Ameliorating effects of cystine and theanine in a cancer cachexia mouse model.

Cachexia is a common cancer complication and is associated with weight loss and anorexia. In this study, we investigated the ameliorating effects of cystine and theanine on cancer cachexia using a mouse model. In mice carrying the colon cancer cell line C-26, there was a suppression of body weight increase and reduction in both internal fat and lower limb muscles. Repeated cystine and theanine administration significantly prevented weight loss, internal fat loss, lower limb muscle loss, and serum IL-6 increase in the cachexia model. These results suggested that cystine and theanine may be effective in ameliorating cancer cachexia.

Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08−0.56), p < 0.01, doxazosin 0.41 (0.10−1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38−0.76), p < 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5−20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32−0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS).

PURPOSE: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. METHODS: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. RESULTS: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. CONCLUSIONS: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory PIPN effects. This review summarizes the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Thus, enhancing translational research to translate pre-clinical research into clinical research is important.

[Passive Orthostatism Using Tilt Table in Critical Patients after Cardiovascular Surgery].

Previously, we performed passive orthostatism using a tilt table for the purpose of early mobilization in intensive care unit patients after cardiovascular surgery. In this study, we introduced VitalGo Total Lift Bed( TLB), which does not require patient-transfer before passive orthostatism, to reduce the burden on patients and medical staff. No obvious adverse events were found throughout the study. In the TLB group, number of medical staff required to perform the passive orthostatism was significantly less compared to the conventional tilt table group.

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome.

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65-0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.

Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence.

Oxaliplatin is an essential drug in the chemotherapy of colorectal, gastric, and pancreatic cancers, but it frequently causes peripheral neuropathy as a dose-limiting factor. So far, animal models of oxaliplatin-induced peripheral neuropathy have been established. The mechanisms of development of neuropathy induced by oxaliplatin have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory effects on neuropathy. In this review, we summarize the basic and clinical evidence for the therapeutic effects of oxaliplatin. In basic research, there are many reports of neuropathy inhibitors that target oxidative stress, inflammatory response, sodium channel, transient receptor potential (TRP) channel, glutamate nervous system, and monoamine nervous system. Alternatively, very few drugs have clearly demonstrated the efficacy for oxaliplatin-induced peripheral neuropathy in clinical trials. It is important to activate translational research in order to translate basic research into clinical research.

The enhancement of fat oxidation during the active phase and suppression of body weight gain in glycerol-3-phosphate dehydrogenase 1 deficient mice.

We investigated whether the deletion of glycerol-3-phosphate dehydrogenase (GPD) 1 would affect carbohydrate oxidation, fat oxidation, and body weight by using the GPD1 null mice (BALB/cHeA (HeA)). We found that fat oxidation in HeA mice was significantly high during the early active phase than in BALB/cBy (By) mice used as a control under ad libitum conditions. Metabolic tracer experiment revealed that fatty acid oxidation in the skeletal muscle of HeA mice tended to be high. The energy expenditure and fat oxidation in HeA mice under fasting conditions were significantly higher than that in the By mice. Moreover, we monitored body weight gain in HeA mice under ad libitum feeding and found lower body weight gain. These data indicate that GPD1 deficiency induces enhancement of fat oxidation with suppression of weight gain. We propose that GPD1 deletion contributes to the reduction of body weight gain via enhancement of fat oxidation.

[Passive Orthostatism Using a Tilt Table in Patients with Impaired Oxygenation after Cardiovascular Surgery].

Passive orthostatism using a tilt table was introduced in patients with impaired oxygenation [Pao2/Fio(2 P/F) ratio < 300] after cardiovascular surgery. Our passive orthostatism protocol was as follows. Patient was transferred to a tilt table under endotracheal intubation with pulmonary artery catheter monitoring, and rested for 10 minutes in a supine position, followed by 45-degree tilt for 5 minutes, and then passive orthostatism at 60-degree for 25 minutes. P/F ratio was significantly improved during passive orthostatism. Improvement in P/F ratio was confirmed even 1 hour after completion of the protocol. No obvious adverse events were found throughout the protocol. On average, 15 hours (2~72 hours, median 4 hours) after the introduction of passive orthostatism, weaning from respirator was achieved.

Clinically Feasible and Accurate View Classification of Echocardiographic Images Using Deep Learning.

