Sesame lignans reduce LDL oxidative susceptibility by downregulating the platelet-activating factor acetylhydrolase.

OBJECTIVE: Low-density lipoprotein (LDL) oxidative susceptibility is recognized as a risk factor for atherosclerosis. We previously reported that the ingestion of a supplement containing sesame lignans (sesamin/episesamin) for 4 weeks reduced LDL oxidative susceptibility in humans. MATERIALS AND METHODS: To elucidate the mechanisms underlying this observation, 12-week-old New Zealand White rabbits were fed a fat/cholesterol-enriched diet (100 g/day) for 6 weeks followed by oral administration of vehicle (control) or sesame lignans (50 mg/kg) for 4 weeks with the fat/cholesterol-enriched diet. RESULTS: The results showed that the ingestion of sesame lignans prolonged LDL oxidation lag time, regardless of the existence of the anti-oxidative catechol metabolite of sesamin/episesamin in LDL. Plasma platelet-activating factor acetylhydrolase (PAF-AH) activity was significantly reduced by sesame lignans. The prolongation of LDL oxidation lag time was abolished by the addition of a PAF-AH inhibitor. The expression level of pro-inflammatory cytokines and macrophage infiltration observed in the liver following the feeding of the fat/cholesterol-enriched diet were also significantly reduced by sesame lignans. CONCLUSIONS: These results indicate that sesame lignans reduce LDL oxidative susceptibility by downregulating plasma PAF-AH activity via the reduction of inflammation in the liver induced by fat/cholesterol-enriched diets.

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia.

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

Clinical features and treatment of patients with esophageal cancer and a history of gastrectomy: a multicenter, questionnaire survey in Kyushu, Japan.

It is still controversial whether patients with a history of gastrectomy have high risk of esophageal carcinogenesis. On the other hand, the treatment strategy for esophageal cancer patients after gastrectomy is complicated. The association between histories of gastrectomy and esophageal carcinogenesis was retrospectively analyzed, and the treatment of esophageal cancer patients after gastrectomy was evaluated based on questionnaire data collected from multiple centers in Kyushu, Japan. The initial subject population comprised 205 esophageal cancer patients after gastrectomy. Among them, 108 patients underwent curative surgical treatment, and 70 patients underwent chemoradiation therapy (CRT). The time between gastrectomy and esophageal cancer development was longer in peptic ulcer patients (28.3 years) than in gastric cancer patients (9.6 years). There were no differences in the location of esophageal cancer according to the gastrectomy reconstruction method. There were no significant differences in the clinical background characteristics between patients with and without a history of gastrectomy. Among the 108 patients in the surgery group, the 5-year overall survival rates for stages I (n = 30), II (n = 18), and III (n = 60) were 68.2%, 62.9%, and 32.1%, respectively. In the CRT group, the 5-year overall survival rate of stage I (n = 29) was 82.6%, but there were no 5-year survivors in other stages. The 5-year overall survival rate of patients with CR (n = 33) or salvage surgery (n = 10) was 61.2% or 36%, respectively. For the treatment of gastrectomized esophageal cancer patients, surgery or CRT is recommended for stage I, and surgery with or without adjuvant therapy is the main central treatment in advanced stages, with surgery for stage II, neoadjuvant therapy + surgery for stage III, and CRT + salvage surgery for any stage, if the patient's condition permits.

Functional performance of female patients more than 6 months after total hip arthroplasty shows greater improvement with weight-bearing exercise than with non-weight-bearing exercise. Randomized controlled trial.

BACKGROUND: Impaired functional performance and decreased muscle strength and muscle atrophy generally persist for a long period after total hip arthroplasty (THA). AIM: To investigate the effects of weight-bearing (WB) and non-weight-bearing (NWB) exercises on functional performance, Harris hip score (HHS), muscle strength and muscle thickness in women after THA. DESIGN: A randomised, controlled trial. SETTING: Community. POPULATION: Sixty-five women who had undergone unilateral or bilateral THA at least 6 months before enrolment in the study. METHODS: Participants were randomly allocated to the following groups: WB (n = 22), NWB (n = 21) and control (n = 22) groups. Participants in the WB and NWB groups performed daily home exercise programs for 8 weeks. Functional performance (timed up and go, sit-to-stand, stair climbing, walking speed and 3-min walk test), HHS, isometric muscle strength of the hip and knee muscle and gluteus and quadriceps muscle thickness were measured at baseline and after 8 weeks. RESULTS: An intention-to-treat analysis revealed that both the intervention groups exhibited significant improvements in almost all functional performance measures compared with the control group. Furthermore, the WB group showed significantly greater pre-post changes in the sit-to-stand and 3-min walk test compared with the NWB group. In terms of HHS, only the WB group showed significantly greater improvement compared with the control group. Relative to the control group, improvements in all isometric strength measures were observed in both the intervention groups. Significant improvement in quadriceps muscle thickness was observed in the WB group compared with the control group. However, no significant difference was observed among the three groups in pre-post changes in gluteus muscle thickness. CONCLUSION: WB and NWB home exercise programs were both effective for improving functional performance and muscle strength in women after THA. However, the WB exercise was more effective than the NWB exercise for improving sit-to-stand ability and walking endurance. CLINICAL REHABILITATION IMPACT: In this study, we demonstrated that the WB exercise was more effective than the NWB exercise for improving functional performance in patients after THA.

