Regulation of mTOR by phosphatidic acid.

mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1 in response to nutrients and growth factors. We review structural findings and propose a model for PA activation of mTORC1. PA binds to a highly conserved sequence in the α4 helix of the FK506 binding protein 12 (FKBP12)/rapamycin-binding (FRB) domain of mTOR. It is proposed that PA binding to two adjacent positively charged amino acids breaks and shortens the C-terminal region of helix α4. This has profound consequences for both substrate binding and the catalytic activity of mTORC1.

Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.

Molecular and clinical profiles of syndecan-1 in solid and hematological cancer for prognosis and precision medicine.

Syndecan-1 (SDC1, CD138) is a key cell surface adhesion molecule essential for maintaining cell morphology and interaction with the surrounding microenvironment. Deregulation of SDC1 contributes to cancer progression by promoting cell proliferation, metastasis, invasion and angiogenesis, and is associated with relapse through chemoresistance. SDC1 expression level is also associated with responses to chemotherapy and with prognosis in multiple solid and hematological cancers, including multiple myeloma and Hodgkin lymphoma. At the tissue level, the expression levels of SDC1 and the released extracellular domain of SDC1 correlate with tumor malignancy, phenotype, and metastatic potential for both solid and hematological tumors in a tissue-specific manner. The SDC1 expression profile varies among cancer types, but the differential expression signatures between normal and cancer cells in epithelial and stromal compartments are directly associated with aggressiveness of tumors and patient's clinical outcome and survival. Therefore, relevant biomarkers of SDC signaling may be useful for selecting patients that would most likely respond to a particular therapy at the time of diagnosis or perhaps for predicting relapse. In addition, the reciprocal expression signature of SDC between tumor epithelial and stromal compartments may have synergistic value for patient selection and the prediction of clinical outcome.

Is clipping superior to cauterization in the treatment of palmar hyperhidrosis?

BACKGROUND: Endoscopic thoracic sympathectomy has been accepted as the most effective treatment for palmar hyperhidrosis (PH). However, there is a debate regarding the surgical techniques in terms of effectiveness, recurrence, and reversibility. In this study, sympathetic chain disruptions were compared in terms of whether the clipping or ablation technique had an effect on the long-term outcomes of patients who underwent thoracic sympathectomy for primary PH. PATIENTS AND METHODS: All patients who underwent video-thoracoscopic sympathectomy for PH between May 2008 and October 2011 were included. Single-port bilateral sympathectomy was performed depending on the sweat distribution. As a standard approach, rib-based terminology was used to describe the blockade level of the sympathetic ganglia, and single-level R3 sympathectomy (between R3 and R4) was performed in all patients. The type of sympathectomy was changed. Monopolar electrocautery was first performed and 5-mm clips were then used for nerve disruption. Both techniques were evaluated and compared in terms of effectiveness, reversibility, and recurrence. RESULTS: Cauterization of the sympathetic chain was applied in 28 (47%) (Group A) patients and clipping in 32 (53%) patients (Group B). CH was the most common adverse effect and was observed in 43 (71.6%) patients (Group A, 71.4%; Group B, 71.8%; p = 0.8). The success rate was 93% for Group A and 100% for Group B (p = 0.15). The satisfaction rate for Group A was 83% and for Group B was 86% (p = 0.77). In Group A two patients (7%), and in Group B three patients (9%) requested reversibility because of severe compensatory hyperhidrosis. Overly dry hands were the other most common side effect and were identified in 12 (25%) patients. Recurrences were observed in 11 patients in Group A and 4 patients in Group B (19 vs. 6%; p = 0.01). The mean follow-up time was 33 ± 10.5 months (range, 13-53 months). CONCLUSION: Both clipping and cauterization are highly effective for the treatment of PH. The methods are comparable in terms of effectiveness and side effects despite the fact that the recurrence rate was higher in the cauterization group. Potential reversibility of compensatory sweating was not observed in our series. Identification of ideal candidates for surgery and education of patients about the permanent side effects of sympathectomy might make these techniques more convenient.

Textiloma mimicking superior sulcus tumor: positron emission tomography/computed tomography findings of a pseudotumor.

We present an interesting case report of a 52-year-old man with a superior sulcus tumor. To evaluate the suspicious left lung tumor, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used. Increased FDG level was indicative of a malignant tumor. Left thoracotomy revealed a textiloma retained during cardiac surgery.

