Background(−)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis.MethodsDifferent analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated.ResultsIn this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (−)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide.ConclusionsThe requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (−)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.Electronic supplementary materialThe online version of this article (doi:10.1186/s13221-015-0030-2) contains supplementary material, which is available to authorized users.
Background and study aims Although endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) is an established modality for pathological sampling of pancreatic and biliary lesions, limited data are available on the diagnostic value of EUS-FNA for evaluation of gallbladder mass lesions, a common cause of obstructive jaundice. We aimed to evaluate the usefulness of EUS-FNA for diagnosis of gallbladder mass lesions presenting with biliary obstruction. Patients and methods This study was a retrospective analysis of data from patients who had undergone EUS-FNA for gallbladder mass lesions. FNA was performed on either a gallbladder mass, metastatic node or liver lesions. Outcome measures were diagnostic yield of EUS FNA and adverse events. Results From April 2011 to August 2018, 101 patients with gallbladder mass lesions with biliary obstruction underwent EUS-FNA. The final diagnosis was malignancy in 98, benign disease in one, and two patients were lost to follow-up. EUS-FNA confirmed the diagnosis in 89 of 98 patients with malignancy (sensitivity 90.81 %); was false negative in nine of 98 cases with malignancy; and was truly negative in the solitary patient with benign disease (specificity 100 %). Positive predictive value, negative predictive value (NPV), and accuracy were 100 %, 10 %, and 90.90 %, respectively. Two patients had self-limiting pain. Conclusion EUS-FNA is a sensitive tool for evaluation of gallbladder mass lesions presenting with obstructive jaundice. However, because of low NPV, lesions in which FNA is negative should be further evaluated.
Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a novel minimally invasive procedure useful for the evaluation and diagnosis of mediastinal lymph nodes and the lung parenchymal lesions. A 75-year-old woman diagnosed as a case of infiltrating duct adenocarcinoma of left breast 15 years back for which she underwent a modified radical mastectomy followed by radiotherapy and chemotherapy. The patient presented to us with haemoptysis. During EBUS, the enlarged left hilar lymph node was seen to be eroding into the left pulmonary artery leading to a filling defect in the left pulmonary artery. This filling defect was first sampled by EBUS-guided TBNA followed by sampling of left hilar lymph node. The results of cytomorphology revealed malignancy which was compatible with a metastasis from a carcinoma breast. EBUS-TBNA is a novel, safe and minimally invasive procedure with a few complications.
Background:The differential diagnosis of tuberculosis (TB) and sarcoidosis on fine needle aspiration material is very challenging in tubercular endemic regions. We carried out a pilot study to explore cytomorphologic features of granulomas which could help in differentiation between sarcoidosis and TB. Final diagnoses in these patients were based on clinical, microbiologic and follow-up studies.Materials and Methods:Endobronchial ultrasound guided transbronchial needle aspiration smears of 49 consecutive patients with a final cytologic diagnosis of granulomatous lymphadenitis were reviewed. Based on cytologic features two cytologic categories were enunciated and the results were correlated with microbiologic studies and/follow-up of minimum of 6 months.Results:The cytologic categories did not correlate with the final clinical outcome of patients.Conclusions:Different patterns of granulomas observed in cytology smears do not help distinguish TB from sarcoidosis. The novel non-invasive techniques of mediastinal sampling though help in confirming granulomatous pathology, distinction between these entities and treatment decisions still depend upon correlating cytologic, microbiologic, clinical and radiological data in a large number of cases in tubercular endemic regions.
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