Genetic variability in swine leukocyte antigen class II and Toll-like receptors affects immune responses to vaccination for bacterial infections in pigs.

The genes encoding swine leukocyte antigen (SLA) and Toll-like receptor (TLR) are highly polymorphic in pig populations, and likely have influences on infection and the effects of vaccination. We explored the associations of different genotypes of SLA class II and of the genes TLR1, TLR4, TLR5, and TLR6 with antibody responses after vaccination against Erysipelothrix rhusiopathiae (ER) and Actinobacillus pleuropneumoniae (APP) serotypes 1, 2, and 5 in 191 Duroc pigs maintained under specific pathogen-free conditions. We demonstrated close relationships between SLA class II and ER antibody response and between TLR genes other than TLR4 and APP antibody responses. Pigs with specific haplotypes in SLA class II or TLR5 showed decreased antibody response to ER vaccination or increased responses to APP2 and APP5 vaccination, respectively. It might be possible to breed for responsiveness to vaccination and to implement new vaccine development strategies unaffected by genetic backgrounds of pigs.

The source of the Ti 3d defect state in the band gap of rutile titania (110) surfaces.

The origin of the Ti 3d defect state seen in the band gap for reduced rutile TiO(2)(110) surfaces has been excitingly debated. The probable candidates are bridging O vacancies (V(O)) and Ti interstitials (Ti-int) condensed near the surfaces. The aim of this study is to give insights into the source of the gap state via photoelectron spectroscopy combined with ion scattering and elastic recoil detection analyses. We have made three important findings: (i) The intensity of the gap state observed is well correlated with the sheet resistance measured with a 4-point probe, inversely proportional to the density of Ti-int. (ii) Sputter∕annealing cycles in ultrahigh vacuum (UHV) lead to efficient V(O) creation and condensation of Ti-int near the surface, while only annealing below 870 K in UHV condenses subsurface Ti-int but does not create V(O) significantly. (iii) The electronic charge to heal a V(O) is almost twice that to create an O adatom adsorbed on the 5-fold Ti row. The results obtained here indicate that both the V(O) and Ti-interstitials condensed near the surface region contribute to the gap state and the contribution to the gap state from the Ti-int becomes comparable to that from V(O) for the substrates with low sheet resistance less than ∼200 Ω∕square.

Successful treatment of Trichosporon fungemia in a patient with refractory acute myeloid leukemia using voriconazole combined with liposomal amphotericin B.

Trichosporon fungemia is a rare and fatal fungal infection that occurs in patients with prolonged neutropenia associated with hematologic malignancies. A 21-year-old male developed Trichosporon fungemia during remission induction therapy for acute myeloid leukemia (AML). Although two courses of induction therapy failed to induce a remission of AML, combination therapy with voriconazole and liposomal amphotericin B (L-AmB) followed by monocyte colony-stimulating factor ameliorated the Trichosporon fungemia and enabled the patient to receive reduced-intensity bone marrow transplantation (BMT) from his human leukocyte antigen-A one-locus mismatched mother. The patient achieved a durable remission after BMT without exacerbation of Trichosporon fungemia. The combination therapy with voriconazole and L-AmB may therefore be useful in controlling Trichosporon fungemia associated with prolonged neutropenia after remission induction therapy for AML.

Stenting for Left Subclavian Artery Stenosis before and after Coronary Artery Bypass Grafting Using the Internal Mammary Artery: A Report of Three Cases.

SUMMARY: Stenosis of the subclavian artery proximal to the origin of the internal mammary artery (IMA) used for coronary artery bypass grafting may produce flow reversal (steal syndrome) and cause myocardial ischemia. We present three cases of subclavian artery stenosis proximal to the IMA before and after CABG. The first case developed symptomatic myocardial ischemia resulting from a variant of coronary-subclavian steal syndrome. The second case had asymptomatic subclavian artery stenosis proximal to the IMA used for CABG. In the third case we planned to perform CABG using the left IMA to treat cardiac ischemia. All of the patients were successfully treated by stent placement without the use of a protection device. In the first and second cases, cardiac ischemia did not appear during balloon inflation of the subclavian artery and no embolic complication occurred. In the third case, CABG was performed six months after stenting. Subclavian artery stenting is a valid alternative to surgical treatment to restore the flow to the IMA before or after CABG.

