Development and effects of an internet-based family resilience-promoting program for parents of children with cancer: A randomized controlled trial.

PURPOSE: The diagnosis of cancer in children can negatively impact their parents, owing to the complex treatment processes. Families with high levels of resilience can overcome these difficulties and thus perform higher family functions. We aimed to develop an internet-based family resilience-promoting program for parents of children with cancer and evaluate its effect on the levels of family resilience, depression, and family function. METHODS: This prospective, parallel-group, randomized-controlled study that was conducted at Yonsei Cancer Center from June to October 2021 included 41 parents of children with cancer. In total, four sessions of the internet-based family resilience-promoting program, led by a nurse, were conducted individually for parents. Levels of family resilience, depression, and family function were measured before, immediately after, and 4 weeks after the program. The data were analyzed using the linear mixed-effect model, and program satisfaction was evaluated through an internet-based questionnaire and interview. RESULTS: The experimental group (the family resilience-promoting program participants) differed more significantly from the control group in the level of change in family resilience (ß = 13.214, p = 0.003, effect size = 0.374) and family function (ß = 1.256, p = 0.018, effect size = 0.394). However, there was no significant difference between the groups in the level of depression (ß = 2.133, p = 0.187, effect size = 0.416). All the program participants showed a high program satisfaction score of 4.75 out of 5.00 points overall. CONCLUSIONS: The applicability of the internet-based family resilience-promoting program as an appropriate nursing intervention was verified. Its application can help the families of children with cancer adapt to the stressful situation of their children's cancer diagnosis and treatment.

Polyherbal formula SC-E3 inhibits rheumatoid arthritis activity in a mouse model of type-II collagen-induced arthritis.

OBJECTIVE: SC-E3 is a polyherbal formula that contains five medicinal herbs used frequently in traditional herbal medicine. In our previous study, we demonstrated the antioxidant and anti-inflammatory effects of SC-E3. The present study examined the effects of SC-E3 in a mouse model of type-II collagen-induced arthritis (CIA). METHODS: In vivo, male DBA/1J mice were immunized by intradermal injection of bovine type-II collagen and complete or incomplete Freund's adjuvant, to induce arthritis. SC-E3 was orally administered daily for 23 days. In vitro, bone marrow-derived macrophages (BMMs) were treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) in the absence or presence of SC-E3. RESULTS: Administrations of SC-E3 were found to have anti-arthritic effects in the joints of CIA mice, as evidenced by reduced paw swelling, bone erosion and deformation, inflammatory cell infiltration, and inflammation in synovial membrane. SC-E3 also reduced serum levels of tumor necrosis factor-α, interleukin-1ß, aspartate aminotransferase and alanine aminotransferase. Furthermore, tartrate-resistant acid phosphatase-positive osteoclast numbers in the joints were significantly lower in SC-E3-treated CIA mice than in CIA mice. In addition, the differentiations of BMMs to multinucleated osteoclasts induced by M-CSF and RANKL stimulation were dose-dependently reduced by SC-E3. CONCLUSION: These results suggest that SC-E3 possesses substantial anti-arthritic activity because it inhibits pro-inflammatory cytokines and osteoclastogenesis, and that SC-E3 has potential therapeutic use for the treatment of rheumatoid arthritis.

Nurse Staffing and Health Outcomes of Psychiatric Inpatients: A Secondary Analysis of National Health Insurance Claims Data.

