Overexpression of Multidrug Resistance Protein Gene in Human Cancer Cell Lines Selected for Drug Resistance to Epipodophyllotoxins

Overexpression of either the multidrug resistance 1 (MDR1) gene or multidrug resistance protein (MRP) gene is involved in acquisition of multidrug-resistant phenotypes in human cancer cells. In this study we examined whether selection for resistance to the epipodophyllotoxins, etoposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26-resistant KB cell lines. Two VP16/VM26-resistant KB cell lines, KB/VM-1 and KB/VM-4, which were selected by stepwise exposure to VM26 had decreased accumulation of [³H]VP16 and increased levels of MRP, but no apparent expression of MDR1 gene was observed. Another VP16/VM26-resistant KB cell line, KB/VP-4, which was further isolated from a VP16-resistant KB cell line, KB/VP-2, had decreased accumulation of [³H]VP16 and showed overexpression of MRP gene, but not that of MDR1 gene. We also isolated a VP16-resistant cell line, IN157/VP-1, from a human glioma cell line IN157. IN157/VP-1 cells showed decreased accumulation of [³H]VP16 and overexpression of MRP gene, but not of MDR1. These findings suggest that selection for resistance to VP16/VM26, preferentially induces overexpression of MRP gene.     

Intramuscular [18F]F-FDG Administration for Successful PET Imaging of Golden Hamsters in a Maximum Containment Laboratory Setting

Positron emission tomography (PET) is becoming an important tool for the investigation of emerging infectious diseases in animal models. Usually, PET imaging is performed after intravenous (IV) radiotracer administration. However, IV injections are difficult to perform in some small animals, such as golden hamsters. This challenge is particularly evident in longitudinal imaging studies, and even more so in maximum containment settings used to study high-consequence pathogens. We propose the use of intramuscular (IM) administration of 2-deoxy-2[¹⁸F]fluoro-D-glucose ([¹⁸F]F-FDG) for PET imaging of hamsters in a biosafety level 4 (BSL-4) laboratory setting. After [¹⁸F]F-FDG administration via IM or IV (through surgically implanted vascular access ports), eight hamsters underwent static or dynamic PET scans. Time–activity curves (TACs) and standardized uptake values (SUVs) in major regions of interest (ROIs) were used to compare the two injection routes. Immediately after injection, TACs differed between the two routes. At 60 min post-injection, [¹⁸F]F-FDG activity for both routes reached a plateau in most ROIs except the brain, with higher accumulation in the liver, lungs, brain, and nasal cavities observed in the IM group. IM delivery of [¹⁸F]F-FDG is an easy, safe, and reliable alternative for longitudinal PET imaging of hamsters in a BSL-4 laboratory setting.     

Effect of canagliflozin on the decline of estimated glomerular filtration rate in chronic kidney disease patients with type 2 diabetes mellitus: A multicenter,randomized, double‐blind,placebo‐controlled,parallel‐group,phase III study in Japan

Aims/IntroductionThe Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial has shown the effects of canagliflozin on preventing clinically important kidney outcomes in patients with type 2 diabetes mellitus and chronic kidney disease; however, not many Japanese patients were included in the trial. The present study evaluated the efficacy and safety of canagliflozin in Japanese chronic kidney disease patients with type 2 diabetes mellitus.Materials and MethodsIn this multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study, chronic kidney disease patients with type 2 diabetes mellitus were randomly assigned to receive either 100 mg canagliflozin or a matching placebo once daily for 104 weeks. The primary efficacy end‐point was the incidence of a 30% decline in estimated glomerular filtration rate.ResultsOverall, 308 patients were randomized to the canagliflozin (n = 154) and placebo (n = 154) groups. The incidence of a 30% decline in estimated glomerular filtration rate at week 104 was 18.2% and 29.5%, respectively, and the point estimate of the intergroup difference (placebo − canagliflozin) was 11.3% (95% confidence interval 1.2–21.5, P = 0.029), which was significant. The overall incidence of adverse events was similar in the two groups.ConclusionsThis study suggests that canagliflozin safely reduces the risk of end‐stage renal disease in Japanese chronic kidney disease patients with type 2 diabetes mellitus.     

