Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum (ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells (DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 microg of LLC-derived gp96 was administered together with 1 x 10(6) irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells (higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.     

Antipneumococcal Activity of BMS 284756 Compared to Those of Six Other Agents

Antipneumococcal activity of BMS 284756 was compared to those of six agents by MIC and time-kill methodologies. BMS 284756 had the lowest MICs compared to those of ciprofloxacin, levofloxacin, and moxifloxacin against quinolone-susceptible (< or =0.016 to 0.06 microg/ml) and quinolone-resistant (0.03 to 1 microg/ml) pneumococci. BMS 284756 was bactericidal against 11 of 12 strains at two times the MIC after 24 h.     

Novel contrast-injection protocol for high-resolution abdominal CT-angiography: vascular visualization improvement with vasodilator

Purpose

To evaluate the usefulness of a novel contrast-injection protocol for high-resolution abdominal computed tomography angiography (CTA) using nitroglycerin (NTG).

Methods

Abdominal CTA was performed in 80 patients using two 64-detector-row CT scanners. Forty patients were examined after administration of sublingual NTG (NTG group), while 40 were examined without NTG administration (non-NTG group). Arterial phase images were acquired with maximum intensity projection and volume rendering. Reduction rates: vessel cross-sectional areas ratio of 10 cm distal to origin at the superior mesenteric artery, contrast enhancements, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were assessed. Three reviewers evaluated degree of depiction of the peripancreatic vasculature using a four-point scale (1 = poor, 4 = excellent).

Results

Reduction rates were significantly lower in the NTG group (P < 0.001), while there were no significant differences in contrast enhancements, SNR, or CNR between groups. Visual evaluation results of the NTG group were significantly better than those of the non-NTG group (P < 0.01).

Conclusion

Abdominal CTA using NTG improved visualization of the abdominal peripheral vessels. This improved arterial view may be beneficial for preoperative evaluation of the arterial anatomy.

     

Balloon-occluded retrograde transvenous obliteration using a new microballoon for gastric varices

We here present a case involving a complicated type of gastric fundal varices treated by balloon-occluded retrograde transvenous obliteration. A newly developed 1.8-Fr tip coaxial microballoon catheter was successfully advanced into narrow and tortuous varices, and a sclerosant could be infused in a reasonable manner, avoiding reflux into collaterals. Divided injections of sclerosant were performed over two days, via a microballoon catheter that remained inserted overnight with balloon inflation, and the sclerosant could be infused sufficiently in the entirety of the varices. The varices were completely thrombosed and prominently reduced.     

Comparison of vascular responses after different types of second-generation drug-eluting stents implantation detected by optical coherence tomography

Few studies have directly compared vascular responses to second-generation drug-eluting stents (DESs). We performed optical coherence tomography examinations in 56 consecutive patients with implanted single stent [19 cobalt-chromium everolimus-eluting stents (CoCr-EES), 22 platinum-chromium EES (PtCr-EES), and 15 resolute zotarolimus-eluting stents (R-ZES)] for de novo lesions, and who did not have restenosis at their 9-month follow-up. Neointimal thickness (NIT), stent apposition, and neointimal coverage were assessed in every strut. A neointimal unevenness score [(NUS), maximum NIT/average NIT in the same cross-section] was determined for every 1-mm cross-section (CS). A total of 8350 struts and 1159 CSs were analyzed. The CoCr- and PtCr-EES had significantly fewer malapposed struts compared to the R-ZES (CoCr-EES: 0.19?% vs. PtCr-EES: 0.19?% vs. R-ZES: 0.61?%, p?=?0.007). Furthermore, the PtCr-EES had a lower frequency of uncovered struts compared to the others (CoCr-EES: 2.0?% vs. PtCr-EES: 1.4?% vs. R-ZES: 2.3?%, p?=?0.047). The NUS correlated with the frequency of uncovered struts (p?<?0.001, r?=?0.54). The EESs demonstrated more homogenous neointimal growth, as shown in the NUS, compared to the R-ZES [CoCr-EES: 1.66 (1.38–1.97) vs. PtCr-EES: 1.67 (1.41–2.00) vs. R-ZES: 1.94 (1.56–2.28), p?<?0.001]. Our results demonstrate that unevenness neointimal growth may relate with strut coverage after second-generation DES implantation. The PtCr-EES had a high frequency of strut coverage with a homogeneous neointima, suggesting fewer risks for stent thrombosis.     

Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension

Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2?±?9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p?=?0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039–1.713; p?=?0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p?=?0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub-groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients.     

Spontaneous hepatic copper accumulation in Long-Evans Cinnamon rats with hereditary hepatitis. A model of Wilson''s disease.

Long-Evans Cinnamon (LEC) rats, an inbred strain of a mutant rat isolated from Long-Evans rats, develop hereditary hepatitis. To elucidate the role of copper metabolism in the development of the hepatitis in LEC rats, we examined the copper concentration in the tissues and serum levels of copper and ceruloplasmin. Copper concentration in the liver of LEC rats was over 40 times that of normal Long-Evans Agouti (LEA) rats, while the serum ceruloplasmin and copper concentrations in LEC rats decreased significantly. The hepatocytes of LEC rats show steatosis in cytoplasm and pleomorphism of mitochondria, resembling the histologic features of the liver in Wilson's disease. These findings suggest that the hereditary hepatitis in LEC rats is closely associated with copper toxicity, and may be dealing with a rat form of Wilson's disease. Thus the LEC rats will provide a unique and useful animal model for clarifying the mechanism and for developing treatment strategies for Wilson's disease and other abnormal copper metabolism in humans.     

Possible Mechanism by Which the Carbapenem Antibiotic Panipenem Decreases the Concentration of Valproic Acid in Plasma in Rats

There is evidence indicating that the carbapenem antibiotic panipenem decreases plasma concentrations of valproic acid (VPA) in epileptic patients during VPA therapy. The mechanism for panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of panipenem on the pharmacokinetics of diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was administered intravenously under the steady-state plasma panipenem concentration of 4 μg/ml, which had been achieved by a constant infusion rate. Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However, panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma diclofenac concentration observed in the absence of panipenem was diminished in the presence of panipenem. These findings suggest that panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a panipenem-induced decrease in the numbers of enteric bacteria.     

Critically ill patients with COVID-19 in Tokyo,Japan: A single-center case series

IntroductionWe reported, in our previous study, a patient with coronavirus disease 2019 (COVID-19) who was successfully treated with extracorporeal membrane oxygenation. Data on clinical courses and outcomes of critically ill patients with COVID-19 in Japan are limited in the literature. This study aimed to describe the clinical courses and outcomes of critically ill patients with COVID-19 in Tokyo, Japan.MethodsThis is a single-center case series study. Patients with COVID-19 treated with mechanical ventilation (MV) were reviewed retrospectively. Data on baseline characteristics, in-hospital treatment, and outcomes were collected.ResultsBetween February 2, 2020, and June 30, 2020, 14 critically ill patients with COVID-19 were treated with MV. Most patients were male and had comorbidities, especially hypertension or diabetes; 35.7% were overweight and 21.4% were obese. The majority of the patients had dyspnea on admission. The median duration of MV was 10.5 days, and the 28-day mortality rate was 35.7%. In the four patients with COVID-19 who died, the cause of death was respiratory failure.ConclusionsAs in previous reports from other countries, the mortality rate of patients with COVID-19 requiring intensive care remains high in Tokyo. Further study on the appropriate timing of MV initiation and specific treatments for critically ill patients with COVID-19 is needed.     

Changes in plasma levels of cyclic nucleotides during low-density lipoprotein apheresis.

The negative charges of dextran sulfate (DS) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by the production of bradykinin. This study was undertaken to see whether cyclic nucleotide plasma levels are affected by DS LDL apheresis. Previously, we showed the rise in plasma levels of prostaglandins and nitric oxide derivatives accompanied by the rise in bradykinin levels. The physiologic effects of prostaglandins and nitric oxide become manifest through the intracellular signal of cyclic nucleotides. The plasma levels of the cyclic nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. The plasma levels of cAMP during LDL apheresis using heparin were 9.2 +/- 0.3 (mean +/- SE) 12.4 +/- 0.6, 12.0 +/- 0.5, and 12.1 +/- 0.3 pmol/ml, respectively, at the 0, 1,000, 2,000, and 3,000 ml stages. The rise in cAMP levels was suppressed during apheresis using NM. There were no significant increases in cGMP during apheresis with heparin or with NM. There were significant negative correlations between changes in cAMP and those in the blood pressure. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects via activation of the adenylate cyclase dependent pathway.