A thoracic surgeon's perspective on the elastofibroma dorsi: A benign tumor of the deep infrascapular region.

BACKGROUND: An elastofibroma is a benign, soft-tissue tumor and is important in the differential diagnosis of thoracic wall masses. Here, patients with elastofibromas who underwent thoracic surgery were retrospectively reviewed to elucidate elastofibroma formation and to facilitate the differential diagnosis. METHODS: This is a retrospective and descriptive study of a series of 30 patients with elastofibroma dorsi. The data was obtained by review of the hospital records. RESULTS: There were 27 female and three male patients (mean age, 55.13 ± 8.7 years) with a total of 42 elastofibroma dorsi tumors (12 bilateral cases, 18 unilateral cases) diagnosed between January 2004 and October 2011. Twenty patients (67%) underwent surgery as a result of subscapular swelling and pain. In 10 (33%) asymptomatic patients, elastofibromas were found incidentally during a thoracotomy. Imaging methods in symptomatic patients included computerized tomography (15 cases), magnetic resonance (three), and ultrasonography (two). For five patients, fluorodeoxyglucose uptake values were available and revealed mild metabolic activity in the elastofibromas. Elastofibromas were significantly larger in symptomatic patients (8.15 ± 1.9 vs. 6.2 ± 2.3; P= 0.02). Exposure to long-term repetitive micro-trauma was a precipitating factor in 23 (77%) patients. Seroma formation, the most common surgical complication, was observed in 40% of patients. CONCLUSION: The differential diagnosis of elastofibroma dorsi is straightforward, and preoperative histology is unnecessary when the clinical, radiological, and metabolic characteristics are known. Repetitive micro-trauma may predispose to hyperproliferation of fibroelastic tissue, and genetics may also play a role. Surgical treatment can be reserved for cases with severe symptoms.

Combined effects of tauroursodeoxycholic Acid and glutamine on bacterial translocation in obstructive jaundiced rats:.

BACKGROUND: Bacterial Translocation is believed to be an important factor on mortality and morbidity in Obstructive Jaundiced. AIMS: We investigated the probable or estimated positive effects of tauroursodeoxycholic acid, which has antibacterial and regulatory effects on intestinal flora, together with glutamine on BT in an experimental obstructive jaundiced rat model. STUDY DESIGN: Animal experimentation. METHODS: Forty adult, male, Sprague Dawley rats were used in this study. Animals were randomised and divided into five groups of eight each: sham (Sh); control (common bile duct ligation, CBDL); and supplementation groups administered tauroursodeoxycholic acid (CBDL+T), glutamine (CBDL+G), or tauroursodeoxycholic acid plus glutamine (CBDL+TG). Blood and liver, spleen, MLN, and ileal samples were taken via laparotomy under sterile conditions for investigation of bacterial translocation and intestinal mucosal integrity and hepatic function tests on the tenth postoperative day. RESULTS: There were statistically significant differences in BT rates in all samples except the spleen of the CBDL+TG group compared with the CBDL group (p=0.041, p=0.026, and p=0.041, respectively). CONCLUSION: It is essential to protect hepatic functions besides maintaining intestinal mucosal integrity in the active struggle against BT occurring in obstructive jaundice. The positive effect on intestinal mucosal integrity can be increased if glutamine is used with tauroursodeoxycholic acid, which also has hepatoprotective and immunomodulatory features.

When is transthoracic approach indicated in retrosternal goiters?

PURPOSE: It is critical to differentiate among pathologies of substernal thyroid gland diseases because surgical approaches (i.e., median sternotomy or thoracotomy) might also include a cervical incision. The aim of this study was to analyze the features of patients with goiter who underwent a thyroidectomy via a cervical incision and a median sternotomy or thoracotomy. METHODS: We reviewed 9 cases of thyroid disease in patients undergoing thoracic incisions with or without a cervical incision for varying indications between March 2003 and Jun 2009 were reviewed. Thyroidal masses were removed via a median sternotomy in six patients and thoracotomy in three patients. Split median sternotomy combining thoracotomy was performed in 1 patient. Cervical incision was added in all patients. RESULTS: Pathologic examination revealed multinodular goiter in 5 patients, thyroid carcinoma in 3, and reidel thyroiditis in 1. All patients were extubated in the early postoperative period. There was no postoperative mortality or morbidity. The mean hospital stay was 8.6 days (range, 4-11 days), and mean follow-up was 24.3 months (range, 4-39 months). CONCLUSIONS: We recommend the use of transthoracic approaches, such as median sternotomy and thoracotomy for retrosternal goiter for surgical exposure, because they provide a wide exposure and facilitate removal of the mass. By using median sternotomy and thoracotomy, we can avoid catastrophic results, such as hemorrhage, as well as completely remove malignancies.

