YTHDF3 Modulates EGFR/ATK/ERK/p21 Signaling Axis to Promote Cancer Progression and Osimertinib Resistance of Glioblastoma Cells.

BACKGROUND/AIM: Despite recent advances in EGFR-tyrosine kinase inhibitor (TKI) drugs for glioblastoma multiforme (GBM), intrinsic EGFR alterations in GBM have resulted in drug resistance and unsatisfactory clinical development of EGFR-TKIs. Determining the unknown mechanisms underlying EGFR-TKI drug resistance is an urgent, but unmet, medical need for GBM. Although several m6A RNA methylation regulators, such as reader YTHDF1/2, were recently predicted to be related to GBM recurrence, none was associated with resistance to the 3rd generation EGFR-TKI osimertinib. MATERIALS AND METHODS: Osimertinib-resistant GBM cells (U87OSR) were established to ascertain the correlation between m6A expression and osimertinib resistance, prior to systemic analyses on m6A writers, erasers, and readers. YTHDF3-silencing was employed to reveal changes in IC50, cellular migration, cancer stemness, and p21-guided senescence in U87OSR cells. Signaling pathways and an in vivo xenograft model of U87OSR cells were investigated to delineate the influence of osimertinib-resistance and elevated YTHDF3 expression. RESULTS: YTHDF3 played a crucial role in inducing cellular proliferation, migration, and stemness in U87OSR GBM cells. Importantly, silencing of YTHDF3 markedly reduced the activation of certain signaling pathways, including EGFR- or ITGA7- AKT, and ERK in U87OSR cells. Our study also revealed the oncogenic function of YTHDF3 in inducing senescence escape via p21 down-regulation. In contrast, silencing of YTHDF3 resulted in increased p21 expression, senescence, and suppressed tumor growth in our osimertinib-resistant preclinical model. CONCLUSION: Overall, our research underscores the novel potential of YTHDF3 as a new pharmacological target in GBM treatment, specifically for patients with osimertinib-resistant or refractory tumors.

Dickkopf-1 Acts as a Profibrotic Mediator in Progressive Chronic Kidney Disease.

Chronic kidney disease (CKD) is a serious public health problem. Due to a high variability in the speed of CKD progression to end-stage renal disease (ESRD) and the critical involvement of Wnt/ß-catenin signaling in CKD, we investigated the role of the Wnt antagonist Dickkopf-1 (DKK1) in CKD progression. Our data revealed that patients with CKD stages 4-5 had higher DKK1 levels in their serum and renal tissues than the control subjects. In an 8-year follow-up, the serum DKK1-high group in the enrolled CKD patients showed a faster progression to ESRD than the serum DKK1-low group. Using a rat model of 5/6 nephrectomy (Nx)-induced CKD, we consistently detected elevated serum levels and renal production of DKK1 in 5/6 Nx rats compared to sham-operated rats. Importantly, the knockdown of the DKK1 levels in the 5/6 Nx rats markedly attenuated the CKD-associated phenotypes. Mechanistically, we demonstrated that the treatment of mouse mesangial cells with recombinant DKK1 protein induced not only the production of multiple fibrogenic proteins, but also the expression of endogenous DKK1. Collectively, our findings suggest that DKK1 acts as a profibrotic mediator in CKD, and elevated levels of serum DKK1 may be an independent predictor of faster disease progression to ESRD in patients with advanced CKD.

Thyroid hormone upregulates LAMP2 expression and lysosome activity.

Thyroid hormone (T3)-induced autophagy and its biological significance have been extensively investigated in recent years. However, limited studies to date have focused on the important role of lysosomes in autophagy. In this study, we explored the effects of T3 on lysosomal protein expression and trafficking in detail. Our findings showed that T3 activates rapid lysosomal turnover and expression of numerous lysosomal genes, including TFEB, LAMP2, ARSB, GBA, PSAP, ATP6V0B, ATP6V0D1, ATP6V1E1, CTSB, CTSH, CTSL, and CTSS, in a thyroid hormone receptor-dependent manner. In a murine model, LAMP2 protein was specifically induced in mice with hyperthyroidism. T3-promoted microtubule assembly was significantly disrupted by vinblastine, resulting in accumulation of the lipid droplet marker PLIN2. In the presence of the lysosomal autophagy inhibitors bafilomycin A1, chloroquine and ammonium chloride, we observed substantial accumulation of LAMP2 but not LAMP1 protein. T3 further enhanced the protein levels of ectopically expressed LAMP1 and LAMP2. Upon knockdown of LAMP2, cavities of lysosomes and lipid droplets accumulated in the presence of T3, although the changes in LAMP1 and PLIN2 expression were less pronounced. More specifically, the protective effect of T3 against ER stress-induced death was abolished by knockdown of LAMP2. Our collective results indicate that T3 not only promotes lysosomal gene expression but also LAMP protein stability and microtubule assembly, leading to enhancement of lysosomal activity in digesting any additional autophagosomal burden.

