed. Purpose To establish a diagnostic model combining O-RADS and contrast-enhanced US and to validate whether O-RADS plus contrast-enhanced US has a better diagnostic performance than O-RADS alone. Materials and Methods This prospective study included participants from May 2018 to March 2021 who underwent contrast-enhanced US before surgery and had lesions categorized as O-RADS 3, 4, or 5 by US, with a histopathologic reference standard. From April 2021 to July 2022, participants with pathologically confirmed ovarian-adnexal lesions were recruited for the validation group. In the pilot group, the initial enhancement time and enhancement intensity in comparison with the uterine myometrium, contrast agent distribution pattern, and dynamic changes in enhancement of lesions were assessed. Contrast-enhanced US features were used to calculate contrast-enhanced US scores for benign (score ≤2) and malignant (score ≥4) lesions. Lesions were then re-rated according to O-RADS category plus contrast-enhanced US scores. Receiver operating characteristic curves were constructed and compared using the DeLong method. The combined system was validated in an independent group. Results The pilot group included 76 women (mean age, 44 years ± 13 [SD]), and the validation group included 46 women (mean age, 42 years ± 14). Differences in initial enhancement time (P < .001), enhancement intensity (P < .001), and dynamic changes in enhancement (P < .001) between benign and malignant lesions were observed in the pilot group. Contrast-enhanced US scores were calculated using these features. The O-RADS risk stratification was upgraded one level for contrast-enhanced US scores of 4 or more and downgraded one level for contrast-enhanced US scores of 2 or less. In the validation group, the diagnostic performance of O-RADS plus contrast-enhanced US score was higher (area under the receiver operating characteristic curve [AUC] = 0.93) than O-RADS (AUC = 0.71, P < .001). Conclusion Contrast-enhanced US improved the diagnostic performance for malignancy of the O-RADS categories 3-5. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Grant in this issue.

Exosome-mediated aptamer S58 reduces fibrosis in a rat glaucoma filtration surgery model.

AIM: To confirm whether exosome-mediated delivery of aptamer S58 (Exo-S58) has a better antifibrotic effect than naked S58 in human conjunctival fibroblasts (HConFs) and a rat glaucoma filtration surgery (GFS) model. METHODS: To enhance the effective reaction time of aptamer S58 in vivo, we loaded aptamer S58 into exosomes derived from HEK293T cells by PEI transfection to determine the effect of Exo-S58 in HConFs and a rat GFS model. RESULTS: Exo-S58 can significantly reduce cell proliferation, migration and fibrosis in TGF-ß2-induced HConFs. In an in vivo experiment, Exo-S58 treatment prolonged filtering bleb retention and reduced fibrosis compared with naked S58 treatment in GFS rats. CONCLUSION: The exosomes are safe and valid carriers to deliver aptamers. Furthermore, Exo-S58 exhibited superior antifibrotic effect than naked S58 both in HConFs cells and rat GFS models.

Anticancer activity of ruthenium(II) plumbagin complexes with polypyridyl as ancillary ligands via inhibiting energy metabolism and GADD45A-mediated cell cycle arrest.

To study the antitumor activity and action mechanism of Ru(II) polypyridyl plumbagin (PLN) complexes, four complexes [Ru(PLN)(DMSO)2]Cl (Ru1), [Ru(bpy)2(PLN)](PF6) (bpy is bipyridine) (Ru2), [Ru(phen)2(PLN)](PF6) (phen is 1,10-phenanthroline) (Ru3), and [Ru(DIP)2(PLN)](PF6) (DIP is 4,7-diphenyl-1,10-phenanthroline) (Ru4) were obtained and fully characterized. Lipophilicity, cellular uptake and cytotoxicity of these Ru(II) complexes are in the order of: Ru1

Recent Advances in Asialoglycoprotein Receptor and Glycyrrhetinic Acid Receptor-Mediated and/or pH-Responsive Hepatocellular Carcinoma- Targeted Drug Delivery.

