Validation of the Korean Version of the Health Care Climate Questionnaire among Cancer Survivors.

Healthcare professionals should support autonomy in their patients in order for them to maintain the motivation to cope actively with their conditions. The Health Care Climate Questionnaire (HCCQ) is useful for assessing patients' perceptions of the autonomy support provided to them. We aimed to validate the psychometric properties of the Korean version of the HCCQ (HCCQ-K) among Korean cancer survivors. This study evaluated the factor structure, concurrent validity, and internal consistency. Data from 367 cancer survivors were analyzed using confirmatory factor analysis (CFA), Pearson's correlations, and Cronbach's α values. The CFA validated that the single-factor structure of the HCCQ-K had an excellent fit that was consistent with that of the original English version. Concurrent validity was confirmed by moderate correlations between the HCCQ-K and both psychological well-being and self-management. Reliability was verified by satisfactory internal consistency, with a Cronbach's α value of 0.91 and strong item-total and inter-item correlations. The HCCQ-K is therefore a valid and reliable tool for assessing autonomy support provided by healthcare professionals to Korean cancer survivors. The HCCQ-K may help healthcare professionals understand their patients' needs for autonomy support and develop strategies to motivate active coping behaviors.

Is wide excision really needed? Correlation between resection margin and recurrence in benign phyllodes tumors of the breast.

Purpose: Phyllodes tumors are similar to fibroadenomas in imaging and in pathological characteristics and are difficult to identify preoperatively. The purpose of this study was to analyze the recurrence rate after excision stratified by the surgical margin width and to propose and emphasize the "wait and watch" treatment strategy for benign phyllodes tumors. Methods: We performed a retrospective cohort study of patients diagnosed with benign phyllodes tumors by surgical excision between January 2000 and December 2022 at our institution. The medical and histopathological records were reviewed. Results: The results were obtained using the Cox proportional hazard regression and logistic regression. Resection margin status and recurrence were the independent variables. In each variable selection model, the resection margin was positive or less than 1 cm, and the recurrence rate was 3.7 and 1.04 times higher than the control group, but the difference was not statistically significant in 2 analyses. Conclusion: The surgical resection margin status of benign phyllodes tumors did not significantly affect locoregional recurrence. Therefore, follow-up imaging at short intervals without additional surgery is a feasible clinical option when the surgical resection margin is positive or less than 1 cm.

Insampaedok-San Extract Exerts an Immune-Enhancing Effect through NF-κB p65 Pathway Activation.

Insampaedok-san (IS) has traditionally been prescribed as a medication for cold-related symptoms in Northeast Asia, including Korea and China. In this study, we focused on elucidating the molecular mechanism underlying the immunomodulatory activity of IS water extract (ISE) in macrophages. ISE significantly enhanced the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) by increasing the expression of inducible NO synthase and cyclooxygenase-2 (COX-2) in a dose-dependent manner. ISE, which consists of many herbs, contains a large number of active compounds whose pharmacological targets and mechanisms are complicated. Therefore, network pharmacology analysis was used to predict the potential key components, targets, and mechanisms of ISE as immunomodulators. Subsequently, the network pharmacology results were validated experimentally. Seven key components were identified through HPLC-QTOF-MS. As predicted by the network pharmacology analysis, ISE increased the mRNA expression of Tnf and Il6. Furthermore, ISE increased the phosphorylation, nuclear translocation, and transcriptional activity of the p65 subunit of the nuclear factor-κB (NF-κB) signaling pathway. In contrast, rapamycin, an NF-κB inhibitor, suppressed the ISE-induced mRNA expression of Tnf and Il6. In conclusion, ISE is an immune activator that can elevate the production of NO, PGE2, and proinflammatory cytokines mediated by NF-κB signaling.

Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma.

Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research on combination therapy using cabozantinib to improve efficacy and safety when treating patients. Here, we investigated the effect of a combination treatment of cabozantinib and CBD on HCC cells. CBD treatment enhanced the sensitivity of HCC cells to cabozantinib-mediated anti-cancer activity by increasing cytotoxicity and apoptosis. Phospho-kinase array analysis demonstrated that the apoptotic effect of the combination treatment was mainly related to p53 phosphorylation regulated by endoplasmic reticulum (ER) stress when compared to other kinases. The inhibition of p53 expression and ER stress suppressed the apoptotic effect of the combination treatment, revealing no changes in the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, or cleaved caspase-9. Notably, the effect of the combination treatment was not associated with cannabinoid receptor 1 (CNR1) and the CNR2 signaling pathways. Our findings suggest that the combination therapy of cabozantinib and CBD provides therapeutic efficacy against HCC.

The Impact of Light Wavelength and Darkness on Metabolite Profiling of Korean Ginseng: Evaluating Its Anti-Cancer Potential against MCF-7 and BV-2 Cell Lines.

Korean ginseng is a source of functional foods and medicines; however, its productivity is hindered by abiotic stress factors, such as light. This study investigated the impacts of darkness and different light wavelengths on the metabolomics and anti-cancer activity of ginseng extracts. Hydroponically-grown Korean ginseng was shifted to a light-emitting diodes (LEDs) chamber for blue-LED and darkness treatments, while white fluorescent (FL) light treatment was the control. MCF-7 breast cancer and lipopolysaccharide (LPS)-induced BV-2 microglial cells were used to determine chemo-preventive and neuroprotective potential. Overall, 53 significant primary metabolites were detected in the treated samples. The levels of ginsenosides Rb1, Rb2, Rc, Rd, and Re, as well as organic and amino acids, were significantly higher in the dark treatment, followed by blue-LED treatment and the FL control. The dark-treated ginseng extract significantly induced apoptotic signaling in MCF-7 cells and dose-dependently inhibited the NF-κB and MAP kinase pathways in LPS-induced BV-2 cells. Short-term dark treatment increased the content of Rd, Rc, Rb1, Rb2, and Re ginsenosides in ginseng extracts, which promoted apoptosis of MCF-7 cells and inhibition of the MAP kinase pathway in BV-2 microglial cells. These results indicate that the dark treatment might be effective in improving the pharmacological potential of ginseng.

Comparison of the differences in iron and anemia-related markers by ultramarathon distance.

BACKGROUND: Iron and anemia-related markers in long-distance runners have mostly been investigated following single distance marathons, with contradictory findings. This study compared iron and anemia-related markers according to marathon distance. METHODS: Iron and anemia-related markers were analyzed from blood samples of healthy, adult male (aged ≥40-60 years) long-distance runners before and after ultramarathon races of 100 km (N.=14), 308 km (N.=14), and 622 km (N.=10). Fe, total iron-binding capacity (TIBC), unsaturated iron-binding capacity (UIBC), transferrin saturation, ferritin, high-sensitivity C-reactive protein (hs-CRP), white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), and hematocrit (Hct) levels were analyzed. RESULTS: On completion of all races, the iron levels and transferrin saturation decreased (P<0.05), while the ferritin and hs-CRP levels and WBC counts significantly increased (P<0.05). The Hb concentrations increased after the 100-km race (P<0.05), although the Hb levels and Hct decreased after the 308- and 622-km races (P<0.05). The highest-to-lowest levels of unsaturated iron-binding capacity were found following the 100-km, 622-km, and 308-km races, whereas those of the RBC count were found following the 622-km, 100-km, and 308-km races. Ferritin levels were significantly higher following the 308-km race than after the 100-km race (P<0.05); hs-CRP levels in the 308- and 622-km races were higher than those in the 100-km race. CONCLUSIONS: Ferritin levels increased due to inflammation following distance races, and runners experienced transient iron deficiency without anemia. However, the differences in iron and anemia-related markers according to the ultramarathon distance remain unclear.

The efficient synthesis and biological evaluation of justicidin B.

A facile new synthetic method for the preparation of a Type-A 1-arylnaphthalene lactone skeleton was developed and used to synthesise justicidin B and several derivatives. Key synthesis steps included Hauser-Kraus annulation of a phthalide intermediate and Suzuki-Miyaura cross coupling between a triflated naphthalene lactone intermediate and various potassium organotrifluoroborates. With two exceptions, the derivatives showed significant inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse macrophages. Moreover, several compounds, including justicidin B, had marked cytotoxicity towards six human tumour cell lines.