Splenectomy for Torsion of a Wandering Spleen in a Patient with Myeloproliferative Disease

We herein report a rare case of torsion of a wandering spleen in a patient with myeloproliferative disease. A 66-year-old Japanese woman presented to our hospital with abdominal pain and a fever. She had a medical history of polycythemia and secondary myelofibrosis. Abdominal enhanced computed tomography showed an enlarged spleen without enhancement in the lower pelvic region. The clinical diagnosis was severe torsion of a wandering spleen in a patient with myeloproliferative disease, necessitating surgical intervention. Splenectomy was performed after de-rotating to revascularize the spleen. After the operation, the platelet count gradually increased, and aspirin was administered to prevent thrombosis.     

Effects of tranexamic acid on coagulofibrinolytic markers during the early stage of severe trauma: A propensity score–matched analysis

Tranexamic acid (TXA) reduces the risk of bleeding trauma death without altering the need for blood transfusion. We examined the effects of TXA on coagulation and fibrinolysis dynamics and the volume of transfusion during the early stage of trauma. This subanalysis of a prospective multicenter study of severe trauma included 276 patients divided into propensity score–matched groups with and without TXA administration. The effects of TXA on coagulation and fibrinolysis markers immediately at (time point 0) and 3 hours after (time point 3) arrival at the emergency department were investigated. The transfusion volume was determined at 24 hours after admission. TXA was administered to the patients within 3 hours (median, 64 minutes) after injury. Significant reductions in fibrin/fibrinogen degradation products and D-dimer levels from time points 0 to 3 in the TXA group compared with the non-TXA group were confirmed, with no marked differences noted in the 24-hour transfusion volumes between the 2 groups. Continuously increased levels of soluble fibrin, a marker of thrombin generation, from time points 0 to 3 and high levels of plasminogen activator inhibitor-1, a marker of inhibition of fibrinolysis, at time point 3 were observed in both groups. TXA inhibited fibrin(ogen)olysis during the early stage of severe trauma, although this was not associated with a reduction in the transfusion volume. Other confounders affecting the dynamics of fibrinolysis and transfusion requirement need to be clarified.     

Conotoxin GIIIA: selective inhibition of 22Na influx via voltage-dependent Na channels in adrenal medullary cells

Summary Conotoxin GIIIA and GIIIB from the marine snail Conus geographus have been reported to inhibit voltage-dependent Na channels in skeletal muscle and postganglionic sympathetic neuron, but have no effect on Na channels in brain, giant axon and heart. In eel electroplax, conotoxins were also shown to share the common binding sites with saxitoxin (see review Gray et al. 1988).In bovine adrenal medullary cells, conotoxin GIIIA inhibited veratridine-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines with an IC₅₀ of 6 mol/l, while saxitoxin suppressed veratridine-induced responses with an IC₅₀ of 6.3 nmol/l. [³H]Saxitoxin binding to the cells was inhibited by unlabeled saxitoxin with an IC₅₀ of 5.1 nmol/l, but was slightly reduced by 10 mol/l conotoxin GIIIA. Conotoxin GIIIA, at 10 mol/l, did not alter carbachol-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines as well as high K-induced ⁴⁵Ca influx and catecholamine secretion.These results indicate that conotoxin GIIIA, at concentrations 950 fold higher than saxitoxin, inhibits Na influx via voltage-dependent Na channels, but has no effect on the nicotinic receptor-ion channel complex or the voltage-dependent Ca channels. Conotoxin GIIIA seems to bind at the sites which are distinct from saxitoxin, but are functionally linked to the voltage-dependent Na channels. Conotoxins may be useful for the classification of Na channels in excitable cell membranes. Send offprint requests to A. Wada at the above address     

Successful Rescue of Life-threatening Hemoptysis Caused by Pulmonary Tuberculosis Bridging with Extracorporeal Membrane Oxygenation

Massive hemoptysis is a fatal complication associated with pulmonary tuberculosis (TB). It can lead to severe respiratory failure. Extracorporeal membrane oxygenation (ECMO) is a life-saving technology that is rarely indicated for bleeding disorders. We herein report a 26-year-old man who presented with severe respiratory failure caused by massive hemoptysis with pulmonary TB. Transcatheter artery embolization was successfully performed with venovenous ECMO support. The hemostatic procedure allowed concomitant anticoagulant use, and neither bleeding nor thrombotic complications occurred throughout the clinical course. Administering the appropriate hemostatic procedure with subsequent management, including anticoagulant therapy, supported ECMO application in a case of bleeding.     

Intravenous immunoglobulin for acute exacerbation of fibrotic idiopathic interstitial pneumonias

Background and aim:Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF.Methods:We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500–1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital.Results:This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3–5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02–0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06–1.33, p < 0.01) were independently associated with 90-day mortality.Conclusions:The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).