Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process Effacement

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays a critical role in cell motility. Movement and retraction of podocyte foot processes, which accompany podocyte injury, suggest focal adhesion disassembly. To understand better the mechanisms by which podocyte foot process effacement leads to proteinuria and kidney failure, we studied the function of FAK in podocytes. In murine models, glomerular injury led to activation of podocyte FAK, followed by proteinuria and foot process effacement. Both podocyte-specific deletion of FAK and pharmacologic inactivation of FAK abrogated the proteinuria and foot process effacement induced by glomerular injury. In vitro, podocytes isolated from conditional FAK knockout mice demonstrated reduced spreading and migration; pharmacologic inactivation of FAK had similar effects on wild-type podocytes. In conclusion, FAK activation regulates podocyte foot process effacement, suggesting that pharmacologic inhibition of this signaling cascade may have therapeutic potential in the setting of glomerular injury.The glomerulus forms the filtration barrier of the kidney and is composed of a fenestrated endothelium, glomerular basement membrane (GBM), and the podocytes that interdigitate to form slit diaphragms.^1,2 When the podocytes are damaged, foot process fusion occurs. This process involves the rearrangement of the actin cytoskeleton and retraction of the foot processes toward the cell body, allowing mechanical forces and signaling events to be transmitted into the cell. Since the identification that mutations of the podocyte slit diaphragm specific NPHS1 gene cause congenital nephrotic syndrome,^3–5 podocytes have been recognized as critical regulators of glomerular injury. Other podocyte slit diaphragm proteins such as podocin, synaptopodin, and CD2AP have generated further interest in the regulation of the kidney filtration barrier^6–8; however, little is still known about cell–matrix interactions in podocytes. Mice lacking the focal adhesion protein integrin-linked kinase (ILK), specifically in the podocytes, also develop proteinuria, resulting in renal failure and death.⁹ Moreover, mice lacking α3β1 integrin have demonstrated inability to form mature foot processes.¹⁰ These cell–matrix interactions, which seem important in podocyte development, may also play a critical role after podocyte injury, because the process of podocyte effacement requires cell process retraction and movement, processes that suggest focal adhesion disassembly.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase, in which integrin- or growth factor–induced autophosphorylation at tyrosine 397 results in activation of critical signaling pathways required for focal adhesion turnover.^11–16 It has been demonstrated that cell spreading and migration are significantly diminished in cells lacking FAK.¹⁷ This inhibition in motility has brought excitement in cancer therapeutics, resulting in the development and use of FAK inhibitors.^18–21 In a recent study, inhibition of urokinase plasminogen activator (uPAR), a glycosylphosphatidylinositol-anchored protein that is important for cell invasion and metastasis, has been demonstrated to reduce proteinuria and podocyte effacement significantly, suggesting that this dynamic podocyte cell movement may mimic the molecular signaling events observed in cancer cell invasion.²²In this study, we demonstrated that after podocyte injury in vivo and in vitro, FAK activation was significantly increased in wild-type (WT) mice, prompting us to address whether inhibition or loss of FAK activation would reduce podocyte cell motility by inhibiting focal adhesion turnover, thereby preventing proteinuria and effacement. Because complete FAK gene deletion results in lethality at embryonic day 8.5, a time point before glomerular development has been initiated, the ability to study this protein''s role in podocyte development as well as repair after injury has been limited.¹⁷ Hence, selective loss of FAK expression in the podocytes of the kidney was achieved using a Cre-loxP approach.^23,24 These mice were born without evidence of podocyte/glomerular developmental defects but were resistant to the foot process fusion and subsequent proteinuria that typically accompany LPS and rabbit anti-mouse GBM-induced podocyte damage. We postulate this inhibition of foot process effacement is due to diminished podocyte spreading and motility, supported by our in vitro data. In addition, pharmacologic treatment of WT mice using the FAK inhibitor TAE-226 significantly reduced proteinuria and podocyte effacement, raising the possibility for therapeutic use in glomerular diseases.     

Lung adenocarcinoma presented with reticular pattern in which both CA19-9 and carcinoembryonic antigen( CEA) were recognized as markers

A 79-year-old male whose chest X-ray revealed a localized reticular shadow in health check was once treated medically with a diagnosis of interstitial pneumonia. Regardless of the treatment, the shadow increased in its size. Positron emission tomography (PET)-computed tomography(CT) was suggestive of a primary lung cancer in clinical stage IIIA. CA19-9 and CEA were 3,568.5 U/ml and 178.2 ng/ml respectively, and a left lower lobectomy was performed. The postoperative course was uneventful. Both tumor markers declined shortly after the surgery. But they increased in 8 months after the surgery associated with tumor recurrence. In spite of chemotherapy, the patient was expired 15 months following the surgery. Immunohistochemical staining showed the tumor was a well differentiated adenocarcinoma with positive findings of both CEA and CA19-9.     