Patients' self-management of adverse events and patient-reported outcomes in advanced renal cell carcinoma treated with targeted therapies: A prospective, longitudinal, observational study.

BACKGROUND: Early intervention to reduce the impact of adverse events (AEs) may improve patients' quality of life and enable optimal treatment duration. METHODS: This nationwide, multicenter, prospective, longitudinal, 1-year observational study investigated patients' self-management of AEs associated with targeted therapy for advanced renal cell carcinoma (RCC) and explored corresponding outcomes, including treatment duration and patient-reported outcomes (PROs). RESULTS: We enrolled 77 advanced RCC patients (mean age 62 years) treated with a first targeted therapy. 210 cases of seven AEs of interest (fatigue, hand-foot syndrome, oral mucosal inflammation, diarrhea, gastrointestinal symptoms, hypertension, and anorexia) were observed. Most AEs were mild to moderate. Overall, 63.4% of patients were identified as managing their AEs well, reporting numerically longer treatment duration and significantly higher PRO scores than patients identified as poor managers. CONCLUSIONS: Longer treatment duration and improved PROs were observed when advanced RCC patients managed targeted therapy-associated AEs well. Repeated education for consolidating AE self-management could be considered to enhance overall treatment outcomes.

Treatment pattern, satisfaction, and productivity loss of patients with ankylosing spondylitis treated with tumor necrosis factor inhibitors in Korea: A multicenter cross-sectional observational study.

AIM: To provide in-depth understanding of real-world tumor necrosis factor inhibitor (TNFi) treatment patterns in patients with ankylosing spondylitis (AS) and treatment satisfaction, productivity loss, and associated factors. METHODS: This was a multicenter observational hybrid retrospective chart review and cross-sectional survey study. Disease activity and physical functioning were measured using the Bath AS Disease Activity Index and Bath AS Functional Index, respectively. Treatment satisfaction was determined with the Treatment Satisfaction Questionnaire for Medication (TSQM). Productivity loss was evaluated using the Korean version of the World Health Organization-Health and Work Performance Questionnaire. RESULTS: A total of 497 patients were enrolled (mean age 40.3 years, 85.3% male, mean AS duration 10 years). The mean duration of TNFi treatment was 6.2 years. Among the four TNFi considered, adalimumab (39.6%) and etanercept (23.5%) were most commonly used at study enrollment. The TSQM convenience domain score was lower than scores in the effectiveness, adverse effects, and global satisfaction domains. Subcutaneous syringe-type injection and intravenous injection were associated with lower patient convenience satisfaction than subcutaneous pen-type injection. Increased costs of lost productivity time were associated with female sex, unemployed status, and higher disease activity. CONCLUSIONS: The most frequently prescribed TNFi was adalimumab, followed by etanercept. Etanercept was used for the longest duration. More convenient treatment options may enhance overall treatment satisfaction. Considerable loss in productivity due to AS was observed in this study. To reflect patients' perspectives, further attention should be paid to factors associated with treatment satisfaction and productivity loss when selecting treatment options.

FBI-1 inhibits epithelial-to-mesenchymal transition, migration, and invasion in lung adenocarcinoma A549 cells by downregulating transforming growth factor-ß1 signaling pathway.

The factor binding inducer of short transcripts-1 (FBI-1) is a POZ-domain Kruppel-like (POK) family of transcription factors and is known as a proto-oncogene or tumor suppressor in various carcinomas. However, the role of FBI-1 on epithelial-to-mesenchymal transition (EMT) and invasiveness in lung cancer remains unknown. Preliminarily, clinical data such as tissue microarray, Kaplan-Meier, and Oncomine were analyzed to confirm the correlation between lung cancer metastasis and FBI-1. To investigate the function of FBI-1 in EMT in lung cancer, EMT was measured in FBI-1-deficient or FBI-1-overexpressing cells. FBI-1 showed decreased expression in tumors metastasized to lymph nodes than in the primary tumor. In addition, it was also associated with improved survival rates of lung cancer patients. FBI-1 knockdown improved E-to-N-cadherin switching, migration, and invasion in A549 cells, similar to the initiation of EMT stimulated by transforming growth factor- ß1 (TGF-ß1). In contrast, overexpression of FBI-1 inhibited the transcription and activation of Smad2, thereby interfering with EMT, despite stimulation by TGF-ß1. These results suggest that FBI-1 plays a negative role in EMT in lung cancer via the TGF-ß1 signaling pathway, implying its use as a new potential therapeutic target and diagnostic indicator for early stage of lung cancer metastasis.

