Solid pseudopapillary neoplasm of the pancreas with liver metastasis initially misinterpreted as benign haemorrhagic cyst.

Solid pseudopapillary neoplasm (SPN) of the pancreas is considered a low-malignant neoplasm with a good prognosis. However, 5% to 15% of patients with SPNs develop metastatic disease, most commonly in the liver. Metastatic hepatic malignancies that show pseudocystic features are rare. Here we describe the case of a middle-aged female with a cystic liver metastasis from SPN. To the best of our knowledge, SPN with a single cystic liver metastasis has not been described, although these tumours frequently undergo haemorrhagic-cystic degeneration. Thus, in these patients the marked cystic change could be misinterpreted as a benign lesion.

Splenic vein thrombosis and pancreatic fistula after minimally invasive distal pancreatectomy.

BACKGROUND: This study aimed to investigate the clinical relevance of splenic vein thrombosis (SVT) in the splenic vein remnant following minimally invasive distal pancreatosplenectomy (DPS). METHODS: Medical records of patients who underwent laparoscopic or robotic distal pancreatectomy (DP) with or without splenectomy between January 2006 and August 2012 were reviewed. Rates of SVT and clinically relevant postoperative pancreatic fistula (POPF) were compared in a group of patients undergoing DPS and a group having spleen-preserving DP. RESULTS: Seventy-nine patients had minimally invasive DP, of whom 38 (48 per cent) developed SVT in the splenic vein remnant. DPS was associated with POPF (P = 0.001) and SVT (P < 0.001). SVT length was closely related to the amount of peripancreatic fluid collection (P = 0.025) and POPF (P = 0.045). In a comparison of splenic vessel-sacrificing, spleen-preserving DP and DPS, postoperative platelet count was significantly higher in the DPS group (P < 0.001). In addition, grade of SVT (P = 0.092) and POPF (P = 0.065) tended to be associated with DPS, suggesting that SVT may be related to both splenectomy and POPF. CONCLUSION: Minimally invasive DPS is associated with SVT and POPF. Preservation of the spleen should be considered when treating patients with benign and borderline malignant tumours of the distal pancreas.

Synergistic effect of surface modification with poly(ethylene glycol) and immunosuppressants on repetitive pancreatic islet transplantation into antecedently sensitized rat.

BACKGROUND: Polymeric modification of islet surface is highly effective in preventing transplanted islets against host immune reactions. However, grafted islets are eventually rejected by the host immune reaction. Thus, repetitive islet transplantation is needed to treat type 1 diabetic patients experiencing graft rejection. We explored whether using poly(ethylene glycol) (PEG) as surface camouflage of islets (PEGylation) can be an affordable immunoprotective remedy for repeated islet transplantation. METHODS: The surface coverage of PEG was evaluated in vitro. The viability of PEGylated islets cocultured with sensitized or nonsensitized splenocytes was evaluated using lactate dehydrogenase assay. In addition, the effect of surface modification on immunoprotection for repetitively transplanted islets was evaluated in a sensitized rat model. RESULTS: Unmodified islets transplanted in combination with Cyclosporine (CsA) and anti-CD4 monoclonal antibody (OX-38) into the sensitized recipients did not maintain a normal level of blood glucose over 20 days. Interestingly, however, three of the five recipients became normoglycemic up to 30 days when PEGylated islets were transplanted in combination with CsA and OX-38. CONCLUSION: These results demonstrated that PEGylation alone was not an affordable immunoprotective method, but the combination of CsA and OX-38 along with PEGylation showed a highly improved a synergic effects on the inhibition of sensitized host immune reactions.

Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells.

The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.

Prions, prion diseases and decontamination.

Prions are extremely resistant to disinfection and sterilization methods used so far. The pathogenic prion protein core (called prion) consists of 142 amino-acids, is resistant to proteolytic enzymes, has a mass of 15 pikograms and is filtrable. Fixed by desiccation or chemicals may retain infectivity for years. It survives dry heat at 200 degrees C for 1-2 hours. Prions are fixed to stainless steel within minutes and remain infectious for long periods. Their pathogenetic properties depend on tertiary spatial structure (conformation) which is specific and transmissible in experiment. The prion decontamination appears by far the most important area of the prion science because very little, or nothing, has been done in the majority of world hospitals to prevent iatrogenic transmission. The number of potentially infectious patients is not known. Therefore, patients undergoing neurosurgery, laryngeal or ophthalmic operations, orthodental treatments and even anaesthetic or endoscopic applications should be classified into risk groups, even if clinically priondisease inapparent. The use (or misuse) of disposable instruments is certainly not the final answer for all cases and classic decontamination procedures, if possible because of the character of medical devices, appear still of greatest importance. We consider the high pathogen safety (HPS) autoclave from FEDEGARI as the best actual equipment for the effective decontamination of prions in the hospital practice. The investment costs are moderate and the handling is simple but must be careful. It appears practicable even in small specialized units.

A new C-methylated flavonoid glycoside from Pinus densiflora.

A new C-methyl flavonol glycoside, 5,7,8,4'-tetrahydroxy-3-methoxy-6-methylflavone 8-O-beta-D-glucopyranoside (1), has been isolated from the needles of Pinus densiflora, together with kaempferol 3-O-beta-(6"-acetyl)-galactopyranoside.

Doppler flow velocity waveforms of human fetal ductus arteriosus and branch pulmonary artery.

