Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer

Annals of Surgical Oncology - Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer...     

Mixed endothelin receptor antagonist, SB209670, decreases portal pressure in biliary cirrhotic rats in vivo by reducing portal venous system resistance

BACKGROUND/AIMS: This study aimed to evaluate the hemodynamic effects of endothelin-1 or mixed endothelin receptor antagonist, SB209670 in cirrhotic rats, and to elucidate the role of endothelin in cirrhotic portal hypertension. METHODS: Secondary biliary cirrhosis was induced by bile duct ligation. Hemodynamics were studied using the radioactive microsphere technique. RESULTS: Plasma and hepatic endothelin levels in cirrhotic rats were significantly higher than those in normal rats (plasma, 9.0+/-1.3 vs. 2.6+/-0.5 pg/ml, p<0.001; liver, 74.8+/-13.3 vs. 12.6+/-2.5 pg/g wet tissue, p<0.001). Intraportal administration of endothelin-1 (3 nmol/kg) progressively raised portal pressure without an initial transient reduction, which was observed in systemic arterial pressure, in both cirrhotic and normal rats. SB209670 (5.4 micromol/kg) reduced portal pressure in cirrhotic rats (-19+/-5%, p<0.01) without modifying systemic arterial pressure and renal blood flow, but not in normal rats. This reduction was associated with reduced portal venous system resistance (vehicle, 2.5+/-0.2 vs. SB209670, 1.7+/-0.1 mmHg x min x 100 g bw/ml, p<0.01), but not with change in portal venous inflow and collateral blood flow. CONCLUSIONS: Mixed endothelin antagonist, SB209670, decreased portal pressure by reducing portal venous system resistance without modifying systemic arterial pressure and renal blood flow in cirrhotic rats. This result, together with the findings that plasma and hepatic endothelin levels were elevated in cirrhotic rats and that exogenous endothelin-1 increased portal pressure, provides further support for a role of endothelin in portal hypertension and suggests a potential use of mixed endothelin antagonist in the pharmacological treatment of portal hypertension.     

Pulmonary vein blood flow velocity waveform--with special reference to pulmonary "systolic runoff" in patients with atrial septal defect

In order to evaluate the magnitude of pulmonary "systolic runoff", we studied the pulmonary vein blood flow velocity waveform by positioning a catheter-tip velocity-pressure transducer into the extraparenchymal pulmonary vein just distal to the left atrium. We recorded blood flow velocity and pressure simultaneously, and subsequently identified the zero blood flow velocity with blood flow velocity level of the pulmonary artery in diastole. Patients with atrial septal defect were used as subjects because of the technical ease although the altered hemodynamics were present. Two kinds of flow velocity waveforms were consistently demonstrated. One was a waveform of two peaks with the first peak in late systole and the second peak in early diastole (n = 9). The other was a waveform of one peak with a summit near the end of systole (n = 5). On the assumption that the blood flow velocity waveform obtained with this method is roughly equivalent to the flow volume waveform, we initiated the second study. The area encompassed between the actual flow velocity waveform and the line of zero flow velocity was divided into two compartments, i.e., ventricular systole (S) and diastole (D). The ratios of the area in systole to the sum of the areas in systole and diastole, i.e., (S)/[S) + (D], which are analogous to the pulmonary "systolic runoff", were 0.45 +/- 0.07 (mean +/- SD, n = 13). This suggests that about 40% of the right ventricular stroke volume flows into the pulmonary veins, the left atrium and a portion of the right atrium through the atrial septal defect during ventricular systole.     

Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe

Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycin‐sensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin‐sensitive mutants using the genome‐deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.     

Cryptococcus gattii genotype VGIIa infection imported from Vancouver Island to Japan

A 71-year-old Japanese man with travel history to the Vancouver Island, Canada was diagnosed the pulmonary and central nervous system infections caused by Cryptococcus gattii genotype VGIIa. This is the first imported case of Cryptococcus gattii genotype VGIIa infection from endemic area of North America to Japan. He was recovery with no residual neurological dysfunction by early resection of brain mass and antifungal therapy. Early surgical resection of cerebellar cryptococcoma may shorten the length of induction therapy with antifungal drugs.     

Urinary prostaglandins and renal function in chronic liver diseases

Changes in urinary PGE2 and PGF2 alpha excretion in chronic liver diseases were observed in relation to renal hemodynamics and sodium balance. After equilibration on a 110-170-meq sodium diet, daily urine collections were analyzed for PGE2 and PGF2 alpha by a new extraction and radioimmunoassay method. PGE2 was significantly greater in cirrhotics than in healthy subjects and in chronic hepatitis. The value was greater in cirrhotics with ascites than in those without ascites (p less than 0.05). PGF2 alpha did not differ among the groups. In cirrhotics PGE2 was correlated negatively with creatinine clearance (Ccr)(r = -0.76, p less than 0.001). After administration of 200 mg indomethacin, a significant fall in Ccr was seen only in cirrhotics with ascites. The percentage fall in PGE2 after indomethacin correlated with that in Ccr (r = 0.89, p less than 0.05) and with that in urinary sodium excretion (r = 0.68, p less than 0.02). These results suggest that PGE2 is essential in the maintenance of renal function in liver cirrhosis with ascites.     