BACKGROUND: Hepatocellular carcinoma (HCC) seriously affects human health, especially, it easily develops multi-drug resistance (MDR) which results in treatment failure. There is an urgent need to develop highly effective and low-toxicity therapeutic agents to treat HCC and to overcome its MDR. Targeted drug delivery systems (DDS) for cancer therapy, including nanoparticles, lipids, micelles and liposomes, have been studied for decades. Recently, more attention has been paid to multifunctional DDS containing various ligands such as polymer moieties, targeting moieties, and acid-labile linkages. The polymer moieties such as poly(ethylene glycol) (PEG), chitosan (CTS), hyaluronic acid, pullulan, poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO) protect DDS from degradation. Asialoglycoprotein receptor (ASGPR) and glycyrrhetinic acid receptor (GAR) are most often used as the targeting moieties, which are overexpressed on hepatocytes. Acid-labile linkage, catering for the pH difference between tumor cells and normal tissue, has been utilized to release drugs at tumor tissue. OBJECTIVES: This review provides a summary of the recent progress in ASGPR and GAR-mediated and/or pH-responsive HCC-targeted drug delivery. CONCLUSION: The multifunctional DDS may prolong systemic circulation, continuously release drugs, increase the accumulation of drugs at the targeted site, enhance the anticancer effect, and reduce side effects both in vitro and in vivo. But it is rarely used to investigate MDR of HCC; therefore, it needs to be further studied before going into clinical trials.

Synthesis, structural characterization and antitumor activity of six rare earth metal complexes with 8-hydroxyquinoline derivatives.

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1-6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate.

MicroRNA-527 inhibits TGF-ß/SMAD induced epithelial-mesenchymal transition via downregulating SULF2 expression in non-small-cell lung cancer.

OBJECTIVE: To explore the potential mechanism which miR-527 targeting the heparan sulfate 6-O-endosulfatase (SULF2) regulates TGF-ß/SMAD signaling pathway induced epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC). METHODS: 38 pairs of lung tumor biopsies and corresponding paracancerous biopsies were obtained from NSCLC patients with surgical resection, normal human bronchial epithelial BEAS-2B cells and five NSCLS cell lines were applied for our study. miR-527 and SULF2 expression were determined by qRT-PCR and immunohistochemistry. MiR-527 and SULF2 biological link were predicted by Targetscan.org and tested by dual luciferase. Cells proliferation and apoptosis were respectively detected by EDU staining and flow cytometry. Cells migration was examined by transwell and scratch-wound assay. Expression of proteins related to EMT and TGF-ß/SMAD signaling pathway, such as E-cadherin, N-cadherin, p-Samd3 and p-Smad2, was detected by western blot. RESULTS: miR-527 expression was decreased in lung tumor tissues and NSCLS cell lines, conversely, SULF2 expression was significantly increased. In addition, we found that miR-527 targeted 3'-untranslated regions (3'-UTR) of SULF2 and mediated its expression. Overexpression of miR-527 evidently suppressed NSCLC proliferation, invasion and EMT via TGF-ß/SMAD signaling pathway. Moreover, the silence of SULF2 exhibited a similar effect. CONCLUSION: miR-527 targeting SULF2 down-regulated SULF2 expression, concurrently, suppressed NSCLC epithelial-mesenchymal transition and invasion via inhibiting TGF-ß/SMAD signaling pathway.

Eukaryotic initiation factor 5A2 and human digestive system neoplasms.

Eukaryotic initiation factor 5A2 (eIF5A2), as one of the two isoforms in the family, is reported to be a novel oncogenic protein that is involved in multiple aspects of many types of human cancer. Overexpression or gene amplification of EIF5A2 has been demonstrated in many cancers. Accumulated evidence shows that eIF5A2 initiates tumor formation, enhances cancer cell growth, increases cancer cell metastasis, and promotes treatment resistance through multiple means, including inducing epithelial-mesenchymal transition, cytoskeletal rearrangement, angiogenesis, and metabolic reprogramming. Expression of eIF5A2 in cancer correlates with poor survival, advanced disease stage, as well as metastasis, suggesting that eIF5A2 function is crucial for tumor development and maintenance but not for normal tissue homeostasis. All these studies suggest that eIF5A2 is a useful biomarker in the prediction of cancer prognosis and serves as an anticancer molecular target. This review focuses on the expression, subcellular localization, post-translational modifications, and regulatory networks of eIF5A2, as well as its biochemical functions and evolving clinical applications in cancer, especially in human digestive system neoplasms.

Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials.

OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, has been used in treating postmenopausal women with schizophrenia with inconsistent results. This meta-analysis of randomized, double-blind, placebo-controlled trials (RCTs) examined its efficacy and safety for postmenopausal women with schizophrenia. METHOD: Standardized mean differences (SMDs) and risk ratio (RR) together with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: The meta-analysis included 5 RCTs (n = 240) comparing raloxifene (n = 125, 60 or 120 mg/day) with placebo (n = 115). Adjunctive raloxifene outperformed placebo with regard to the Positive and Negative Syndrome Scale (PANSS) total psychopathology [n = 240, SMD:-0.64 (95%CI:-0.90, -0.37), P < 0.00001; I2 = 0%], positive symptoms [n = 240, SMD:-0.49 (95%CI:-0.81, -0.16), P = 0.003; I2 = 29%], negative symptoms [n = 240, SMD:-0.43 (95%CI:-0.68, -0.17), P = 0.001; I2 = 0%], and general psychopathology scores [n = 240, SMD:-0.66 (95%CI:-0.92, -0.39), P < 0.00001; I2 = 0%]. Both groups had similar rates of adverse events and discontinuation (n = 159, RR: 1.32 (95%CI: 0.65, 2.70), P = 0.44, I2 = 0%). CONCLUSION: Adjunctive raloxifene appears to be effective and safe in improving psychotic symptoms for postmenopausal women with schizophrenia. Review registration: CRD 42017059946.

Serum IL-6, IL-23 profile and Treg/Th17 peripheral cell populations in pediatric patients with inflammatory bowel disease.

IL-6 and IL-23 are both pleiotropic cytokines involved in the regulation of the immune response, inflammation, and hematopoeisis. They also could mediate effector cells and tolerance mediated by cells with regulatory function. Inflammatory bowel disease (IBD) is associated with a reduced ratio of Treg cells ato Th17 effector cells in peripheral blood and is characterised by a pro-inflammatory cytokine microenvironment which supports the continued generation of Th17 cells. It is well described in adults but little is known in a pediatric population. This study was aimed to investigate the role of IL-6, IL-23 and its association with Treg and Th17 subsets in pediatric IBD patients. Peripheral blood mononuclear cells from patients and controls were stimulated with PMA, ionomycin, and brefeldin A. The frequencies of CD4+Foxp3+ cells, and CD4+IL17a+ cells were analyzed by flow cytometry. The serum level of IL-6 and IL-23 was determined by Elisa kit. The mRNA expression of Foxp3, IL-17a, IL-6 and IL-23 was detected by real-time quantitative PCR. The ratio of Treg/Th17 decreased in pediatric IBD patients, and it strongly correlated with IL-6 and IL-23. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with IBD and its association with serum IL-6 and IL-23 level.

Comparison of phacotrabeculectomy and sequential surgery in the treatment of chronic angle-closure glaucoma coexisted with cataract.

AIM: To compare the safety and effectiveness of phacotrabeculectomy versus sequential surgery in chronic angle-closure glaucoma (CACG) with coexisting cataract. METHODS: One hundred and sixty-two CACG patients (162 eyes) were retrospectively analyzed. Of them, 87 patients (87 eyes) in group A had underwent phacotrabeculectomy with intraocular lens (IOL) implantation, and 75 patients (75 eyes) in group B had underwent sequential surgery with IOL implanted. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), complications and anterior chamber angle (ACA) were measured. RESULTS: Demographic characteristics of the two groups were similar. A mean follow-up period was 15±6mo (range 13 to 24mo), a mean IOP of 16.61±6.43 mm Hg in group A and 15.80±5.35 mm Hg in group B (P=0.84) at the last follow up. The Kaplan-Meier analysis revealed that the cumulative probability of success in both groups was similar (P=0.61). Anterior uveitis and hypotony were the most common complications in group A, whereas group B experienced shallow anterior chamber with trabeculectomy. With the exception of anterior uveitis, no complications occurred to 11 trabeculectomized eyes. All postoperative measurements of anterior chamber showed statistically significant differences in each group according to the preoperative data (P<0.05). However, fewer changes occurred in group B than in group A. CONCLUSION: Phacotrabeculectomy and sequential surgery exhibit similar IOP reduction, visual recovery, and complications when treating CACG patients with cataract. However, for a wider ACA, phacotrabeculectomy has demonstrated higher effectiveness than sequential surgery.

MDA-7/IL-24 suppresses tumor adhesion and invasive potential in hepatocellular carcinoma cell lines.