PURPOSE: The present study investigated the association between nurse staffing and health outcomes among psychiatric inpatients in Korea by assessing National Health Insurance claims data. METHODS: The dataset included 70,136 patients aged 19 years who were inpatients in psychiatric wards for at least two days in 2016 and treated for mental and behavioral disorders due to use of alcohol; schizophrenia, schizotypal and delusional disorders; and mood disorders across 453 hospitals. Nurse staffing levels were measured in three ways: registered nurse-to-inpatient ratio, registered nurse-to-adjusted inpatient ratio, and nursing staff-to-adjusted inpatient ratio. Patient outcomes included length of stay, readmission within 30 days, psychiatric emergency treatment, use of injected psycholeptics for chemical restraint, and hypnotics use. Relationships between nurse staffing levels and patient outcomes were analyzed considering both patient and system characteristics using multilevel modeling. RESULTS: Multilevel analyses revealed that more inpatients per registered nurse, adjusted inpatients per registered nurse, and adjusted inpatients per nursing staff were associated with longer lengths of stay as well as a higher risk of readmission. More adjusted inpatients per registered nurse and adjusted inpatients per nursing staff were also associated with increased hypnotics use but a lower risk of psychiatric emergency treatment. Nurse staffing levels were not significantly associated with the use of injected psycholeptics for chemical restraint. CONCLUSION: Lower nurse staffing levels are associated with negative health outcomes of psychiatric inpatients. Policies for improving nurse staffing toward an optimal level should be enacted to facilitate better outcomes for psychiatric inpatients in Korea.

Co-culture of 3D tumor spheroids with fibroblasts as a model for epithelial-mesenchymal transition in vitro.

Epithelial-mesenchymal transition (EMT) acts as a facilitator of metastatic dissemination in the invasive margin of malignant tumors where active tumor-stromal crosstalks take place. Co-cultures of cancer cells with cancer-associated fibroblasts (CAFs) are often used as in vitro models of EMT. We established a tumor-fibroblast proximity co-culture using HT-29 tumor spheroids (TSs) with CCD-18 co fibroblasts. When co-cultured with TSs, CCD-18 co appeared activated, and proliferative activity as well as cell migration increased. Expression of fibronectin increased whereas laminin and type I collagen decreased in TSs co-cultured with fibroblasts compared to TSs alone, closely resembling the margin of in vivo xenograft tissue. Active TGFß1 in culture media significantly increased in TS co-cultures but not in 2D co-cultures of cancer cells-fibroblasts, indicating that 3D context-associated factors from TSs may be crucial to crosstalks between cancer cells and fibroblasts. We also observed in TSs co-cultured with fibroblasts increased expression of α-SMA, EGFR and CTGF; reduced expression of membranous ß-catenin and E-cadherin, together suggesting an EMT-like changes similar to a marginal region of xenograft tissue in vivo. Overall, our in vitro TS-fibroblast proximity co-culture mimics the EMT-state of the invasive margin of in vivo tumors in early metastasis.

Indirect modulation of sensitivity to 5-fluorouracil by microRNA-96 in human colorectal cancer cells.

5-FU is an anticancer drug that is widely used to treat cancers, including colorectal cancer (CRC); however, chemoresistance to 5-FU remains an important problem to be resolved. The role of microRNAs (miRs) in chemosensitivity has recently been studied in the development of therapeutic strategies to overcome drug resistance. Here, we focused on miR-96, which has been reported to demonstrate chemosensitivity. We investigated whether 5-FU sensitivity may be modulated by miR-96 in monolayer cells and whether this relationship also applies for drug resistance in 3D tumor spheroids (TSs). When the level of miR-96 increased, the expression of the anti-apoptotic regulator XIAP and p53 stability regulator UBE2N decreased, resulting in increased apoptosis and growth inhibition following 5-FU exposure. Transfection of miR-96 inhibitors resulted in an overexpression of XIAP and UBE2N, yet only minimal change was induced in apoptosis. Nonetheless, luciferase assay failed to show direct interactions between miR-96 and these genes. In TSs, 5-FU resistance corresponded to a significantly lower level of miR-96, however only XIAP, not UBE2N, was up-regulated demonstrating partial agreement with the 2D condition regarding target expression. Overall, these results suggest that miR-96 may modulate 5-FU sensitivity in CRC cells by promoting apoptosis; however, differential expression of target genes in TSs warrants further studies on the 5-FU resistance mechanism under 3D conditions.