Insights into the Molecular Mechanisms of NRF2 in Kidney Injury and Diseases.

Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. In non-stressed conditions, NRF2 maintains the hemostasis of redox with housekeeping work. It expresses constitutively with basal activity, maintained by Kelch-like-ECH-associated protein 1 (KEAP1)-associated ubiquitination and degradation. When encountering stress, it can be up-regulated by several mechanisms to exert its anti-oxidative ability in diseases or inflammatory processes to protect tissues and organs from further damage. From acute kidney injury to chronic kidney diseases, such as diabetic nephropathy or glomerular disease, many results of studies have suggested that, as a master of regulating redox, NRF2 is a therapeutic option. It was not until the early termination of the clinical phase 3 trial of diabetic nephropathy due to heart failure as an unexpected side effect that we renewed our understanding of NRF2. NRF2 is not just a simple antioxidant capacity but has pleiotropic activities, harmful or helpful, depending on the conditions and backgrounds.

Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic Nephropathy.

Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compounds extracted from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compounds on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was observed in mouse renal mesangial cells treated with 0-1 µg/mL MTE. Western blot analysis indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochemical staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid-Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy.

Immune Modulation by Myeloid-Derived Suppressor Cells in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1ß, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD.

LPAL2 Suppresses Tumor Growth and Metastasis of Hepatocellular Carcinoma by Modulating MMP9 Expression.

Tumor metastasis is a complex process modulated by both intrinsic and extrinsic factors that ultimately result in poorer patient outcomes, including diminished survival. Pseudogene-derived long non-coding RNAs (lncRNA) play important roles in cancer progression. In the current study, we found that the pseudogene-derived lncRNA LPAL2 is downregulated in hepatocellular carcinoma (HCC) tissues, and further showed that elevated LPAL2 expression is positively correlated with survival outcome. The knockdown of LPAL2 in hepatoma cells induced tumor formation, migration, invasion, sphere formation, and drug resistance. Metalloproteinase 9 (MMP9) was identified as an LPAL2-regulated target gene, consistent with clinical findings that LPAL2 expression is significantly associated with MMP9 expression. Furthermore, patients with a higher expression of LPAL2 and lower expression of MMP9 (LPAL2-high/MMP9-low) had a higher survival rate than those with other combinations. Collectively, our findings establish LPAL2 as a novel tumor suppressor in HCC, and suggest targeting LPAL2 and MMP9 as a therapeutic approach for the treatment of HCC.

New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid.

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.

CMAHP promotes metastasis by reducing ubiquitination of Snail and inducing angiogenesis via GM-CSF overexpression in gastric cancer.

Pseudogenes are generally considered "junk" DNA or "genomic fossils" generated during the evolution process that lack biological activity. However, accumulating reports indicate that pseudogenes have biological functions critical for cancer development. Experiments from the current study showed marked overexpression of the cytidine monophospho-N-acetylneuraminic acid hydroxylase pseudogene (CMAHP) in gastric cancer, which was associated with poor overall survival. However, the mechanisms underlying the activity of CMAHP in tumor development are largely unknown. Gene Set Enrichment Analysis (GSEA) revealed that CMAHP-correlated genes are significantly involved in epithelial-mesenchymal transition (EMT) and angiogenesis. Functional studies further confirmed that CMAHP mediates metastasis and angiogenesis in vitro and in vivo. Furthermore, CMAHP promoted cancer cell migration, invasion, and metastasis through Snail overexpression, which decreased ubiquitination mediated by NF-κB signaling. Angiogenesis is known to be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. CMAHP increased GM-CSF transactivation via promoting direct binding of c-Jun to the -1981/-1975 region of the GM-CSF promoter. Notably, CMAHP interacts with Histone H1.4 promoting histone acetylation to enhance c-Jun and RelA (p65) expression. Our collective findings provide novel evidence that CMAHP contributes to tumor progression and modulates metastasis and angiogenesis in gastric cancer.

Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer.

