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Pruritus can be associated with chronic liver disease, particularly cholestatic liver disease. Although the pathophysiology is uncertain, there are a few proposed mechanisms and much is still being discovered. Workup involves an assessment to rule out a dermatologic, neurologic, psychogenic, or other underlying systemic disorder. First-line therapy is cholestyramine, which is generally well tolerated and effective. In those who fail cholestyramine, alternative drugs including rifampicin and μ-opioid receptor antagonists can be considered. If medical therapy is ineffective and pruritus is significant, alternative experimental therapies such as albumin dialysis, photopheresis, plasmapheresis, and biliary diversion can be considered.

Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non–small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis.Implications: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952–63. ©2013 AACR.

PDF file - 80K, Vav2 domains and regulation via tyrosine phosphorylation.

PDF file - 120K, Fer promotes migration and invasion of A549 cells.

PDF file - 267K, Specificity of Fer IHC staining in NSCLC.

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PDF file - 196K, Fer promotes wound healing migration of H1299 cells.

The most reliable treatment for hepatocellular carcinoma (HCC) is liver transplantation (LT). Recurrence of HCC after LT is the most serious problem; therefore, early diagnosis of recurrent HCC is very important. This study investigated the efficacy of tumor markers in patients with LT for HCC.From January 2008 to December 2016, 242 patients underwent LT for HCC. The operation of LT and immunosuppressive methods were the same as those of general LT patients. All patients were followed up with alpha-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA)-II. The 41 patients (16.9%) recurred during follow-up period.The factors associated with recurrence were tumor markers (AFP, PIVKA-II), maximum tumor diameter, number, microvascular invasion, Milan criteria, and Edmondson-Steiner grade. In 41 patients with recurrent HCC, 14 patients (34.15%) were both elevated in 2 markers and 18 patients (43.9%) were elevated in 1 tumor marker. There was no relationship between tumor marker and recurrent site. The survival rate of patients with recurrence in 1, 3, and 5 years were 78.6%, 34.7%, and 23.7%, respectively. Curability of treatment and elevation of tumor marker before treatment were correlated with patient survival after recurrence. When the receiver operating characteristic curve was used, the area under the curve value using the sum of AFP and PIVKA-II before LT was 0.827.In this study, tumor markers (AFP, PIVKA-II) for HCC were correlated with post-transplant recurrence factors and may be a useful tool for early diagnosis and to predict the prognosis after recurrence.

Steroid-resistant rejection (SRR) in liver transplant occurs in about 10% of T cell-mediated rejection; prognosis of SRR is known to be worse than steroid-sensitive rejection (SSR). Only a few studies describe treatment methods or features for SRR, and there is no clear consensus yet. Therefore, the purpose of this study is to describe the difference between SSR and SRR and to compare the effect of the SRR treatment method performed our institution.This study is a 10-year, retrospective cohort study at Seoul St Mary's Hospital; clinical data were collected from January 2008 to December 2017. Of 663 cases, 154 patients (23.3%) underwent steroid pulse therapy for rejection; we excluded 30 patients who did not undergo liver biopsy. A total of 124 patients (18.7%) with biopsy-proven rejection were analyzed for this study.Child-Turcotte-Pugh score, cold ischemia time, and cytomegalovirus (CMV) infection showed a statistically significant difference in 2 groups. Multivariate analysis was performed on risk factors of SRR at first rejection. CMV infection and total bilirubin at first rejection and numbers of rejection were significant results. Both overall survival and allograft survival rate of SSR are higher than SRR (P.001). Of second-line treatment patients, 13 patients (54.2%) recovered, and 11 patients (45.8%) failed to recover. Survival was the highest in patients using antithymocyte globulin and in patients with liver retransplant.When the first rejection in liver transplant occurs, patients with high bilirubin level ​​and previous CMV infections are more likely to have SRR, so if they do not respond to steroid pulse therapy for the first time, either using antithymocyte globulin or liver retransplant preparation should be considered.