Background parenchymal signal enhancement ratio at preoperative MR imaging: association with subsequent local recurrence in patients with ductal carcinoma in situ after breast conservation surgery.

PURPOSE: To retrospectively investigate whether the background parenchymal features around a tumor at preoperative dynamic contrast material-enhanced magnetic resonance (MR) imaging are associated with ipsilateral breast tumor recurrence (IBTR)-free survival in patients with ductal carcinoma in situ (DCIS) after breast conservation surgery. MATERIALS AND METHODS: The institutional review board approved this study, and the requirement for informed consent was waived. Between 2004 and 2009, 215 consecutive women with pure DCIS who had undergone preoperative dynamic contrast-enhanced MR imaging and curative breast conservation surgery were identified. Clinical-pathologic features (age, menopausal status, presentation of clinical findings, biopsy method, tumor size, nuclear grade, hormonal receptor status, margin status, and adjuvant therapy) and MR imaging features (lesion size, background parenchymal enhancement grade, fibroglandular density, parenchymal signal enhancement ratio [SER] around the tumor, lesion type, and lesion kinetics) were analyzed. A Cox proportional hazards model was used to determine the association between MR imaging variables and IBTR-free survival after controlling for clinical-pathologic variables. Reproducibility of SER measurements was evaluated by using the intraclass correlation coefficient. RESULTS: There were 15 of 215 (7.0%) IBTR cases (nine DCIS cases and six invasive cases) at a median of 36 months (range, 11-61 months). Multivariate analysis showed that higher parenchymal SER (hazard ratio [HR] = 2.028, P < .001 for reader 1; HR = 1.652, P < .001 for reader 2) and larger histologic tumor size (HR = 1.360, P = .009 for reader 1; HR = 1.402, P = .006 for reader 2) were independent factors associated with worse IBTR-free survival. The intraclass correlation coefficient of SER measurements between two readers was 0.852 (95% confidence interval: 0.811, 0.885). CONCLUSION: Higher parenchymal SER around the tumor at preoperative dynamic contrast-enhanced MR imaging and larger histologic tumor size were independent factors associated with worse IBTR-free survival in patients with DCIS after breast conservation surgery.

Differentiation of large (≥ 5 cm) gastrointestinal stromal tumors from benign subepithelial tumors in the stomach: radiologists' performance using CT.

PURPOSE: To identify significant CT findings for the differentiation of large (≥ 5 cm) gastric gastrointestinal stromal tumors (GIST) from benign subepithelial tumors and to assess whether radiologists' performance in differentiation is improved with knowledge of significant CT criteria. MATERIALS AND METHODS: One-hundred twenty patients with pathologically proven large (≥ 5 cm) GISTs (n=99), schwannomas (n=16), and leiomyomas (n=5) who underwent CT were enrolled. Two radiologists (A and B) retrospectively reviewed their CT images in consensus for the location, size, degree and pattern of enhancement, contour, growth pattern and the presence of calcification, necrosis, surface ulceration, or enlarged lymph nodes. CT findings considered significant for differentiation were determined using uni- and multivariate statistical analyses. Thereafter, two successive review sessions for the differentiation of GIST from non-GIST were independently performed by two other reviewers (C and D) with different expertise of 2 and 9 years using a 5-point confidence scale. At the first session, reviewers interpreted CT images without knowledge of significant CT findings. At the second session, the results of statistical analyses were provided to the reviewers. To assess improvement in radiologists' performance, a pairwise comparison of receiver operating curves (ROC) was performed. RESULTS: Heterogeneous enhancement, presence of necrosis, absence of lymph nodes, and mean size of ≥ 6 cm were found to be significant for differentiating GIST from schwannoma (P<0.05). Non-cardial location, heterogeneous enhancement, and presence of necrosis were differential CT features of GIST from leiomyoma (P<0.05). Multivariate analyses indicated that absence of enlarged LNs was the only statistically significant variable for GIST differentiating from schwannoma. The area under the curve of both reviewers obtained using ROC significantly increased from 0.682 and 0.613 to 0.903 and 0.904, respectively, with information of the significant CT findings differentiating GISTs from non-GISTs (P<0.001). CONCLUSION: Non-cardial location, heterogeneous enhancement, presence of necrosis, larger lesion size, and absence of lymphadenopathy are highly suggestive CT findings for large GISTs in differentiation from schwannomas or leiomyomas. Regardless of radiologists' expertise, diagnostic performance in differentiation can be significantly improved with knowledge of these CT findings.