Liver cancer is the leading cause of cancer-related mortality in the world. This mainly reflects the lack of early diagnosis tools and effective treatment methods. MicroRNAs (miRNAs) are a class of non-transcribed RNAs, some of which play important regulatory roles in liver cancer. Here, we discuss microRNAs with key impacts on liver cancer, such as miR-122, miR-21, miR-214, and miR-199. These microRNAs participate in various physiological regulatory pathways of liver cancer cells, and their modulation can have non-negligible effects in the treatment of liver cancer. We discuss whether these microRNAs can be used for better clinical diagnosis and/or drug development. With the advent of novel technologies, fast, inexpensive, and non-invasive RNA-based biomarker research has become a new mainstream approach. However, the clinical application of microRNA-based markers has been limited by the high sequence similarity among them and the potential for off-target problems. Therefore, researchers particularly value microRNAs that are specific to or have special functions in liver cancer. These include miR-122, which is specifically expressed in the liver, and miR-34, which is necessary for the replication of the hepatitis C virus in liver cancer. Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer.

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development.

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.

Functional roles of non-coding RNAs regulated by thyroid hormones in liver cancer.

Recent reports have shown the important role of the non-coding part of human genome RNA (ncRNA) in cancer formation and progression. Among several kinds of ncRNAs, microRNAs (miRNA) play a pivotal role in cancer biology. Accumulating researches have been focused on the importance of non-coding genes in various diseases. In addition to miRNAs, long non-coding RNAs (lncRNAs) have also been extensively documented. Recently, the study of human liver cancer has gradually shifted to these non-coding RNAs that were originally considered "junk". Notably, dysregulated ncRNAs maybe influence on cell proliferation, angiogenesis, anti-apoptosis, and metastasis. Thyroid hormones play critical roles in human development and abnormalities in thyroid hormone levels are associated with various diseases, such as liver cancer. Thyroid hormone receptors (TR) act as ligand-activated nuclear transcription factors to affect multiple functions through the gene-level regulation in the cells and several studies have revealed that thyroid hormone associated with ncRNAs expression. TR actions are complex and tissue- and time-specific, aberrant expression of the various TR isoforms have different effects and are associated with different types of tumor or stages of development. In this review, we discuss various aspects of the research on the thyroid hormones modulated ncRNAs to affect the functions of human liver cells.

Malnutrition associated with an increased risk of postoperative complications following hepatectomy in patients with hepatocellular carcinoma.

BACKGROUND: The aim of this study was to analyze the nutritional risk factors for postoperative complications following hepatic resection for hepatocellular carcinoma (HCC). METHODS: The preoperative nutritional status of patients with HCC who underwent hepatic resection was evaluated using the scored Patient-Generated Subjective Global Assessment (PG-SGA). The perioperative variables were compared between well-nourished and malnourished patients. Regression analysis was employed to identify the risk factors for postoperative complications. RESULTS: The overall operative mortality and morbidity of 287 patients who underwent resection for HCC were 1.7% and 44.3%, respectively. Upon admission, 96 (33.4%) study participants were malnourished, which was associated with a significantly higher PG-SGA score (P < 0.001), higher frequency of comorbidity (P < 0.001), more postoperative complications (P < 0.001) and a longer length of hospital stay (P < 0.001). In addition, major complications (Clavien-Dindo classification ≥ IIIa) occurred significantly more frequently in the malnourished group (P < 0.01). Age ≥70 years (risk ratio [RR] = 2.50, P = 0.008) and PG-SGA score ≥ 4 ([RR] = 9.85, P < 0.001) were significant risk factors for postoperative complications. CONCLUSIONS: The PG-SGA score is an effective tool for predicting postoperative complications in patients with HCC following hepatic resection.

Chemical characteristics, source apportionment, and regional transport of marine fine particles toward offshore islands near the coastline of northwestern Taiwan Strait.