Liver transplantation (LT) has the limitation of graft shortage. Therefore, to increase the donor pool, even marginal grafts are being transplanted depending on the recipient's condition. This study was conducted to analyze the post-LT prognosis using discarded liver grafts.From January 2010 to September 2020, deceased-donor LT was performed in 160 patients in our center. Among them, 121 patients (allocated group) were preferentially allocated to our center, and the remaining 39 patients (24.4%, discarded group) received liver grafts that were discarded by prioritized centers.The preoperative model for end-stage liver disease score were 27.0 ± 10.41 and 27.0 ±11.79 for each group (P = .99). There were no differences between the 2 groups in operation time (P = .06) and intraoperative packed red cell transfusion (P = .90). There were no differences between the 2 groups in early allograft dysfunction (P = .48) and hospital stay (P = .26) after deceased-donor LT. In-hospital mortality occurred in 10 patients (8.3%) in the allocated group and 4 patients (10.3%) in the discarded group. Only the length of intensive care unit stay was significantly longer in the discarded group (P = 0.04). The 5-year survival rate was 73.8% in the allocated group and 72.2% in the discarded group.The outcome of the discarded group is never worse than that of the allocated group. deceased-donor LT from the discarded graft can be acceptable. As a result, the number of discarded grafts can be reduced.

Acute kidney injury (AKI) is a common complication in patients undergoing liver transplantation (LT) for end-stage liver disease (ESLD), and renal replacement therapy (RRT) is required in many cases. This study was performed to identify the prognostic factors for patients undergoing RRT owing to AKI before living donor liver transplantation (LDLT).From January 2010 to December 2018, LDLT was performed in 464 adult patients in our center. We reviewed 33 patients who underwent RRT before LDLT among 464 consecutive cases. Patients who continued to RRT after LDLT or who underwent subsequent kidney transplantation were considered to have not recovered from renal impairment.Among 33 patients, there were 23 patients in the recovery group and 10 patients in the nonrecovery group. The preoperative duration of RRT was shorter in the recovery group, but it was not statistically significant. In the nonrecovery group, diabetes mellitus was found to have a higher prevalence and ischemic time was longer. Other perioperative factors were not significantly different between the 2 groups. After LDLT, the peak total bilirubin level was higher, and the intensive care unit stay was longer in the nonrecovery group. The overall survival rate was higher in the recovery group.Liver transplant recipients who maintain RRT after LDLT have poor outcome. It is necessary to know the risk factors and manage them well, perioperatively.

This article reviews the incidence of acute hepatitis B virus (HBV) infection, its clinical course, strategies to prevent acute HBV infection in susceptible individuals, and the management of patients with acute HBV.

Acute alcoholic hepatitis is a clinical entity with significant consequences. Those with severe disease can have high short-term mortality, and considerations for liver transplant candidacy may be raised. Estimating prognosis and mortality is of the utmost importance, as it can guide decision making for corticosteroid therapy and help patients gain an understanding of their illness. Maddrey's discriminant function and MELD score are 2 commonly used static models validated to help estimate severity and prognosis in acute alcoholic hepatitis. This article reviews the 2 models and others used in this difficult setting to assess these patients and guide decision making.

The current study investigates the influence of different welding sequences and external constraints on development of welding- induced angular distortion and residual stresses in the short fillet welds made of the high strength steel (HSS), S700, using the finite element (FE) method. Three-dimensional thermo-elastic-plastic FE modeling was performed in the ABAQUS FE software based on the double-ellipsoidal heat source model, temperature-dependent material properties, and considering geometrical non-linearity. The accuracy of the FE models were verified by comparing the simulation results and experimentally measured data. Both the numerical method and measurements show that external constraint has relatively larger influence than welding sequence on the development of angular distortion and the peak magnitude of residual stresses. To determine the significance of short fillet welds in terms of induced distortion and residual stress fields, the results captured by simulation and validated by measurements were compared to those of continuous fillet welds. From a numerical point of view, the results of this study are meaningful to understand the reasonable accuracy required to capture the necessary details of the welding process. From an engineering prospect, the results of this study can be important as they indicate that transverse residual stress fields due to short fillet welds are localized with considerably larger peak magnitudes compared to continuous fillet welds. With respect to the angular distortion, the results of this study show that stiffness of external constraint has a greater impact on prevention of angular distortion in continuous fillet welds than in short fillet welds. In the case of fillet welds with small lengths, beside proper clamping, other deformation control techniques such as pre-alignment of the welded members need to be considered. Publishers version

Focal nodular hyperplasia and hepatocellular adenoma are benign liver lesions that occur most frequently in women and may be found as incidental findings on imaging. hepatocellular adenomas may be infrequently associated with malignant progression or risk of rupture and as such, require surveillance or definitive treatments based on their size threshold. It is important clinically to differentiate these lesions, and utilizing imaging modalities such as contrast enhanced ultrasound or magnetic resonance imaging can be helpful in diagnosis. Further molecular subtyping of hepatocellular adenoma lesions may be beneficial to describe risk factors and potential future clinical complications.