The management of gastric perforation in a girl with Rett syndrome: report of a case.

INTRODUCTION: Rett syndrome is a neurologically disorder that affects approximately one in 10,000 females. CASE REPORT: A 21-year-old girl with Rett syndrome was hospitalized for abdominal distention and pain. Physical examination revealed abdominal tenderness. Radiology investigation revealed bilateral free air in subdiaphragmatic area. Gastric perforation observed at laparotomy. Primary suturing and omentoplasty were performed. In the follow-up, the symptoms of intestinal obstruction occurred. Conservative treatment failed and second intervention was performed. At laparotomy severe gastric and intestinal dilatation and bowel adhesions were detected. Adhesiolysis, tube gastrostomy, and feeding jejunostomy performed. DISCUSSION: Rett syndrome and associated gastric complications are uncommon. These pathologic disorders may cause gastric, intestinal necrosis, intestinal obstructions. Because of the late occurring of physical findings and insidious presentation of the gastrointestinal perforations in Rett syndrome, physicians should keep in mind this rare entity to reduce morbidity and mortality.

Necessity of lung resection in neglected cases of pulmonary hydatidosis.

In pulmonary hydatid disease, lung resection is not a desirable treatment. Two young boys, aged 9 and 15, presented at our institution, the 9-year-old with a destroyed lung as the result of a delayed diagnosis of a giant cyst; the second with a massive hemoptysis as the result of preoperative albendazole use. Both children underwent a lobectomy for the treatment of pulmonary hydatidosis. Delayed diagnosis and use of albendazole, respectively, were considered the causes necessitating lung resection in these cases of giant and complicated pulmonary hydatid disease.

Management of descending mediastinal infections with an unusual cause: a report of 3 cases.

Mediastinal infections are a life-threatening and distinctly rare event, especially when they are caused by a dental abscess or by a foreign body that has not perforated the esophagus. We evaluated how best to treat descending mediastinal infections occurring from an unusual cause. We report 3 female patients with mediastinal infections: two aged 45 and 80 years, each with a dental abscess, and one 62 with a foreign-body injury of the retropharyngeal wall. A retropharyngeal abscess and descending necrotizing mediastinitis developed in two of these patients. The mediastinal abscess was detected by computed tomographic scanning. All patients were successfully treated by drainage of their abscesses via cervicotomy or thoracotomy. A mediastinal abscess can be a serious complication. Mediastinitis is associated with a high mortality rate if the diagnosis is not quickly established and adequate therapy is not provided. In this report, we discuss the management and possible pathophysiological mechanisms of descending mediastinal infections that have an unusual cause. Clinicians should be aware of the possibility of descending mediastinal infections in patients with a retropharyngeal abscess or a dental abscess associated with persistent signs, such as fever. Imaging modalities must be used as soon as possible to enable early diagnosis. Aggressive treatment includes surgical drainage, and medical management in an intensive care unit may prevent a catastrophic outcome.

The amount of comorbidities as a single parameter has no effect in predicting the outcome in appendicitis patients older than 60 years.

BACKGROUND: Retrospective analysis of acute appendicitis patients older than 60 and statistical evaluation of the association between the accompanying illnesses, severity of peritonitis, morbidity, and mortality rates. INTRODUCTION: Although acute appendicitis is not frequent among aged populations, accompanying comorbidities of the geriatric patients are always fear factors before an emergency abdominal surgery even for acute appendicitis. METHODS: The data of the 27 patients older than 60 years who underwent appendectomy were retrospectively analyzed. The patients were grouped according to the total number of their comorbidities, Mannheim peritonitis index scores, and the period between the onset of abdominal pain and the admission to the hospital. RESULTS: The mean age of the patients was 73 years. The morbidity and mortality rates were statistically significantly higher in perforated cases. The comparison of patients with or=2 comorbidities did not show any statistical difference in morbidity and mortality. The sensitivity, specificity, positive predictive value, and negative predictive values for mortality in geriatric acute appendicitis patients with Mannheim peritonitis index scores greater than 26 were found to be 75%, 86%, 50%, and 95%, respectively. DISCUSSION: Retrospective evaluation of geriatric patients with acute appendicitis, according to the total number of their comorbidities, surprisingly revealed no statistical difference between groups. We thought that a high Mannheim peritonitis index score is a more reliable criteria than the total number of comorbidities in predicting the prognosis of patients with acute appendicitis in the geriatric population.

