Effective magnetic hyperthermia induced by mitochondria-targeted nanoparticles modified with triphenylphosphonium-containing phospholipid polymers.

Magnetic hyperthermia (MHT) is a promising cancer treatment because tumor tissue can be specifically damaged by utilizing the heat generated by nano-heaters such as magnetite nanoparticles (MNPs) under an alternating magnetic field. MNPs are taken up by cancer cells, enabling intracellular MHT. Subcellular localization of MNPs can affect the efficiency of intracellular MHT. In this study, we attempted to improve the therapeutic efficacy of MHT by using mitochondria-targeting MNPs. Mitochondria-targeting MNPs were prepared by the modification of carboxyl phospholipid polymers containing triphenylphosphonium (TPP) moieties that accumulate in mitochondria. The mitochondrial localization of polymer-modified MNPs was supported by transmission electron microscopy observations of murine colon cancer CT26 cells treated with polymer-modified MNPs. In vitro and in vivo MHT using polymer-modified MNPs revealed that the therapeutic effects were enhanced by introducing TPP. Our results indicate the validity of mitochondria targeting in enhancing the therapeutic outcome of MHT. These findings will pave the way for developing a new strategy for the surface design of MNPs and therapeutic strategies for MHT.

Combination of magnetic hyperthermia and immunomodulators to drive complete tumor regression of poorly immunogenic melanoma.

Hyperthermia using magnetic nanoparticles enables tumor-specific heating and can destroy tumor tissues. This approach works as in situ vaccination with tumor antigens released from dying tumor cells. However, in situ vaccination caused by magnetic hyperthermia is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment. In this study, we explored a novel strategy for immunotherapy using magnetic hyperthermia to regress poorly immunogenic melanoma. Magnetic hyperthermia induced tumor cell death in a B16-F10 melanoma mouse model. After hyperthermia treatment, we found elevated levels of HMGB1, which is known to be released from dying cells to promote inflammation, and the proinflammatory cytokine TNF-α was increased in serum of the mice. Systemic administration of glycyrrhizin, an HMGB1 inhibitor, reduced the levels of TNF-α in serum and successfully delayed the regrowth of tumors after magnetic hyperthermia. To achieve complete tumor regression, TLR9 activation by intratumor injection of CpG was combined with systemic administration of anti-PD-1 antibody and anti-CTLA-4 antibody. The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors. These findings have important implications for the development of novel cancer immunotherapy using magnetic hyperthermia for poorly immunogenic tumors.

Inhibition Effect of Eucommia ulmoides Leaf Extract on Interleukin 8 Production by A549 Cells.

Asthma is characterized by chronic inflammation of the airway mucosa. As Eucommia ulmoides Oliv. leaf extract (ELE) has been known to have anti-inflammatory properties, herein, we investigated the effect of ELE on interleukin (IL-) 8 production in A549 cells, a human airway epithelial cell line. The addition of ELE 1 h before tumor necrosis factor-alpha (TNFα) stimulation inhibited IL-8 production by A549 cells in a concentration-dependent manner. The addition of geniposidic acid, the main component of ELE, also inhibited IL-8 production. To further investigate the mechanism by which ELE inhibits IL-8 production, the effect of ELE or geniposidic acid on TNFα-stimulated p38 phosphorylation was examined by Western blotting. After 30 min of TNFα stimulation, p38 phosphorylation was inhibited by the addition of ELE or geniposidic acid, suggesting that ELE inhibited IL-8 production in TNFα-stimulated A549 cells by suppressing one of the signal transducers of p38 phosphorylation. These results indicate that ELE can be used as an effective measure against asthma, particularly neutrophilic asthma.

Comparison of local recurrence in transcatheter arterial chemoembolization of hepatocellular carcinoma with or without accumulation of iodized oil beyond corona enhancement area: Short-term results.