Right delayed traumatic diaphragmatic hernia; report of a case

An 80-year-old woman was admitted to our hospital with abnormal shadow on chest X-ray 8 years after a chest trauma during which multiple ribs on the right side were fractured causing hemothorax. A diagnosis of right delayed traumatic diaphragmatic hernia was based on the findings on plain X-ray and multislice computed tomography. We performed surgery via thoracic approach with thoracoscopic assist. The transverse colon, liver, and omentum were dislocated into the right thoracic cavity and hardly adhered to the lung. We successfully repaired the ruptured diaphragm. The postoperative course was uneventful and the patient was discharged on the 33rd postoperative day.     

Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes

Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1-associated PI 3-kinase.     

Disturbed XIAP and XAF1 Expression Balance Is an Independent Prognostic Factor in Gastric Adenocarcinomas

Background  Dysregulation of apoptosis is a key factor in carcinogenesis and tumor progression. X-linked inhibitor of apoptosis (XIAP) is the most potent member of the inhibitor of apoptosis protein (IAP) family, which directly inhibits apoptosis by binding to caspases. Antagonists of XIAP have recently been identified: second mitochondria-derived activator of caspase/direct IAP-binding protein with low PI (Smac/DIABLO) and XIAP-associated factor 1 (XAF1). However, little research has been conducted on the association between gastric cancer survival and the mechanism of apoptosis involving XIAP and its antagonists, Smac/DIABLO and XAF1. Methods  XIAP, Smac/DIABLO, and XAF1 expression was analyzed by immunohistochemistry (IHC) in 187 gastric adenocarcinomas. Correlations between XIAP, Smac/DIABLO or XAF1 expression and clinicopathological factors were analyzed. Disease-specific survival after surgery was examined. Results  Of 187 samples, XIAP was overexpressed in 140, Smac was overexpressed in 117, and XAF1 was overexpressed in 106. Individually, XIAP, Smac, and XAF1 were not significantly associated with disease-specific survival. However, patients showing high expression of XIAP and low expression of XAF1 had significantly poorer survival when compared with other groups (P = 0.024). Conclusion  The expression balance of XIAP and XAF1 is an independent prognostic factor in gastric adenocarcinoma.     

Functional characteristics of the pylorus in patients undergoing pylorus--preserving gastrectomy for early gastric cancer

BACKGROUND: This study investigates the functional characteristics of the pylorus in patients undergoing pylorus-preserving gastrectomy (PPG) for early gastric cancer. METHODS: In study 1, postprandial symptoms and gastric emptying were compared between 2 groups of 12 patients with early gastric cancer more than 1 year after either PPG (PPG group) or distal gastrectomy (DG) (DG group). Gastric emptying was evaluated with the dual isotope technique for liquids and solids separately. In study 2, pyloric motility was evaluated with a sleeve/sidehole manometric assembly in 7 patients undergoing PPG, which was compared with that in the preoperative patients. RESULTS: In study 1, the overall modified Visick score of postprandial symptoms and the Sigstad dumping score were significantly lower in the PPG group compared with the DG group (P <.05). Early accelerated gastric emptying was observed in both groups for liquids, but only in the DG group for solids. In study 2, isolated pyloric pressure waves induced by intraduodenal lipid infusion and phase III-like activity induced by intravenous erythromycin infusion were preserved after PPG. CONCLUSIONS: The quantitative analysis of postoperative symptoms revealed that PPG patients were associated with better clinical conditions than DG patients. The clinical benefits of PPG are considered to be based on the function of the preserved pylorus.     

Surgical procedure of thoracoscopic and video-assisted anatomical segmentectomy for small peripheral lung cancer

Recently, small peripheral lung cancers which is indicated limited resection are frequently found by HRCT or PET. The limited resection for lung cancer includes thoracic and video-assisted anatomical segmentectomy (VATS segmentectomy) and wedge resection of the lung parenchyma. In anatomical segmentectomy, intra-plumonary lymph nodes are dissected, on the other hand, those lymph nodes can not be dissected in wedge resection. Consequently, segmentectomy will be radical procedure for lung cancer compared with wedge resection. Thoracic surgeons are required to perform anatomical segmentectomy for small peripheral lung cancer. The anatomical segmentectomy is not familiar procedure for recent thoracic surgeons. Thoracic surgeons should be skilled in that procedures. This is a review of basic procedures of VATS segmentectomy for lung cancer for young thoracic surgeones.     

Surgical management of aggressive vertebral hemangiomas causing spinal cord compression: long-term clinical follow-up of five cases

Background  

Aggressive vertebral hemangiomas causing spinal compression are rare, and there is controversy with regard to treatment. The purpose of this study was to evaluate the clinical results of patients with aggressive vertebral hemangiomas at a mean follow-up of more than 10 years after total excision and discuss the treatment options for the tumors.