The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes.

Background/Aim: Transforming growth factor-beta (TGF-ß) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-ß signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-ß signatures showed a better prognosis than those with late TGF-ß signatures. The expression status of early and late TGF-ß signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. Methods: The expression of TGF-ß signatures, early and late responsive signatures of TGF-ß were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. Results: The expression levels of TGF-ß signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-ß (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-ß signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-ß signaling, whereas FBP1 expression was inversely correlated with that of stemness markers. Conclusions: The enrichment of the late responsive signatures of TGF-ß with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-ß are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.

Appendiceal mucocele masquerading as an epithelial borderline ovarian tumor: a case report and literature review.

Appendiceal mucocele is a rare mucin-producing neoplasm of appendiceal origin. Due to its location and imaging findings, appendiceal mucocele is easily confused with tumors of the right adnexa. We present a rare case of a patient initially misdiagnosed with an ovarian tumor intraoperatively diagnosed as an appendiceal mucocele and successfully treated. A 66-year-old postmenopausal woman was admitted to the gynecology department for an asymptomatic pelvic mass. Preoperative pelvic imaging showed an 8-cm cystic mass. Exploratory laparoscopy for the suspected epithelial borderline tumor from the right ovary revealed a cystic mass in the right pelvic area and normal uterus, fallopian tubes, and ovaries. Intraoperative consultation with the general surgery department confirmed the appendiceal origin. Laparoscopic appendectomy was performed. Histopathological examination confirmed a low-grade mucinous neoplasm of appendiceal origin. The patient was discharged on a postoperative day 5 without complications. The outpatient follow-up performed 1 month later showed no evidence of disease progression. Despite the use of advanced diagnostic tools, appendiceal mucocele may be confused for ovarian malignancies. Because the clinical features of appendiceal mucocele are nonspecific, clinicians and radiologists know the specific imaging findings. A multidisciplinary approach including general surgery, gynecology, and radiology is required for preoperative diagnosis and treatment.

Subretinal versus intravitreal administration of human CD34+ bone marrow-derived stem cells in a rat model of inherited retinal degeneration.

BACKGROUND: To evaluate whether subretinal or intravitreal injection of human CD34+ bone marrow-derived stem cells (BMSC) can have protective effects on retinal degeneration that may be enhanced by coadministration of exosomes harvested from human bone marrow mesenchymal stem cells (MSCs). METHODS: Human CD34+ cells were harvested from the mononuclear cell fraction of bone marrow using magnetic beads and labeled with EGFP. Exosomes were harvested from cultured human MSCs under hypoxic conditions. Royal College of Surgeons (RCS) 3-weeks-old rats, immunosuppressed with cyclosporine A, received subretinal or intravitreal injection of CD34+ cells (50,000 cells), CD34+ cells with exosomes (50,000 cells+10 µg), exosomes alone (10 µg), or PBS. Retinal function was examined using electroretinography (ERG), and the eyes were harvested for histologic and immunohistochemical analysis. RESULTS: The b-wave amplitude of ERG at 2 weeks after injection was significantly higher in eyes with subretinal or intravitreal CD34+ BMSC alone or in combination with exosomes when compared to PBS injected eyes or untreated contralateral eyes. At 4 weeks after injection, the ERG signal decreased in all groups but eyes with subretinal CD34+ BMSCs alone or combined with exosomes showed partially preserved ERG signal and preservation of the outer nuclear layer of the retina near the injection site on histology when compared to eyes with PBS injection. Immunohistochemical analysis identified the human cells in the outer retina. Subretinal or intravitreal exosome injection had no effect on retinal degeneration when administered alone or in combination with CD34+ cells. CONCLUSIONS: Both subretinal and intravitreal injection of human CD34+ BMSCs can provide functional rescue of degenerating retina, although the effects were attenuated over time in this rat model. Regional preservation of the outer retina can occur near the subretinal injection site of CD34+ cells. These results suggest that CD34+ cells may have therapeutic potential in retinal degeneration.

YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior.

The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016-0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18-0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.

Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study.

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.

Imaging Hydrogen Sulfide in Hypoxic Tissue with [99mTc]Tc-Gluconate.

Hydrogen sulfide (H2S) is the third gasotransmitter and is generated endogenously in hypoxic or inflammatory tissues and various cancers. We have recently demonstrated that endogenous H2S can be imaged with [99mTc]Tc-gluconate. In the present study, we detected H2S generated in hypoxic tissue, both in vitro and in vivo, using [99mTc]Tc-gluconate. In vitro uptake of [99mTc]Tc-gluconate was measured under hypoxic and normoxic conditions, using the colon carcinoma cell line CT26, and was higher in hypoxic cells than that in normoxic cells. An acute hindlimb ischemia-reperfusion model was established in BALB/c mice by exposing the animals to 3 h of ischemia and 3 h of reperfusion prior to in vivo imaging. [99mTc]Tc-gluconate (12.5 MBq) was intravenously injected through the tail vein, and uptake in the lower limb was analyzed by single-photon emission computed tomography/computed tomography (SPECT/CT). SPECT/CT images showed five times higher uptake in the ischemic limb than that in the normal limb. The standard uptake value (SUVmean) of the ischemic limb was 0.39 ± 0.03, while that of the normal limb was 0.07 ± 0.01. [99mTc]Tc-gluconate is a novel imaging agent that can be used both in vitro and in vivo for the detection of endogenous H2S generated in hypoxic tissue.

Jeju Magma-Seawater Inhibits α-MSH-Induced Melanogenesis via CaMKKß-AMPK Signaling Pathways in B16F10 Melanoma Cells.

Melanin protects skin from ultraviolet radiation, toxic drugs, and chemicals. Its synthesis is sophisticatedly regulated by multiple mechanisms, including transcriptional and enzymatic controls. However, uncontrolled excessive production of melanin can cause serious dermatological disorders, such as freckles, melasma, solar lentigo, and cancer. Moreover, melanogenesis disorders are also linked to neurodegenerative diseases. Therefore, there is a huge demand for safer and more potent inhibitors of melanogenesis. In the present study, we report novel inhibitory effects of Jeju magma-seawater (JMS) on melanogenesis induced by α-melanocyte stimulating hormone (α-MSH) in B16F10 melanoma cells. JMS is the abundant underground seawater found in Jeju Island, a volcanic island of Korea. Research into the physiological effects of JMS is rapidly increasing due to its high contents of various minerals that are essential to human health. However, little is known about the effects of JMS on melanogenesis. Here, we demonstrate that JMS safely and effectively inhibits α-MSH-induced melanogenesis via the CaMKKß (calcium/calmodulin-dependent protein kinase ß)-AMPK (5' adenosine monophosphate-activated protein kinase) signaling pathway. We further demonstrate that AMPK inhibits the signaling pathways of protein kinase A and MAPKs (mitogen-activated protein kinase), which are critical for melanogenesis-related gene expression. Our results highlight the potential of JMS as a novel therapeutic agent for ameliorating skin pigmentation-related disorders.

Diospyros kaki leaves inhibit HGF/Met signaling-mediated EMT and stemness features in hepatocellular carcinoma.

Persimmon (Diospyros kaki L.f.) trees are widely cultivated for their edible fruits in Asia. D. kaki leaves are abundant in phytochemicals that have numerous medicinal properties. Hepatocyte growth factor (HGF) and its receptor Met lead to poor prognosis via the promotion of metastasis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, inhibitors targeting the HGF/Met pathway are regarded as promising drugs against HCC. Here, we investigated the effects of D. kaki leaves on HGF-induced epithelial-to-mesenchymal transition (EMT) and stemness traits in HCC. The ethanol extract of D. kaki leaves (EEDK) markedly suppressed HGF-mediated cell migration and invasion through upregulation of CDH1 and downregulation of SNAI1, VIM, MMP1, MMP2, and MMP9. Moreover, EEDK increased the cytotoxicity of sorafenib, which was reduced by HGF, and decreased the expression of the stemness markers KRT19 and CD44. Additionally, we found a clear correlation between stemness and EMT markers in HCC patients. Importantly, EEDK reduced Met activity and attenuated HGF-mediated activation of JNK/c-Jun. Our findings provide new evidence that EEDK can ameliorate HCC with poor prognosis and aggressive phenotype by blocking HGF/Met signaling.