This study aims to investigate the spatiotemporal variation, chemical composition, and source apportionment of marine fine particles (PM2.5) as well as their regional transport toward the Matsu Islands located near the coastline of northwestern Taiwan Strait. Four offshore island sites located at the Matsu Islands were selected to conduct both regular and intensive sampling of marine PM2.5. Water-soluble ionic species, metallic elements, and carbonaceous contents were then analyzed to characterize the chemical characteristics of marine PM2.5. In order to identify the potential sources and their contributions to marine PM2.5, chemical mass balance (CMB) receptor model was employed along with the backward trajectory simulation to resolve the source apportionment of marine PM2.5 and to explore their transport routes in different seasons. The results showed that high PM2.5 concentrations were commonly observed during the northeastern monsoon periods. Additionally, marine PM2.5 concentration decreased from the west to the east with the highest PM2.5 at the Nankang Island and the lowest PM2.5 at the Donyin Island in all seasons, indicating an obvious concentration gradient of PM2.5 transported from the continental areas to the offshore islands. In terms of chemical characteristics of PM2.5, the most abundant water-soluble ions of PM2.5 were secondary inorganic aerosols (SO42-, NO3-, and NH4+) which accounted for 55-81% of water-soluble ions and 29-52% of marine PM2.5. The neutralization ratios of PM2.5 were always less than unity, indicating that NH4+ cannot solely neutralize nss-SO42+ and NO3- in marine PM2.5 at the Matsu Islands. Although crustal elements (Al, Ca, Fe, K, and Mg) dominated the metallic content of marine PM2.5, trace anthropogenic metals (Cd, As, Ni, and Cr) increased significantly during the northeastern monsoon periods, particularly in winter. Organic carbons (OCs) were always higher than elemental carbons (ECs), and the mass ratios of OC and EC were generally higher than 2.2 in all seasons, implying that PM2.5 was likely to be aged particles. During the poor air quality periods, major air mass transport routes were the northern transport and the anti-cyclonic circulation routes. Source apportionment results indicated that fugitive soil dusts and secondary aerosols were the major sources of marine PM2.5 at the Matsu Islands, while, in winter, biomass burning contributed up to 15% of marine PM2.5. This study revealed that cross-boundary transport accounted for 66~84% of PM2.5 at the Matsu Islands, suggesting that marine PM2.5 at the Matsu Islands has been highly influenced by anthropogenic emissions from neighboring Fuzhou City as well as long-range transport from Northeast Asia.

Central Hepatectomy Still Plays an Important Role in Treatment of Early-Stage Centrally Located Hepatocellular Carcinoma.

BACKGROUND: Surgical management of centrally located hepatocellular carcinoma (CL-HCC) poses a great challenge. Major hepatectomy (MH) might compromise future remnant liver volume (FRLV), while the long-term benefits of central hepatectomy (CH) had not been well demonstrated. METHODS: Consecutive patients with early-stage CL-HCC who underwent liver resection were enrolled. Fifteen patients underwent CH, while thirty-three were subjected to MH. All relevant clinicopathological variables were analyzed. Disease-free survival (DFS) and overall survival (OS) of both groups were compared. RESULTS: There were no differences between CH and MH in terms of predisposing liver disease, tumor size, blood loss, complication rate and vascular invasion. Mean FRLV increased from 40.9 to 69.2% by using CH resection lines. The parenchymal transection time is longer in CH. There were no differences of DFS between two groups. The 5-year OS rates of CH and MH were 93.3 and 62.6%, respectively. MH was a poor prognostic factor. CONCLUSIONS: CH is a relatively time-consuming and technique-demanding procedure, but excellent long-term survival could be achieved. CH could increase liver volume preservation without compromising intra-hepatic recurrence. In an endemic area of hepatitis and cirrhosis, CH should still play an important role in surgical treatment of CL-HCC.

Living Donor Liver Transplantation for Combined Hepatocellular Carcinoma and Cholangiocarcinoma: Experience of a Single Center.

BACKGROUND Because the outcome of liver transplantation for cholangiocarcinoma is often poor, cholangiocarcinoma is a contraindication for liver transplantation in most centers. Combined hepatocellular carcinoma and cholangiocarcinoma is a rare type of primary hepatic malignancy containing features of hepatocellular carcinoma and cholangiocarcinoma. Diagnosing combined hepatocellular carcinoma and cholangiocarcinoma pre-operatively is difficult. Because of sparse research presentations worldwide, we report our experience with living donor liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma. MATERIAL AND METHODS A total of 710 patients underwent living donor liver transplantation at our institution from April 2006 to June 2014; 377 of them received transplantation because of hepatocellular carcinoma with University of California San Francisco (UCSF) staging criteria fulfilled pre-operatively. Eleven patients (2.92%) were diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma confirmed pathologically from explant livers; we reviewed these cases retrospectively. Long-term survival was compared between patients diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma and patients diagnosed with hepatocellular carcinoma. RESULTS The mean age of the patients in our series was 60.2 years, and the median follow-up period was 23.9 months. Four patients were diagnosed with a recurrence during the follow-up period, including one intra-hepatic and three extra-hepatic recurrences. Four patients died due to tumor recurrence. Except for patients with advanced-stage cancer, disease-free survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma compared with that of patients with hepatocellular carcinoma was 80% versus 97.2% in 1 year, and 46.7% versus 92.5% in 3 years (p<0.001), and overall survival was 90% versus 97.2% in 1 year, and 61.7% versus 95.1% in 3 years (p<0.001). CONCLUSIONS Outcomes of liver transplantation for patients with combined hepatocellular carcinoma and cholangiocarcinoma were worse than those for patients with hepatocellular carcinoma in this study. Combined hepatocellular carcinoma and cholangiocarcinoma are presumed to be a relative contraindication for liver transplantation.

Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery.

Nutritional status assessed by scored patient-generated subjective global assessment associated with length of hospital stay in adult patients receiving an appendectomy.

BACKGROUND: Malnutrition has been associated with poor health outcomes in hospitalized patients. This study assessed the validity of the scored patient-generated subjective global assessment (PG-SGA) in adult patients who had undergone an open appendectomy, and examined the association of this assessment tool with length of hospital stay. METHODS: Nutritional status was determined by using the scored PG-SGA in adult patients (n = 86) who had undergone an open appendectomy within 24 hours of admission. Variables were compared between well-nourished and malnourished participants. Regression analysis was used to identify potential predictors for length of hospital stay. Receiver operator characteristic (ROC) analysis was used to examine the validity of the PG-SGA score to predict the nutritional status. RESULTS: On admission, 17% of the study subjects were malnourished and associated with a significantly older age (53.0 vs. 39.5), greater PG-SGA score (8 vs. 2), higher comorbidity (67% vs. 27%), and longer length of hospital stay (6.9 d vs. 4.1 d). The PG-SGA score and comorbidity were the determined risk factors for length of hospital stay after performing multiple regression analysis. Furthermore, the PG-SGA score had a significantly positive correlation with length of hospital stay (Spearman's rho = 0.378, p < 0.001). The area under the ROC curve indicating the PG-SGA score, compared with nutritional status, is 0.9751. CONCLUSIONS: The scored PG-SGA in adults receiving an appendectomy is significantly associated with length of hospital stay, and is an effective tool for assessing the nutritional status of patients with cancer and chronic illness, as well as of patients with acute surgical abdomen.

Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis.

Cystic fibrosis (CF) is an inherited disease of the secretory glands caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. The clinical manifestations of CF are repetitive lung infections, biliary cirrhosis, pancreatic abnormalities, and gastrointestinal disorders. We report a 21-year-old Taiwanese man with CF who had abdominal pain for 2 days. The diagnosis of CF had been confirmed by peripheral blood analysis of the CFTR gene 5 years before admission. He presented to the emergency department with nausea, vomiting, abdominal distension, and crampy abdominal pain, which is atypical for acute appendicitis. The physical examination and a series of studies revealed intestinal obstruction, but acute appendicitis could not be ruled out. After conservative treatment, together with empiric antibiotics, the refractory abdominal pain and leukocytosis with a left-shift warranted surgical intervention. A diagnostic laparoscopy revealed a swollen, hyperemic appendix, a severely distended small intestine, and serous ascites. The laparoscopic procedure was converted to a laparotomy for open disimpaction and appendectomy. He was discharged on the eighth postoperative day. The histologic examination of the appendix was consistent with early appendicitis. In conclusion, acute abdominal pain in adult CF patients is often associated with intestinal obstruction syndrome. The presentation of concurrent appendicitis may be indolent and lead not only to diagnostic difficulties, but also a number of therapeutic choices.

Preoperative serum C-reactive protein and gastric cancer; clinical-pathological correlation and prognostic significance.

BACKGROUND: C-reactive protein (CRP) is a widely-used systemic biomarker for inflammation. Serum CRP is elevated in many malignancies, and is also a prognostic indicator of malignant potential. However, the prognostic significance for survival from gastric cancer has not yet been clarified. We studied the clinical- pathologic association and prognostic significance of preoperative serum CRP in gastric cancer patients. METHODS: A total of 170 gastric cancer patients were included in this study. The mean age of the patients was 65.1 years (range, 29-89), and 112 were men. All gastric cancer patients had undergone gastric resection. The serum CRP levels of patients before the operation along with those from 405 healthy controls were measured by a high sensitivity CRP test. RESULTS: The 95th percentile value (=3.0 mg/L) of the serum CRP data in 405 healthy controls was set as the upper cut-off value of the normal range. Abnormally high levels of serum CRP were observed in 65 (38.2%) of our 170 patients in contrast to only 20 (4.9%) of the 405 healthy controls (p<0.001). Elevated CRP was associated with older age (p=0.009), grossly infiltrative type (p=0.001), larger tumors (p<0.001), serosal invasion (p=0.001), lymph node metastasis (p<0.001), distant metastasis (p=0.017), and lymphatic invasion (p=0.002). Overall, a higher CRP level was strongly parallel to a pathologically more advanced stage (p=0.001). The 5-yr survival rate of patients with an elevated (>3.0 mg/L) CRP was significantly worse than those without (