Interaction of NADPH oxidase 1 with Toll-like receptor 2 induces migration of smooth muscle cells.

AIMS: NADPH oxidase (Nox) isozymes that generate intracellular reactive oxygen species (ROS) and Toll-like receptor 2 (TLR2), an inflammatory mediator, are both involved in the development of atherosclerotic lesions. To identify the molecular connection between TLR2 and Nox isozymes in vascular remodelling, we analysed generation of ROS and pro-inflammatory cytokines in aortic smooth muscle cells from Nox1-deficient mice in response to the synthetic triacylated lipoprotein Pam3CSK, a TLR2 agonist. METHODS AND RESULTS: We showed that TLR2 signalling stimulates progression of the pro-inflammatory phenotype in mouse aortic smooth muscle cells (MASMCs) through activation of Nox1. We demonstrated the interaction of TLR2 with Nox1 using yeast two-hybrid and co-immunoprecipitation assays. MASMCs from Nox1-deficient mice failed to generate of ROS in response to Pam3CSK4, indicating that Nox1 is essential for TLR2-dependent production of ROS. We also found that Pam3CSK4 stimulated migration of MASMCs from wild-type mice in a Transwell system, but MASMCs from Nox1-deficient mice failed to show this response. Wild-type MASMCs produced matrix metalloprotease 2 in response to Pam3CSK4, whereas Nox1-deficient MASMCs failed to generate this protease. Moreover, stimulation of MASMCs with Pam3CSK4 resulted in increased expression of the pro-inflammatory cytokine macrophage inflammatory protein 2 in a Nox1-dependent manner, leading to enhanced monocyte-endothelial cell adhesion and trans-endothelial migration of U937 cells. CONCLUSION: These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling.

Axial growth and binocular function following bilateral lensectomy and scleral fixation of an intraocular lens in nontraumatic ectopia lentis.

PURPOSE: To evaluate binocular function (BF) and changes in axial length (AL) bilaterally in pseudophakic eyes of children after lensectomy and scleral fixation of an intraocular lens (IOL) for nontraumatic ectopia lentis. METHODS: In 15 children who had undergone bilateral lensectomy and scleral fixation of an IOL for nontraumatic ectopia lentis, AL was measured preoperatively and at last follow-up, and BF was assessed at last follow-up. Axial growth was compared with the expected and observed patterns of normal eyes, and the results were compared between patients with isolated ectopia lentis and those with Marfan syndrome. RESULTS: Ten of the 15 patients had Marfan syndrome. Mean age at surgery was 5.2 +/- 2.4 years; mean follow-up was 51.7 +/- 29.2 months. A mean axial growth rate of 0.39 mm/year during 51.7 postoperative months was greater than the expected (0.07 mm/year) or the observed (0.09-0.24 mm/year) rates in age-matched normal eyes. The axial growth rates in isolated ectopia lentis patients and Marfan patients were not significantly different (P = 0.159). Binocular fusion and stereoacuity of < or =800 seconds of arc were achieved by nine patients, and worse or no BF was achieved by the remaining six patients. These six patients were significantly more likely to have pre- or postoperative anisometropia of > or =3.0 D (66.6%) than the other nine patients (0%). CONCLUSIONS: Because of greater than normal axial growth, more undercorrection of the IOL power is required than is usual in bilateral surgery for nontraumatic ectopia lentis. Good or moderate levels of postoperative BF were achieved in more than half of patients.