Evaluation of treatment with a combination of mycophenolate mofetil and prednisolone in dogs with meningoencephalomyelitis of unknown etiology: a retrospective study of 86 cases (2009-2017).

BACKGROUND: Combination therapy with glucocorticoids and adjunctive immunomodulating drugs has been generally accepted as a standard treatment regimen for meningoencephalomyelitis of unknown etiology (MUE). We hypothesized that treatment with MMF as an adjunctive agent along with glucocorticoids would be effective and well-tolerated protocol in dogs with MUE. Eighty-six dogs with MUE between May 2009 and June 2017 were included (59 females and 27 males; mean age of 5.93 years; mean body weight of 3.83 kg). The medical records of dogs with MUE treated with prednisolone and MMF were retrospectively evaluated to determine the therapeutic response, survival time, and treatment-related adverse effects. RESULTS: A partial or complete response (CR) was recorded for 75 dogs. The overall median survival time from the initiation of treatment was 558 days. Dogs that showed CR with no relapse over the treatment period (from diagnosis to death) had significantly longer median survival times. A significantly higher mortality hazard ratio of 4.546 was recorded in dogs that failed to achieve CR. The interval between the onset of clinical signs and the clinical presentation was not significantly associated with CR, relapse rate, and survival time. Adverse effects included gastrointestinal upsets in 26 dogs (30.23%), sporadic infections in 17 dogs (19.77%), and pancreatitis in seven dogs (8.14%). CONCLUSIONS: The results suggest that adjunctive MMF treatment for MUE is safe and comparable to other immunosuppressive protocols. The treatment should focus on the achievement of CR and preventing relapse for successful management.

Expression of platelet-derived growth factor receptor-α/ß, vascular endothelial growth factor receptor-2, c-Abl, and c-Kit in canine granulomatous meningoencephalitis and necrotizing encephalitis.

BACKGROUND: Given the active research on targeted therapy using tyrosine kinase (TK) inhibitors (TKIs) in the field of oncology, further studies have recently been conducted to evaluate their use in autoimmune disorders. Based on immunological investigations, previous studies have suggested that granulomatous meningoencephalomyelitis (GME) and necrotizing encephalomyelitis (NE) are similar to multiple sclerosis (MS), which is a human autoimmune demyelinating central nervous system disease. OBJECTIVES: Considering this perspective, we hypothesized that canine GME and NE have significant expression of one or more TKs, which are associated with human MS pathogenesis. METHODS: To determine the possible use of conventional multi-targeted TKIs as a treatment for canine GME and NE, we characterized the immunohistochemical expression of platelet-derived growth factor receptor (PDGFR)-α, PDGFR-ß, vascular endothelial growth factor receptor (VEGFR)-2, c-Abl and c-Kit in GME and NE samples. RESULTS: Histological samples from four dogs with GME and three with NE were retrieved. All samples stained positive for PDGFR-ß (7/7 [100%]). PDGFR-α and c-Kit were expressed in 3/7 (42.8%) samples each. c-Abl was identified in 2/7 (28.5%) samples; no sample showed VEGFR-2 (0%) expression. Co-expression of TKs was identified in 6/7 (85.7%) dogs. CONCLUSIONS: All samples were positive for at least one or more of PDGFR-α, PDGFR-ß, c-Kit and c-Abl, which are known as the target TKs of conventional multi-targeted TKIs. Their presence does suggest that these TKs may play a role in the pathogenesis of GME and NE. Therefore, multi-targeted TKIs may provide benefits in the treatment of canine GME and NE by suppressing the activity of these TKs.