Effects of intraperitoneal melatonin on caustic sclerosing cholangitis due to scolicidal solution in a rat model.

BACKGROUND: Hydatid disease is a worldwide health problem. Treatment is surgical or percutaneous, using scolicidal agents. Caustic sclerosing cholangitis might develop after the contact of scolicidal agents with the biliary ducts. Melatonin, an antioxidant, anti-inflammatory, and anticarcinogenic agent, might be used in the treatment of caustic sclerosing cholangitis due to its possible preventive effects on fibrosis and cell damage. OBJECTIVE: The aim of the study was to investigate the effects of melatonin on an experimentally developed caustic sclerosing cholangitis with scolicidal solution (formalin) in a rat model. METHODS: Forty female Sprague-Dawley rats aged 11 to 13 weeks and weighing 250 ± 30 g were randomly assigned to 1 of 4 groups of 10: formalin 5% at 0.5 mL/d + melatonin placebo; formalin placebo + intraperitoneal melatonin 10 mg/kg/d; formalin 5% at 0.5 mL/d + melatonin 10 mg/kg/d; and formalin placebo and melatonin placebo (control). Hepatobiliary function was assessed using dynamic scintigraphy with technetium-99m-mebrofenin on study day 60. The histology of the liver and biliary duct specimens was examined on study day 60. In each group, histopathologic alterations were scored as absent, slight, mild, or severe. RESULTS: Mean severity scores for parenchymal necrosis in the liver (P < 0.01), portal fibrosis (P < 0.01), biliary duct proliferation (P < 0.001), cholangitis/ pericholangitis (P < 0.01), hyperemia in the biliary ducts (P < 0.01), and fibrosis (P < 0.01) were significantly lower in rats treated with formalin + melatonin compared with those treated with formalin alone. No significant differences were observed between the 3 treatment groups with respect to t½, a parameter used to assess the secretion function of the hepatocytes. However, the t½ was significantly longer in the treatment groups compared with controls (P < 0.001). CONCLUSION: In this experimental study in a rat model of caustic sclerosing cholangitis, the histopathologic and scintigraphic findings suggested that melatonin is effective in attenuating the damage caused by scolicidal agents on the liver and biliary ducts.

The effects of melatonin on postoperative intraabdominal adhesion formation.

PURPOSE: Postoperative intraabdominal adhesion formation is a major clinical problem. No previous study was found, reporting the relationship between adhesion formation and melatonin administration, but melatonin, a strong antioxidant, is recognized to have certain effects on the progression of adhesion formation mechanism. It was therefore decided to investigate the effects of melatonin on postoperative adhesion formation. MATERIALS AND METHODS: A total number of 24 Sprague-Dawley rats were utilized. Three groups, described as: Group A, sham laparatomy (n=8), Group B, rats that underwent only ischemia-reperfusion (n=8) and Group C, rats that underwent ischemia- reperfusion and were given 10 mg/kg melatonin solution i.v. (n=8). For Groups B and C, the ileocolic vessels were clamped. Blood glutathione peroxidase levels of all study groups were assessed, then microscopic and macroscopic adhesion scores were evaluated. RESULTS: Glutathione peroxidase levels of the melatonin-treated group were significantly higher and fibroblast proliferation and macroscopic adhesion scores were significantly lower, than in the melatonin-free group. CONCLUSION: The results of this study supported the hypothesis, that melatonin administration may prevent intraabdominal adhesions resulting from surgery.

Low-molecular-weight heparin for treatment of submassive pulmonary embolism after pneumonectomy.