A proper echocardiographic study requires several video clips recorded from different acquisition angles for observation of the complex cardiac anatomy. However, these video clips are not necessarily labeled in a database. Identification of the acquired view becomes the first step of analyzing an echocardiogram. Currently, there is no consensus whether the mislabeled samples can be used to create a feasible clinical prediction model of ejection fraction (EF). The aim of this study was to test two types of input methods for the classification of images, and to test the accuracy of the prediction model for EF in a learning database containing mislabeled images that were not checked by observers. We enrolled 340 patients with five standard views (long axis, short axis, 3-chamber view, 4-chamber view and 2-chamber view) and 10 images in a cycle, used for training a convolutional neural network to classify views (total 17,000 labeled images). All DICOM images were rigidly registered and rescaled into a reference image to fit the size of echocardiographic images. We employed 5-fold cross validation to examine model performance. We tested models trained by two types of data, averaged images and 10 selected images. Our best model (from 10 selected images) classified video views with 98.1% overall test accuracy in the independent cohort. In our view classification model, 1.9% of the images were mislabeled. To determine if this 98.1% accuracy was acceptable for creating the clinical prediction model using echocardiographic data, we tested the prediction model for EF using learning data with a 1.9% error rate. The accuracy of the prediction model for EF was warranted, even with training data containing 1.9% mislabeled images. The CNN algorithm can classify images into five standard views in a clinical setting. Our results suggest that this approach may provide a clinically feasible accuracy level of view classification for the analysis of echocardiographic data.

[Thoracentesis under Standing with Assistance of a Tilt Table in Critical Patients after Cardiovascular Surgery].

For safe and effective drainage in patients with pleural effusion after cardiac surgery, ultrasound-guided thoracocentesis was carried out under standing with assistance of a tilt table. Thoracocentesis was performed in 5( 11%) of the 44 patients who were treated under passive orthostatism using a tilt table. Four cases were under intubated-ventilator assist, and 2 cases were under intraaortic balloon pumping( IABP). No adverse events occurred. Thoracocentesis under standing with assistance of a tilt table can be safely performed.

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway.

Excessive intake of fructose increases lipogenesis in the liver, leading to hepatic lipid accumulation and development of fatty liver disease. Metabolic alterations in the liver due to fructose intake have been reported in many studies, but the effect of fructose administration on hepatic gluconeogenesis is not fully understood. The aim of this study was to evaluate the acute effects of fructose administration on fasting-induced hepatic gluconeogenesis. C57BL/6J mice were administered fructose solution after 14 h of fasting and plasma insulin, glucose, free fatty acids, and ketone bodies were analysed. We also measured phosphorylated AKT and forkhead box O (FoxO) 1 protein levels and gene expression related to gluconeogenesis in the liver. Furthermore, we measured glucose production from pyruvate after fructose administration. Glucose-administered mice were used as controls. Fructose administration enhanced phosphorylation of AKT in the liver, without increase of blood insulin levels. Blood free fatty acids and ketone bodies concentrations were as high as those in the fasting group after fructose administration, suggesting that insulin-induced inhibition of lipolysis did not occur in mice administered with fructose. Fructose also enhanced phosphorylation of FoxO1 and suppressed gluconeogenic gene expression, glucose-6-phosphatase activity, and glucose production from pyruvate. The present study suggests that acute fructose administration suppresses fasting-induced hepatic gluconeogenesis in an insulin-independent manner.

Effects of the dietary carbohydrate-fat ratio on plasma phosphatidylcholine profiles in human and mouse.

Phosphatidylcholines (PCs), a major class of human plasma phospholipids, are composed of highly diverse fatty acids. Because the dietary carbohydrate-fat ratio alters the hepatic fatty acid metabolism, plasma fatty acids that bind PCs, which are secreted as lipoproteins from the liver, may be affected by long-term consumption of a high-carbohydrate diet or a high-fat diet. Therefore, in this study, we profiled the plasma PC species comprehensively in formulated dieting conditions to identify those phospholipid molecules that reflect the dietary carbohydrate-fat ratio. C57BL6J mice were fed diets containing different amounts of fat for 8 weeks, and plasma PC species were analyzed under fasting conditions using liquid chromatography-mass spectrometry. In addition, a cross-sectional study of 78 middle-aged Japanese men, who participated in health checkups, was conducted. Nutrient intakes were estimated by a brief self-administered diet-history questionnaire. The plasma PC profiles changed depending on the dietary carbohydrate-fat ratio. Especially, PC (16:0/16:1) and PC (16:0/18:1) levels increased as the dietary carbohydrate-fat ratio increased in human and mouse, suggesting that these PC species reflected the increase in de novo lipogenesis and might become useful biomarkers of the dietary carbohydrate-fat ratio. Since these PCs act as ligands for peroxisome proliferator-activated receptor α, PC species reflecting the dietary carbohydrate-fat ratio may influence metabolism of glucose and lipids.