BACKGROUND: Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, named as the secretome, have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages. AIM: To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials. METHODS: We collected the secretory materials (named as inducers) released from AML12 hepatocytes that had been pretreated with thioacetamide (TAA) and generated the TAA-induced secretome (TAA-isecretome) after stimulating adipose-derived stem cells with the inducers. The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy. RESULTS: TAA-isecretome infusion showed higher therapeutic potential in terms of (1) restoring disorganized hepatic tissue to normal tissue; (2) inhibiting proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α); and (3) reducing abnormally elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase) compared to the naïve secretome infusion in mice with TAA-induced hepatic failure. However, the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice. Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome. In addition, peroxiredoxin-1, a potent antioxidant protein, was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury. CONCLUSION: Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins, especially peroxiredoxin-1, with higher antioxidant activity. Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen. This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.

BACKGROUND Hepatic artery reconstruction during living donor liver transplantation is a critical step. To perform this risky procedure, a microscope has been used. However, it takes a long time to complete the procedure and it has a long and steep learning curve. Recently, some transplant surgeons have performed the procedure using a surgical loupe. We conducted this study to compare the outcomes after hepatic artery reconstruction using a microscope versus using a surgical loupe. MATERIAL AND METHODS We retrospectively reviewed the outcomes of 300 patients at our institution from April 2014 to July 2020. From April 2014 to September 2017 (era 1), hepatic artery reconstruction was performed using a microscope by an experienced plastic surgeon. From September 2017 to the end date (era 2), it was performed using a loupe (×5.0) by an experienced transplantation surgeon. RESULTS There was no difference in most perioperative outcomes between the 2 groups, including the major postoperative complications of hepatic artery complications (2/150 versus 2/150, P=1.000), postoperative bleeding (10/150 versus 5/150, P=0.185), and biliary leakage (18/150 versus 13/150, P=0.343). There was a statistically significant difference between the 2 groups in anastomosis time (42.4±11.8 versus 24.2±7.8, P

In living donor liver transplant, graft steatosis is very important for donor safety and recipient outcome. The purpose of this study was to evaluate the accuracy of noninvasive methods to estimate graft steatosis and establish preoperative selection criteria based on the results.From January 2014 to September 2018, a total of 204 patients underwent donor hemihepatectomy (right lobe) in our center. Imaging studies, such as computed tomography (CT) and magnetic resonance spectroscopy (MRS) were routinely performed. Patients were divided into 4 groups by the macrovesicular steatosis based on the pathologic report (group 1:5%, group 2: ≥5 and10%, group 3: ≥10 and20%, group 4: ≥20%). Hepatic and splenic attenuation values were measured on noncontrast CT scans by using circular region-of-interest cursors in the liver and spleen.Of the 204 donors, 112 (55.1%) were in group 1, 59 (28.5%) were in group 2, 21 (10.8%) were in group 3, and 12 (5.6%) were in group 4. There were no statistical differences in age and sex among 4 groups, but, body mass index, aspartate aminotransferase, alanine aminotransferase, and all imaging studies were significantly different among the 4 groups. Body mass image, alanine aminotransferase, and imaging studies showed a linear relationship with pathologic data. As a result of drawing receiving operating characteristic curves, excellent area under the curve value is shown at average of regions of interest in liver and MRS.Preoperative CT and MRS provide and accurate method to estimate graft steatosis. If the 2 modalities are properly combined, they can be helpful for donor selection.

BACKGROUND Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome. AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs). METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared. RESULTS MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. CONCLUSION We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.

BACKGROUND The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

As one of the most important additive manufacturing (AM) techniques, laser metal deposition (LMD) has been extensively studied specially during the last few years. Similar to other AM techniques, the quality of LMD parts is highly dependent on the processing parameters that need to be optimized so as to obtain geometrically accurate parts as well as favorable microstructures and, thus, mechanical properties. The present review paper therefore aims to present a critical analysis and overview of the relationship between processing parameters, microstructure, and mechanical properties of LMD components made from the Ti–6Al–4V alloy. Moreover, we discuss the applications of LMD parts in the aerospace and biomedical industries as well as the potential of LMD techniques for fabrication of more complex parts such as cellular structures. The paper concludes with a summary of the most important findings and suggestions for future research.