Doppler waveforms of the human fetal ductus arteriosus and the branch pulmonary artery are distinct in their shape and might reflect fetal cardiovascular hemodynamics and vessel wall characteristics. The waveform of ductus arteriosus had two peaks, a higher one in systole and a lower one in diastole. Both peaks had slow acceleration and deceleration and looked like two narrow base isosceles triangles. This unique waveform might be due to vessel wall characteristics and an instantaneous pressure gradient between the main pulmonary artery and descending aorta. The waveform of the branch pulmonary artery showed very steep acceleration with the onset of ejection followed by steep decline, then low velocity flow during diastole. The characteristic shape of the branch pulmonary artery might be related to high vascular resistance, decreased capacitance and the earlier reflection wave of pulmonary vessels.

Anomalous subaortic position of the brachiocephalic vein (innominate vein): an echocardiographic study.

In 24 (0.98%) of 2457 patients with congenital heart disease the brachiocephalic vein was in an anomalous position below the aortic arch. This is a much higher proportion of such cases than reported so far. This high frequency may arise from differences in the study population and the method of diagnosis. This venous anomaly was more common in patients with tetralogy of Fallot or ventricular septal defect with pulmonary atresia. Patients with the venous anomaly were more likely to have a right aortic arch. The anomalous course of the brachiocephalic vein from the neck to the junction of the superior vena cava was shown by cross sectional echocardiography. In doubtful cases, Doppler study usually clarified the anatomical arrangement.

New fluoroketones as human renin inhibitors.

Renin inhibition has been evaluated for a new class of fluorinated ketones, true analogues of peptides that have been retroinverted at the C-terminal position. The readily formed hydrate of the ketone is proposed to mimic the tetrahedral intermediate that occurs during the enzyme-catalyzed hydrolysis of amide linkage. From this series of compounds it appears that the number of reverted amide bonds is crucial in terms of activity. Furthermore, a shortening of the C-terminal part of our peptide analogues and the replacement of the leucine residue in P1 by a cyclohexylalanine leads to the tripeptide analogue 12 a potent renin inhibitor (IC50 = 3.5 x 10(-9) M).

Synthesis and biological properties of alpha-mono- and alpha-difluoromethyl derivatives of tryptophan and 5-hydroxytryptophan.

The syntheses of alpha-mono- and alpha-difluoromethyl derivatives of tryptophan and 5-hydroxytryptophan are described. In an attempt to selectively regulate serotonin synthesis, alpha-(mono- and difluoromethyl)tryptophan were tested in vivo as precursors (or prodrugs) of their 5-hydroxy analogues. Although alpha-(mono- and difluoromethyl)-5-hydroxytryptophans are potent irreversible inhibitors of aromatic amino acid decarboxylase (equipotent to alpha-difluoromethyl-Dopa), only alpha-(monofluoromethyl)tryptophan affects the level of serotonin in vivo (small decrease), alpha-(difluoromethyl)tryptophan being a very poor substrate of the activating (or helper) enzyme, tryptophan hydroxylase.

Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors.

The syntheses of four derivatives of gamma-vinyl-GABA, in which vinylic hydrogen atoms were replaced by fluorine, are described. With use of 5-ethenyl-2-pyrrolidinone as starting material, the E and Z isomers of 4-amino-6-fluoro-5-hexenoic acid were prepared. The 6,6-difluoro and 5,6,6-trifluoro analogues could be synthesized from 4-oxobutanoic acid tert-butyl ester and (2,2-difluoroethenyl)- and (trifluoroethenyl)lithium correspondingly. The compounds were tested as inhibitors of GABA-T, and their in vitro and in vivo biochemistry is reported. The most active derivative was (Z)-4-amino-6-fluoro-5-hexenoic acid; the structure-activity relationship in the series is discussed.

Irreversible inhibition of GABA-T by halogenated analogues of beta-alanine.

beta-Difluoromethyl-beta-alanine (3-amino-4,4-difluorobutanoic acid) is a potent in vitro and in vivo inhibitor of GABA-T. The rate of inhibition of GABA-T is concentration- and time-dependent. The inactivation is active-site directed. No reactive species escapes from the active site before reacting with the enzyme. The inhibition is irreversible and stereospecific. The use of beta-2H-beta-difluoromethyl-beta-alanine results in a marked primary isotope effect in vitro and in vivo. The use of differently substituted dihalogeno derivatives of beta-alanine suggests that the rate of inhibition is dependent on the nature and position of the leaving group. The mechanism of inhibition is discussed on the basis of spectral changes.

Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.

6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labelled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the two kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (Ki 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 microM-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. We suggest therefore that 6-fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated.

Stereochemistry of the inactivation of 4-aminobutyrate: 2-oxoglutarate aminotransferase and L-glutamate 1-carboxylase by 4-aminohex-5-ynoic acid enantiomers.

Incubation of rat brain or bacterial 4-aminobutyrate aminotransferase (EC 2.6.1.19) with both (S)-(+)- and (R)-(-)-enantiomers of 4- aminohex -5- ynoic acid results in a time-dependent irreversible loss of enzymatic activity. Rat brain glutamate decarboxylase (EC 4.1.1.15) is inactivated by the (S)-(+)-enantiomer while the bacterial glutamate decarboxylase is inactivated by the (R)-(-)-enantiomer. In addition, we demonstrate that (R)-(-)-4- aminohex -5- ynoic acid is a selective and effective inhibitor of rat brain 4-aminobutyrate aminotransferase in vivo.