Renoprotective effect of the addition of losartan to ongoing treatment with an angiotensin converting enzyme inhibitor in type-2 diabetic patients with nephropathy.

Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects. To many patients who are nonresponsive to monotherapy with these agents, combination therapy appears to be a good treatment option. In the present study, we examined the effects of the addition of an ARB (losartan) followed by titration upon addition and at 3 and 6 months (n=14) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months (n=20) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure (BP) of 130/80 mmHg and to reduce urinary albumin to <30 mg/day. During the 12-month treatment, addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure (SBP) by 10% and 12%, diastolic blood pressure (DBP) by 7% and 4%, and urinary albumin excretion by 38% and 20% of the baseline value, respectively. However, the effects on both BP and urinary albumin were not significantly different between the two therapies. In conclusion, addition of losartan or an ACE-I to an ongoing treatment with an ACE-I, or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP, and provided renal protection in patients with type-2 diabetic nephropathy.     

Efficacy of domiciliary noninvasive positive pressure ventilation in chronic obstructive pulmonary disease patients]

OBJECTIVE: The aim of this study was to assess the clinical features and efficacy of domiciliary noninvasive positive pressure ventilation (NPPV) in patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We conducted a retrospective study of 16 patients with COPD who received NPPV between March 1996 and April 2005. The patient characteristics, clinical features, a change in arterial PaCO2 and prognoses were evaluated. RESULTS: The study population consisted of 15 males and 1 female, mean age 68.4 +/- 9.9 yrs. The mean values of pulmonary function tests were as follows; FEV1 = 0.73L, FEV1% = 29.8%, VC = 2.49L, %VC = 77.5%, RV/ TLC 55.4%, PaO2 59.8 Torr, PaCO2 71.4 Torr (on admission). Fourteen of 16 patients presented desaturation in the night and 6 patients had sleep apnea syndrome. Eight of the 16 patients received NPPV during acute exacerbation. NPPV yielded dramatic improvement in daytime hypercapnia and clinical symptoms. However, arterial PaCO2 gradually elevated during the long-term clinical course. The duration of treatment was from 2 months to 9 years, with a mean value of 2.3 years. The cause of death of 7 patients was respiratory failure in 5 cases and lung cancer in 2, respectively, and the mortality was significantly higher in patients who received NPPV during acute exacerbation than stable COPD patients receiving NPPV. CONCLUSIONS: Long-term improvement in daytime clinical symptoms and arterial blood gas tensions can be achieved by NPPV in patients with COPD.     

Diastolic compliance of the left atrium in man: A determinant of preload of the left ventricle

Summary During the ventricular slow-filling period, both the left atrium and left ventricle fill passively, and their respective internal pressures equalize, becoming evenly elevated. If the diastolic chamber compliance of the left atrium is smaller than that of the left ventricle, we expect the inflowing blood to be distributed more to the left ventricle than to the left atrium during this period. We examined the magnitude of the diastolic compliance of the left atrium and the left ventricle at the end of the slow-filling period.We studied 10 patients, mostly with a mild degree of coronary artery disease, in whom hemodynamic variables were almost within normal limits. To estimate the compliance of the left atrium, we recorded the left atrial pressure directly (by the Brockenbrough technique) and determined the left atrial volume by biplane cineatriography. We determined the diastolic compliance of the left atrium from the pressure-volume relations between the nadir of the x trough and the peak of the v wave by fitting them to an exponential equation, P=b · e^aV (P = pressure, V = volume, a, b = constants). The diastolic compliance of the left ventricle was determined from the pressure-volume relations during the ventricular slow-filling period.The compliances of the left atrium and the left ventricle at the pressure at the end of the ventricular slow-filling period were 1.60±0.41 (mean ± SD) ml · mmHg^–1 · m^–2 and 4.22±1.12, respectively. The ratio of compliance of the left ventricle to that of the left atrium was 2.60±0.71.Since the diastolic compliance of the left ventricle is 2–3 times larger than that of the left atrium, we suggest that during the slow-filling period, the interaction between the left atrial and left ventricular diastolic compliances provides preferential delivery of blood to the left ventricle and acts as a determinant of volume at the end of the slow-filling period of the left ventricle.