Melanoma differentiation associated gene-7 (MDA-7)/interleukin­24 (IL-24) has been considered as a tumor-suppressor gene, which suppresses the growth and induces the apoptosis of cancer cells. In the present study, we investigated the effect and mechanisms of MDA-7/IL-24 regarding the inhibition of metastasis of HepG2 and BEL-7402 human hepatocellular carcinoma (HCC) cells in vitro. We established MDA-7/IL-24-overexpressing HepG2 and BEL-7402 cell lines and found that MDA-7/IL-24 overexpression inhibited tumor cell adhesion and invasion, and induced G2/M arrest in tumor cells. To explore its mechanism of action, western blotting and real-time-PCR assay were used to investigate the expression of E-cadherin, CD44, ICAM-1, matrix metalloproteinase (MMP)-2 and -9, CyclinB, Twist, survivin, p-ERK and p-Akt. ELISA assay was used to measure the secretion of TGF-ß, and a reporter gene assay was used to detected the transcriptional activity of NF-κB and AP-1 in HepG2 and BEL-7402 cells. The results showed that MDA-7/IL-24 overexpression decreased the expression of CD44, ICAM-1, MMP-2/-9, CyclinB, Twist, survivin, TGF-ß and p-Akt, transcriptional activity of NF-κB, and increased the expression of E-cadherin and p-ERK and transcriptional activity of AP-1 in HepG2 and BEL-7402 cells. Our results revealed that MDA-7/IL-24 mediated the inhibition of adhesion and invasion in HepG2 and BEL-7402 cells by suppressing metastasis-related gene expression. Thus, MDA-7/IL-24 may be used as a novel cancer-suppressor gene for the therapy of human HCC.

[The value of real-time PCR analysis of serum samples for early diagnosis of invasive pulmonary aspergillosis in organ transplant recipients].

OBJECTIVE: To study the value of Aspergillus real-time PCR as a tool for diagnosing invasive pulmonary aspergillosis(IPA) from serum samples in organ transplant recipients. METHODS: From Jan.2004 to Mar.2006, 59 organ transplant recipients from Shanghai First People's Hospital with high possibility of invasive pulmonary aspergillosis were evaluated. Of the 59 patients, 5 had proven, 6 had probable, and 18 had possible invasive Aspergillus infection according to European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions. A total of 274 serum samples were analyzed using real-time PCR. RESULTS: Seven of these immunocompromised patients were PCR positive, correlating with positive sputum cultures, positive histology, and positive signs of CT scans. False negative results were found in 2 patients. They had positive PCR results without any correlation to clinical or other diagnostic criteria. Twenty-eight immunocompromised patients with a negative PCR result showed no evidence of invasive fungal disease. Compared with sputum culture, CT scan and galactomannan test, PCR positivity preceded diagnosis by a mean of 7.9 d, 6.0 d, 1.5 d, respectively. CONCLUSION: Aspergillus real-time PCR is a helpful test for the early diagnosis of IPA in high-risk organ transplant recipients.

[Expression of nuclear factor-kappa B and effect of pyrrolidine dithiocarbamate in Pseudomonas aeruginosa pneumonia rat model].

OBJECTIVE: To investigate the expression of nuclear factor-kappa B (NF-kappaB) and cytokines in Pseudomonas aeruginosa (PA)-induced pneumonia of rats, and the effect of pyrrolidine dithiocarbamate (PDTC). METHODS: Seventy-two male SD rats were divided into three groups at random:a control group, a PA group and a PDTC group (n = 24 each). The PA induced pneumonia model was established in SD rats. The rats of the control group and the PA group were intraperitoneally given saline (1 ml) at 60 min before PA exposure, while the rats of the PDTC group received the same volume of PDTC (200 mg/kg). After 60 min, the rats of the PA group and the PDTC group were intratracheally instilled with PA 0.2 ml (6 x 10(8) CFU/ml), while the rats of the control group received the same volume of saline. At 3 h, 6 h, 16 h, 24 h after PA exposure, the rats were examined. Then they were sacrificed and the lung were excised for routine histological analysis. Immunohistochemical staining with an antibody against activated NF-kappaB and Western blot were performed to detect the expression of NF-kappaB. The change of TNFalpha mRNA was identified by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Histological findings demonstrated that the lung exposed to PA showed significant changes in the lung structure, edema and pronounced inflammatory cell infiltration. Both symptoms and damages of the lung were less severe in the rats of PDTC group than those of the PA group. Compared with the PDTC group, the activation of NF-kappaB and the expression of TNFalpha in the PA group were significantly upregulated after PA challenge 3 - 24 h (P < 0.01), respectively; peak expression of NF-kappaB and TNFalpha were observed at 3 - 6 h after PA exposure. CONCLUSIONS: The expression of NF-kappaB and TNFalpha induced by NF-kappaB play an important role in the pathogenesis of pneumonia. The inhibitor of NF-kappaB, PDTC, can relieve the lung damages produced by pneumonia.