Pulmonary embolism (PE) after lung resection has a high mortality rate, and it is one of the most severe complications after lung resection. Early diagnosis and treatment are essential. We present a case of severe PE after left pneumonectomy for lung cancer. Computed tomography angiography was useful for confirming the diagnosis of PE. Low-molecular-weight heparin (LMWH) was used to treat the embolism, and the patient was discharged on the seventh day. LMWH is an effective and safe agent for the treatment of PE after pneumonectomy and may reduce the need for surgery. It may be used as an initial procedure. Secondary severe complications, including hemorrhage and subsequent empyema, may be avoided with the use of LMWH.

Management of complicated hydatid cyst of the thorax.

BACKGROUND: Complicated hydatid cyst of the thorax is important to the clinical approaches and treatment methods in hydatid disease. The aim of this study was to evaluate the problems of complicated pulmonary hydatid cyst, including choice of surgical methods, diagnostic clues and to discuss the inherent risks of medical therapy and the delay of surgical treatment in pulmonary hydatid disease. METHODS: Between 2002 and 2006, 40 operations were carried out in 37 patients whose diagnoses were complicated hydatid cyst. The surgical approach was a posterolateral thoracotomy in all patients; a phrenotomy in two patients and a thoracoabdominal approach in one patient and two-stage bilateral thoracotomy in four patients. The preferred surgical treatment procedure was cystotomy and modified capitonnage, which was carried out in 26 patients (70%). Other procedures included a cystotomy in five (14%) and decortication in six (16%) patients. Segmentectomy was carried out in 1 (3%), and wedge resection in four patients (11%). RESULTS: In 25 patients (67.5%), there were single hydatid cysts; whereas 12 patients (32.5%) had multiple cysts. Eleven patients had preoperative hydatid cyst history. Iatrogenic rupture of an intact hydatid cyst occurred in three patients. Extrathoracic involvement was apparent in 10 patients (27%). Intrathoracic but extrapulmonary involvement was apparent in six patients (16%). The morbidity ratio was 5%; there was prolonged air leak and atelectasis in one patient each. The mortality ratio was 3% (one patient). The average hospitalization duration for all patients was 5.7 days (range, 3-17 days). The mean follow up was 18.4 months with no recurrence. CONCLUSION: Complicated hydatid cyst may have different clinical manifestations and may present radiologically as a primary lung tumour. In patients with suspicious lung masses owing to endemic area, history of a hydatid cyst or contralateral or extrathoracic hydatid cyst involvement at the same time should indicate a complicated pulmonary hydatid cyst. Preoperative anthelmintic therapy must be avoided owing to the risk of perforation. Treatment of a complicated hydatid cyst differs from that of an intact hydatid cyst. Anatomic resection may be necessary owing to destroyed lung tissue secondary to suppuration from a hydatid cyst; however, parenchymal preserving surgery is preferable in an uncomplicated hydatid cyst. A modified capitonnage method is recommended for complicated hydatid cyst treatment as it has a low morbidity rate.

Primary hydatid disease of the chest wall.

The chest wall is an unusual location for primary echinococcus disease. We report on case of a primary chest wall hydatid cysts, resembling a mass lesion, in a 50-year-old woman who had no prior surgery for hydatid disease before. Chest wall hydatid disease should be considered in the atypical location and differential diagnosis of chest wall masses.

Hepatic hydatid disease in children and adults living in different areas in Turkey.

OBJECTIVE: To compare the clinical features of the hepatic hydatid disease in the operated children and adults living in the east and west part of Turkey. METHODS: Between January 2001 and May 2005, 105 patients were operated with the diagnosis of hepatic hydatid cyst in Trakya and Yuzuncu Yil University Hospitals, Turkey. The patients (n=105) were retrospectively evaluated in 4 groups; Edirne Ch: (18 children under 18 year-old) and Edirne Ad: (20 adults) were from Edirne, Van Ch: (22 children under 18 year-old) and Van Ad: (44 adults) from Van. The patients in each group were analyzed according to their clinical and radiological findings. RESULTS: The frequency of hepatic hydatid cysts in children was significantly higher in boys in Edirne Ch group and in girls in Van Ch group (p<0.05). In adults, the disease was also seen significantly higher in males in Edirne Ad group and females in Van Ad group (p<0.05). There were no difference symptoms of the disease, concomitant extra hepatic cysts and total cyst number in children and adults in the same region (p>0.05). The number of huge hepatic cysts and history of contact with animal were more common in children and adults living in Van. CONCLUSION: While the course of hepatic hydatid disease has the similar clinical features among the children and adults in the same region, remarkable regional differences have been found on it.