Bifidobacterium lactis inhibits NF-kappaB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice.

BACKGROUND: The aim of this study was to investigate the antiinflammatory effects of Bifidobacterium lactis on intestinal epithelial cells (IECs) and on experimental acute murine colitis and its tumor prevention effects on colitis-associated cancer (CAC) in mice. METHODS: Human HT-29 cells were stimulated with IL-1beta, lipopolysaccharides, or tumor necrosis factor-alpha with and without B. lactis, and the effects of B. lactis on nuclear factor kappa B (NF-kappaB) signaling in IEC were examined. For in vivo study, dextran sulfate sodium (DSS)-treated mice were fed with and without B. lactis. Finally, we induced colonic tumors in mice by azoxymethane (AOM) and DSS and evaluated the effects of B. lactis on tumor growth. RESULTS: B. lactis significantly suppressed NF-kappaB activation, including NF-kappaB-binding activity and NF-kappaB-dependent reporter gene expression in a dose-dependent manner, and suppressed IkappaB-alpha degradation, which correlated with the downregulation of NF-kappaB-dependent gene products. Moreover, B. lactis suppressed the development of acute colitis in mice. Compared with the DSS group, the severity of DSS-induced colitis as assessed by disease activity index, colon length, and histological score was reduced in the B. lactis-treated group. In the CAC model, the mean number and size of tumors in the B. lactis-treated group were significantly lower than those in the AOM group. CONCLUSIONS: Our data demonstrate that B. lactis inhibits NF-kappaB and NF-kappaB-regulated genes in IEC and prevents acute colitis and CAC in mice. These results suggest that B. lactis could be a potential preventive agent for CAC as well as a therapeutic agent for inflammatory bowel disease.

Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2.

Oxidative modification of low-density lipoprotein (LDL) plays a causative role in the development of atherosclerosis. In this study, we demonstrate that minimally oxidized LDL (mmLDL) stimulates intracellular reactive oxygen species (ROS) generation in macrophages through NADPH oxidase 2 (gp91phox/Nox2), which, in turn, induces production of RANTES and migration of smooth muscle cells. Peritoneal macrophages from gp91phox/Nox2(-/-) mice or J774 macrophages in which Nox2 was knocked down by small interfering RNA failed to generate ROS in response to mmLDL. Because mmLDL-induced cytoskeletal changes were dependent on Toll-like receptor (TLR)4, we analyzed ROS generation in peritoneal macrophages from wild-type, TLR4(-/-), or MyD88(-/-) mice and found that mmLDL-mediated ROS was generated in a TLR4-dependent, but MyD88-independent, manner. Furthermore, we found that ROS generation required the recruitment and activation of spleen tyrosine kinase (Syk) and that mmLDL also induced phospholipase PLCgamma1 phosphorylation and protein kinase C membrane translocation. Importantly, the phospholipase Cgamma1 phosphorylation was reduced in J774 cells expressing Syk-specific short hairpin RNA. Nox2 modulated mmLDL activation of macrophages by regulating the expression of proinflammatory cytokines interleukin-1beta, interleukin-6, and RANTES. We showed that purified RANTES was able to stimulate migration of mouse aortic smooth muscle cells and addition of neutralizing antibody against RANTES abolished the migration of mouse aortic smooth muscle cells stimulated by mmLDL-stimulated macrophages. These results suggest that mmLDL induces generation of ROS through sequential activation of TLR4, Syk, phospholipase Cgamma1, protein kinase C, and gp91phox/Nox2 and thereby stimulates expression of proinflammatory cytokines. These data help explain mechanisms by which endogenous ligands, such as mmLDL, can induce TLR4-dependent, proatherogenic activation of macrophages.