The CCL2 chemokine is a negative regulator of autophagy and necrosis in liminal B breast cancer cells

Luminal A and B breast cancers are the most prevalent forms of breast cancer diagnosed in women. Compared to luminal A breast cancer patients, patients with luminal B breast cancers experience increased disease recurrence and lower overall survival. The mechanisms that regulate the luminal B subtype remain poorly understood. The chemokine CCL2 is overexpressed in breast cancer, correlating with poor patient prognosis. The purpose of this study was to determine the role of CCL2 expression in luminal B breast cancer cells. Breast tissues, MMTV-PyVmT and MMTV-Neu transgenic mammary tumors forming luminal B-like lesions, were immunostained for CCL2 expression. To determine the role of CCL2 in breast cancer cells, CCL2 gene expression was silenced in mammary tumor tissues and cells using TAT cell-penetrating peptides non-covalently cross linked to siRNAs (Ca-TAT/siRNA). CCL2 expression was examined by ELISA and flow cytometry. Cell growth and survival were analyzed by flow cytometry, immunocytochemistry, and fluorescence microscopy. CCL2 expression was significantly increased in luminal B breast tumors, MMTV-PyVmT and MMTV-Neu mammary tumors, compared or normal breast tissue or luminal A breast tumors. Ca-TAT delivery of CCL2 siRNAs significantly reduced CCL2 expression in PyVmT mammary tumors, and decreased cell proliferation and survival. CCL2 gene silencing in PyVmT carcinoma cells or BT474 luminal B breast cancer cells decreased cell growth and viability associated with increased necrosis and autophagy. CCL2 expression is overexpressed in luminal B breast cancer cells and is important for regulating cell growth and survival by inhibiting necrosis and autophagy

Torsion of the Gallbladder

A 77-year-old woman was seen with progressive abdominal pain. A CT scan was made and showed a large gallbladder extending into the right lower abdomen. Ultrasound was performed but demonstrated no gallstones. Laparoscopy showed a tordated, necrotic gallbladder that was attached to the liver only by the cystic artery and cystic duct. Cholecystectomy was performed. Torsion of the gallbladder is a rare but clinically important condition in which the diagnosis seldom is made preoperatively. In radiological and clinical signs of cholecystitis without gallstones, this condition should be considered

Eph receptors in breast cancer: roles in tumor promotion and tumor suppression

Eph receptor tyrosine kinase signaling regulates cancer initiation and metastatic progression through multiple mechanisms. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. In addition, Eph molecules function in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of these molecules to promote carcinoma progression and metastasis. The complex nature of Eph receptor signaling and crosstalk with other receptor tyrosine kinases presents a unique challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer

The relationship between applied energy and ablation zone volume in patients with hepatocellular carcinoma and colorectal liver metastasis

To study the ratio of ablation zone volume to applied energy in computed tomography (CT)-guided radiofrequency ablation (RFA) and microwave ablation (MWA) in patients with hepatocellular carcinoma (HCC) in a cirrhotic liver and in patients with colorectal liver metastasis (CRLM). In total, 90 liver tumors, 45 HCCs in a cirrhotic liver and 45 CRLMs were treated with RFA or with one of two MWA devices (MWA_A and MWA_B), resulting in 15 procedures for each tumor type, per device. Device settings were recorded and the applied energy was calculated. Ablation volumes were segmented on the contrast-enhanced CT scans obtained 1 week after the procedure. The ratio of ablation zone volume in milliliters to applied energy in kilojoules was determined for each procedure and compared between HCC (R (HCC)) and CRLM (R (CRLM)), stratified according to ablation device. With RFA, R (HCC) and R (CRLM) were 0.22 mL/kJ (0.14-0.45 mL/kJ) and 0.15 mL/kJ (0.14-0.22 mL/kJ; p = 0.110), respectively. With MWA_A, R (HCC) was 0.81 (0.61-1.07 mL/kJ) and R (CRLM) was 0.43 (0.35-0.61 mL/kJ; p = 0.001). With MWA_B, R (HCC) was 0.67 (0.41-0.85 mL/kJ) and R (CRLM) was 0.43 (0.35-0.61 mL/kJ; p = 0.040). With RFA, there was no significant difference in energy deposition ratio between tumor types. With both MWA devices, the ratios were higher for HCCs. Tailoring microwave ablation device protocols to tumor type might prevent incomplete ablations. aEuro cent HCCs and CRLMs respond differently to microwave ablation aEuro cent For MWA, CRLMs required more energy to achieve a similar ablation volume aEuro cent Tailoring ablation protocols to tumor type might prevent incomplete ablations

Human Cataract Mutations in EPHA2 SAM Domain Alter Receptor Stability and Function

The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity

Liver transplantation in paediatric patients in the Netherlands; evolution over the past two decades

OBJECTIVE: To evaluate the results of the national paediatric liver transplantation programme in the University Medical Centre (UMC) Groningen in the Netherlands during the past two decades.DESIGN: Retrospective cohort study.METHOD: We analysed data from paediatric patients who underwent liver transplantation at UMC Groningen in the period 1995-2016. We compared outcomes from children who had undergone a liver transplantation in the period 1995-2005 (cohort A; n = 126) and in the period 2006-2016 (cohort B; n = 169). We performed a subanalysis in cohort B between liver transplantations with deceased donor livers (n = 132) and living donor liver transplantations (LDLT; n = 37).RESULTS: In cohort A, almost all livers came from deceased donors (99%), whereas in cohort B, 37 LDLTs (22%) were performed. The median age of recipients was significantly higher in cohort A (4.4 vs. 2.5 years; p = 0.015). Postoperative complications were comparable for both cohorts. Re-transplantations within a year after transplantation were more often performed in cohort A than in cohort B (25% vs. 12%; p = 0.004). Following LDLT, there was 2 times (5.4%) an indication for re-transplantation. In cohort B the 5-year survival rate was better than in cohort A (83 vs. 71%; p = 0.014). In cohort B, 5-year survival was higher after LDLT than after transplantation with a deceased donor liver (95 vs. 81%; p = 0.025).CONCLUSION: Outcomes after paediatric liver transplantation in the Netherlands have further improved during the past two decades. With an actuarial 5-year survival of 83% in the most recent cohort, and as high as 95% following LDLT, we can say that the UMC Groningen has a successful national paediatric liver transplant programme.</p

Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion

The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser435 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser897 by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart. Genetic disruption of RCP or EphA2 opposes cell:cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma—whereas conditional knockout of another RCP cargo, α5 integrin, does not suppress pancreatic cancer metastasis—indicating a role for RCP-dependent trafficking of an Eph receptor to drive tumour dissemination in vivo