BACKGROUND: Local tumor recurrence of hepatocellular carcinoma (HCC) often occurs in blood drainage areas. Corona enhancement is determined by computed tomography during hepatic arteriography (CTHA) and is considered to represent the blood drainage area. This study aimed to investigate the relationship between embolization of corona enhancement area and local tumor recurrence of patients with HCC who underwent transcatheter arterial chemoembolization (TACE). PATIENTS AND METHODS: The study retrospectively selected 53 patients with 60 HCC nodules that showed corona enhancement area on late-phase CTHA and showed homogenous accumulation of iodized oil throughout the nodule on non-contrast-enhanced CT performed immediately after TACE. We divided the nodules into two groups, according to whether the accumulation of iodized oil covered the entire corona enhancement area (group A) or not (group B). Local tumor recurrence was compared between the two groups. RESULTS: The cumulative local tumor recurrence rates for group A (n = 36) were 2.8%, 2.8%, 8.3% at 3, 6, and 12 months, respectively, whereas the recurrence rates for group B (n = 24) were 20.8%, 45.8%, 75% at 3, 6, and 12 months, respectively. The cumulative local tumor recurrence rates for group A were significantly lower than those for group B (hazard ratio, 0.079; 95% confidence interval, 0.026-0.24; p < 0.001). CONCLUSIONS: The results of the study suggest that the corona enhancement area may be an accurate safety margin in TACE which should be performed until the embolic area covers the entire corona enhancement area.

The effect of standard and high dose of rikkunshito on achievement of enteral nutrition target in critically ill patients: a pilot randomized controlled trial.

AIM: Rikkunshito is a traditional Japanese medicine used for delayed gastric emptying in intensive care units in Japan. This study aimed to investigate whether standard- or high-dose rikkunshito can improve the achievement of enteral calorie target among critically ill adults. METHODS: This open-label, single-center, pilot randomized controlled trial was carried out from March 2018 until December 2018 and enrolled critically ill adult patients requiring enteral nutrition by gastric tube for at least 5 days. Patients were randomized into the control group, the standard-dose rikkunshito group (2.5 g three times daily), and the high-dose rikkunshito group (5 g three times daily). Intervention was given for 5 days. The primary outcome measure was the percentage of enteral calorie intake achieved in the target at the fifth day after randomization. RESULTS: The cohort comprised 26 patients; of these, 9, 8, and 9 were included in the control group, the standard-dose group, and the high-dose group, respectively. Twenty-one patients (81%) were included in the primary analysis. The percentage of enteral calorie intake achieved in the target at the fifth day was 59% (interquartile range [IQR], 39-63%), 40% (IQR, 26-61%), and 62% (IQR, 17-83%) in the control, the standard-dose, and the high-dose groups, respectively (P = 0.42). The number of adverse events did not differ significantly between the groups (control group, 4 [44%]; standard-dose group, 3 [38%]; and high-dose group, 4 [44%], P = 1.00). CONCLUSIONS: Standard- or high-dose rikkunshito did not improve the achievement of enteral calorie target in critically ill adults.

Recurrence of colonic cancer twice at the site of stapled colorectal anastomosis.

Recurrence at the site of a stapled anastomosis is generally believed to result from the luminal implantation of viable cancer cells during stapling. We report a case in which colon cancer recurred twice at the site of a stapled anastomosis, despite povidone iodine (PVP-I) lavage consisting of an enema with 5% PVP-I solution before the operation and intraoperative lavage of the rectal remnant and the descending colon with a 10% PVP-I solution. Three months after sigmoidectomy to resect a carcinoma of the sigmoid colon, a circular anastomotic recurrence was found at the suture line after anastomosis with a stapler. However, 11 months after the subsequent resection and reanastomosis to remove the first anastomotic recurrence, another anastomotic recurrence was found. We performed abdominoperineal resection for the second recurrence at the site of the stapled anastomosis. Suture-line recurrence could not be prevented in the present case despite lavage with a PVP-I solution for prophylaxis.

Lack of carcinogenicity of enzymatically modified isoquercitrin in F344/DuCrj rats.

The present study was conducted to evaluate the potential carcinogenicity of enzymatically modified isoquercitrin, administered in the diet at doses of 0.5% or 1.5% to groups of 50 male and female F344/DuCrj rats. Control males and females (50 rats each) were maintained on basal diet. Animals were observed for 104 weeks. There were no treatment-related clinical signs of toxicity in the treated groups. Body weights, feed consumption, survival rates and hematological findings for exposed rats of both sexes showed no variations among the groups. There was a slight but significant dose-dependent decrease in relative spleen weights in all treated groups, albeit with no histopathological variation. Overall histopathological evaluation of neoplasms and all tissues after 2 years showed that tumors developed in all groups including the controls. There was a non-significant tendency for increase in the incidence of pituitary gland adenomas in the high dose-treated females (45.5%) as compared to controls (27.7%), with a slight increase in hemorrhage incidences, but values for males were low and similar in both control and treated rats. There were no apparent effects of isoquercitrin on development of kidney neoplasms, hyperplasias or chronic nephropathy. Parathyroid adenomas or hyperplasias were found not affected by isoquercitrin treatment, and there were no differences in mammary gland fibroadenomas or hyperplasias between treated and control rats. Various tumors were found in other organs with no significant differences between the groups. In conclusion, under the conditions of this 2-year feeding experiment, no evidence was obtained of carcinogenicity of enzymatically modified isoquercitrin in male or female F344 rats.