Background Clinically, liver fibrosis and cholestasis are two major disease entities, ultimately leading to hepatic failure. Although autophagy plays a substantial role in the pathogenesis of these diseases, its precise mechanism has not been determined yet. Materials and methods Mouse models of liver fibrosis or cholestasis were obtained after the serial administration of thioacetamide (TAA) or surgical bile duct ligation (BDL), respectively. Then, after obtaining liver specimens at specific time points, we compared the expression of makers related to apoptosis (cleaved caspases), inflammation (CD68), necrosis (high-mobility group box 1), phospho-c-Jun N-terminal kinase (p-JNK), and autophagy (microtubule-associated protein light chain 3B and p62) in the fibrotic or cholestatic mouse livers, by polymerase chain reaction, Western blot analysis, immunohistochemistry, and immunofluorescence. Results Although cholestatic livers exhibited the tendency of progressively increasing the expression of most apoptosis-related markers (cleaved caspases), it was not prominent when it was compared with the tendency found in the livers of TAA-treated mice. Contrastingly, the necrosis-related factor (high-mobility group box 1) was significantly increased in the livers of BDL mice over time, reaching their peak values on day 7 after BDL. In addition, the inflammation-related factor (CD68) was highly expressed in BDL mice compared with TAA-treated mice over time. Autophagy marker studies indicated that autophagy was upregulated in fibrotic livers, whereas it was downregulated in cholestatic livers. We also observed mild to moderate activation of p-JNK in the livers of TAA-treated mice, whereas significantly higher p-JNK activation was detected in the livers of BDL mice. Conclusions Unlike TAA-treated mice, BDL mice exhibited higher expression of the markers related with inflammation and necrosis, especially including p-JNK, while maintaining low levels of autophagic process. Therefore, obstructive cholestasis is characterized by higher p-JNK activation, which could be related with marked necrotic cell death resulting from extensive inflammation and little chance of compensatory autophagy.

The case-based reasoning methodology fundamentally relies on historical cases to solve new problems. Supplementing insufficient data by the reproduction of appropriate values can mitigate the potential negative effects on the solutions resulting from sudden changes. However, CBR researchers have rarely examined this issue. To address this challenge, this research proposes a learning method for knowledge retention based on CBR by applying a data-mining approach to manage missing dataset values. A case study on a 164-apartment project was conducted to compare the estimation accuracy of the suggested learning method to that of past research with the same experiment conditions. The learning method with the CBR model achieved higher accuracy of the overall cost estimation and higher stability compared with the previous model. This research shows how cases can be generated and retained as learned cases to overcome the difficulties of continuous updates in a wide range of construction projects, as well as why the case bases need to be continuously updated. The research outcomes could support work related to cost estimation for decision makers ranging from beginners to experts in both academia and industry.

Vibration-controlled transient elastography (VCTE) is a non-invasive method of evaluating liver fibrosis and steatosis. It can easily be performed in the outpatient setting and has been suggested as an alternative to liver biopsy. However, VCTE and biopsy discrepancies commonly occur. Patient characteristics, procedure performance, and liver features can impact the reliability of VCTE results. We identified 82 patients who received VCTE and biopsy within one month to assess how frequently major discrepancies occur and to determine the role of the liver biopsy in this workup. In our study, 35.4% of patients had a major fibrosis discrepancy, which was defined as advanced fibrosis or cirrhosis by VCTE and no to minimal fibrosis on biopsy. This was significantly associated with increased BMI, and liver features including steatohepatitis, inflammation, congestion, and cholestasis were important contributors to discrepancies. All patients with advanced fibrosis or cirrhosis on liver biopsy were appropriately detected by VCTE (n = 28). Detection of steatosis was less sensitive as 19% (n = 4 of 21) of patients with moderate to severe steatosis on biopsy were missed by VCTE. Liver biopsy has been traditionally performed for diagnosis, but with the emergence of non-invasive tools to evaluate for liver fibrosis and steatosis, biopsies are now additionally being performed to confirm findings from noninvasive procedures. Although VCTE is a highly sensitive tool for liver fibrosis, it is not as specific, and therefore, the liver biopsy remains the gold standard for accurate fibrosis assessment.

The incidence and mortality related to hepatocellular carcinoma (HCC) continue to increase in the United States, with most patients presenting at advanced stages where curative therapy and long-term survival is unlikely. Fortunately, significant progress has been made in identifying the landscape of HCC mutations due to advances in whole genome expression profiling. Drug development has also evolved in recent years with multiple first- and second-line systemic chemotherapy agents approved for HCC for the first time in over a decade. However, despite advances in molecular profiling, mutations that were identified at the highest frequency were not amenable to drug development, and curative therapy for advanced HCC remains elusive. This review focuses on the current understanding of HCC genomics and the limitations of translating the current HCC molecular profiling into clinical practice and examines the effectiveness and benefits of approved systemic therapies for advanced HCC.