Evaluation of effects of dietary carbohydrate on formation of struvite crystals in urine and macromineral balance in clinically normal cats.

OBJECTIVE: To evaluate effects of dietary carbohydrate on urine volume; struvite crystal formation; and calcium, phosphorus, and magnesium balance in clinically normal cats. ANIMALS: 21 healthy adult cats (15 sexually intact males and 6 sexually intact females). PROCEDURE: Diets containing no carbohydrate source (control diet), control plus starch, or control plus fiber were given in a 3 X 3 Latin-square design. The diets were available ad libitum in study 1 (n = 12) and given under restrictions in study 2 (9) to equalize daily intakes of crude protein among the 3 groups. Formation of struvite crystals and balance of calcium, phosphorus, and magnesium were measured. RESULTS: Urine volume was lower in the starch group and fiber group in study 1, whereas no differences were detected among the groups in study 2. Urinary pH and struvite activity product were higher in the starch group in both studies, and the fiber group also had higher struvite activity product in study 2. In both studies, urinary concentrations of HCl-insoluble sediment were higher in the starch group and fiber group. In the fiber group, a net loss of body calcium, phosphorus, and magnesium was detected in study 2. CONCLUSIONS AND CLINICAL RELEVANCE: Starch and fiber in diets potentially stimulate formation of struvite crystals. Hence, reducing dietary carbohydrate is desirable to prevent struvite urolith formation. In addition, a net loss of body calcium, phosphorus, and magnesium during feeding of the fiber diet suggests that dietary inclusion of insoluble fiber could increase macromineral requirements of cats.

Effects of a high-protein diet versus dietary supplementation with ammonium chloride on struvite crystal formation in urine of clinically normal cats.

OBJECTIVE: To evaluate the effects of a high-protein diet versus dietary supplementation with ammonium chloride (NH4Cl) on struvite crystal formation in the urine of clinically normal cats by measuring the urine concentration of hydrochloric acid (HCl)-insoluble sediment, urine pH, struvite activity product (SAP), number of struvite crystals in urine, and urine volume. ANIMALS: 23 healthy adult cats. PROCEDURE: Urine was fractionated by centrifugation with subsequent extraction of the sediment with 1 N HCl (study 1). Diets containing either 29% crude protein or 55% crude protein were fed to cats in a crossover trial of 3 weeks/period (study 2). Diets supplemented with either sodium chloride (NaCl) or NH4Cl were fed, by use of a 3 x 3 Latin-square design with 3 wk/period (study 3). In studies 2 and 3, urine samples were collected for the last 7 days of each period. RESULTS: The HCl-insoluble sediment contained Tamm-Horsfall glycoprotein (THP; study 1). The high-protein diet (study 2) and dietary supplementation with NH4Cl (study 3) resulted in a decrease in urine pH, SAP, and the number of struvite crystals in urine. However, the high-protein diet decreased urine concentrations of HCl-insoluble sediment containing THP (study 2), in contrast to the NH4Cl supplementation that increased urine volume without a significant effect on the urine concentration of the HCl-insoluble sediment (study 3). CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that compared with dietary supplementation with NH4Cl, the high-protein diet is preferable as a urine acidifier for the prevention of struvite crystal formation in clinically normal cats.

White, but not Red, Ginseng Inhibits Progression of Intestinal Carcinogenesis in Rats.

Ginseng is a well known traditional medicine in Asian countries which has attracted attention as a potential chemopreventive agent. In the present study, inhibitory effects of white and red ginseng on tumor development were examined using medium-term liver and multi-organ carcinogenicity bioassay systems. No modifying potential of the ginseng preparations were evident in terms of the numbers or areas of glutathione S-transferase placental form (GST-P)-positive foci in rat livers. However, white ginseng, although not its red counterpart, was found to decrease the incidences of adenocarcinoma of the small intestine and colon in the medium-term multi-organ carcinogenesis model, without any affect on the numbers of aberrant crypt foci (ACF). These results indicate that white ginseng may have inhibitory effects on the progression stage of rat intestinal carcinogenesis, but the influence is not strong. Ginseng did not appear to have promoting or inhibitory effects in other organs under the present experimental conditions. Possible application on ginseng for chemoprevention of colon cancer in humans, can be concluded given the lack of obvious adverse effects.