Cyclooxygenase-2 expression is related to prognosis in patients with esophageal squamous cell carcinoma.

AIM: Esophageal carcinoma is one of the most aggressive malignancies. Many studies have examined various biological factors associated with the malignant potential of esophageal carcinoma. Cyclooxygenase (COX)-2 is overexpressed in various types of human malignancies, including esophageal carcinomas. Although some groups have described COX-2 expression in esophageal adenocarcinoma, few studies have reported COX-2 expression in esophageal squamous cell carcinoma (ESCC). METHODS: We immunohistochemically investigated relationships between COX-2 overexpression in surgical specimens of primary tumors in 228 patients with ESCC. Relationships between COX-2 expression and clinicopathological factors, including prognosis, were analyzed. COX-2 expressions were classified into 4 criteria: Score 0, no staining; Score 1, <10% staining; Score 2, 10-90% staining; and Score 3, >90% staining. RESULTS: Scores of COX-2 immunoreactivity in 228 patients were as follows: Score 0, 21 of 228; Score 1, 71of 228; Score 2, 117 of 228; and Score 3, 19 of 228, respectively. COX-2 expression was significantly correlated with depth of invasion and tumor stage (p=0.03 and p=0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p=0.005). Multivariate regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC. CONCLUSIONS: COX-2 overexpression was significantly correlated with depth of invasion, tumor stage and survival in ESCC. Evaluation of COX-2 expression should be useful for determining tumor properties, including prognosis, in patients with ESCC.

Isolated tumour cells in blood and E-cadherin expression in oesophageal squamous cell cancer.

BACKGROUND: Patients with oesophageal squamous cell carcinoma have a high rate of recurrence, even after curative resection. The aim of this study was to examine the correlation between the presence of isolated tumour cells (ITCs) in the blood and recurrence, and between the presence of ITCs and E-cadherin expression in the primary tumour in these patients. METHODS: Blood samples obtained immediately before and after resection in 125 patients with oesophageal squamous cell carcinoma were examined by real-time reverse transcription-polymerase chain reaction using carcinoembryonic antigen mRNA. Blood samples from 28 healthy volunteers and 42 patients with benign diseases were used as controls. RESULTS: Seventy-seven patients (61.6 per cent) were ITC positive. ITC positivity correlated significantly with tumour depth, lymph node metastasis, stage, lymphatic invasion and venous invasion. Multivariable analysis revealed that tumour depth and ITC positivity were independent factors for a shortened haematogenous disease-free interval. A significant correlation was found between ITC positivity and reduced E-cadherin expression in the primary tumour (P < 0.001). ITC-positive patients with preserved E-cadherin expression had a longer disease-free interval (P = 0.016), haematogenous disease-free interval (P = 0.020) and overall survival (P = 0.004) than those with reduced E-cadherin expression. CONCLUSION: Examination of ITCs in the blood is useful for predicting haematogenous recurrence in patients with oesophageal squamous cell carcinoma.

Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation.

Platelet regeneration represents an important and separate element in the engraftment process for allogeneic stem cell transplantation. Fully automated flow cytometry using blood cell counters now allows reliable quantification of reticulated platelets, expressed as the immature platelet fraction (IPF). We studied the kinetics of IPF in six patients grafted with allogeneic peripheral blood stem cell transplantation (PBSCT), 12 patients with bone marrow transplantation (BMT) and seven patients with cord blood transplantation (CBT). Preconditioning therapy caused an immediate and rapid fall in tri-lineage hematopoiesis. IPF rose transiently above 3% after a mean duration of 11 days post-PBSCT, 18 days post-BMT and 19 days post-CBT. This was 1, 4 and 13 days earlier than platelet engraftment, respectively. A linear correlation model showed a close association between the rise of IPF and tri-lineage engraftment after transplantation. IPF counting may thus provide an accessible measure of thrombopoietic activity, leading to early evaluation of marrow function and allowing monitoring of platelet regeneration.

Safety and efficacy of foscarnet for preemptive therapy against cytomegalovirus reactivation after unrelated cord blood transplantation.

In association with the increased use of unrelated cord blood transplantation (UCBT) in adults, numerous patients have developed cytomegalovirus (CMV) reactivation concomitant with cytopenia. Although foscarnet appears to offer similar efficacy and higher safety as a preemptive therapy against CMV infection than ganciclovir, little is known about the usefulness of foscarnet in such patients. Foscarnet was administered as preemptive therapy against CMV antigenemia in 10 UCBT recipients who were unable to receive ganciclovir due to cytopenia or poor response to ganciclovir. Fatal CMV disease developed in one patient, whereas CMV antigenemia resolved without progression to CMV disease in the remaining nine patients. Foscarnet was well tolerated without serious hematotoxicity and was not discontinued due to adverse events in any patient. Foscarnet represents a safe and effective agent for preemptive therapy against CMV infection and may offer a feasible alternative to ganciclovir in UCBT recipients.

Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men.

Serum fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor and important for the regulation of inorganic phosphate (Pi) homeostasis. In this study, we examined an acute effect of oral Pi loading on serum FGF23 levels to clarify the role in rapid adjustment of serum Pi level. We performed a randomized, double-blind, crossover study in eight healthy male volunteers. The subjects were alternately served one of three test meals containing different Pi amounts (400 mg (P400), 800 mg (P800), and 1200 mg (P1200)) as lunch at noon. The postprandial changes in serum levels of Pi, Ca, 1,25-dihydroxyvitamin D, intact-parathyroid hormone (iPTH), intact-FGF23 (iFGF23), and urinary excretion of Pi and Ca until 8 h after Pi loading were estimated. Serum Pi levels and urinary Pi excretion significantly increased within 1 h after P400 and P800 intake. Serum iPTH levels at 1-2 and 4-6 h after P1200 intake was significantly higher than those of P400 intake. Serum iFGF23 levels slightly decreased up to 8 h after P400 intake and up to 6 h after P800 intake, but not changed in P1200 intake. Significant increase of iFGF23 was observed at 8 h after P1200 intake compared with both P400 and P800 intake. Additionally, negative association was detected between iFGF23 and serum Pi, whereas positive association was observed between iPTH and serum Pi during the short period. We conclude that oral Pi loading cannot rapidly increase serum FGF23 level. FGF23 may be not associated with rapid adaptation of Pi homeostasis.

Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution.

The purpose of the present study was to compare the clinical results between preoperative chemoradiotherapy followed by surgery (CRT group) and surgery alone (Surgery group) by a randomized controlled study. Twenty-two patients were assigned to the CRT group and 23 to the Surgery group. A total radiation dose of 40 Gy was applied and in the same period, intravenous chemotherapy was performed using cisplatin (7 mg over 2 h) and 5-fluorouracil (5-FU; 350 mg over 24 h). Surgical treatment was performed in 20 patients in the CRT group except for two patients with bone metastasis after CRT. According to histological effects of primary tumors, the number of patient with Grades 1, 2 and 3 was 11, 7 and 3, respectively. Frequency of lymphatic and venous invasion was significantly lower in the CRT group than in the Surgery group. The 5-year survival rate was 57% in the CRT group and 41% in the Surgery group (P = 0.58). According to the histological effect in the CRT group, 5-year survival was 30% for Grade 1, 83% for Grade 2 and 100% for Grade 3 (P = 0.0069). This randomized trial did not demonstrate a statistically significant survival difference between the CRT group and the Surgery group.

Reduced-intensity unrelated cord blood transplantation for treatment of metastatic renal cell carcinoma: first evidence of cord-blood-versus-solid-tumor effect.

We report a 69-year-old man with cytokine-resistant metastatic renal cell carcinoma treated with reduced-intensity unrelated cord blood transplantation. The patient achieved durable donor engraftment with minimal graft-versus-host disease. The patient showed regression of metastatic disease, providing the first evidence of a graft-versus-tumor effect on a solid tumor resulting from cord blood graft.

Expression of osteopontin in oesophageal squamous cell carcinoma.

Osteopontin is a multifunctional 34 kDa extracellular matrix protein with a cell-binding domain. It is involved cell adhesion and cell migration and is therefore considered to influence tumorigenesis and/or metastasis. The purpose of the present study was to evaluate the clinical significance of Osteopontin expression in oesophageal squamous cell carcinoma (ESCC). In the present study, we immunohistochemically investigated the relationship between Osteopontin expression and clinicopathological factors including prognosis in surgical specimens of primary tumours in 175 patients with ESCC. Osteopontin was expressed in 48% of 175 patients. Osteopontin expression was significantly correlated with lymph node metastasis, lymphatic invasion, and stage (P=0.0015, 0.037 and 0.033, respectively). Tumours with expressing Osteopontin exhibited more lymph node metastasis, lymphatic invasion and advanced stage than the tumour with negative Osteopontin expression. Five-year survival rate was better in patients with negative Osteopontin expression than in those with positive Osteopontin expression (P=0.035). However, multivariate analysis revealed that Osteopontin expression was not an independent prognostic factor. As our findings suggest that Osteopontin may play an important role in progress of ESCC, the evaluation of Osteopontin expression is useful for predicting the malignant properties of ESCC.

Effect of late evening snack with rice ball on energy metabolism in liver cirrhosis.

OBJECTIVE: This study investigates the effects of a late evening snack (LES), of 200 kcal of rice ball, on energy metabolism in cirrhotic patients. Impaired nutritional metabolism has been associated with cirrhosis, and frequent intake of small meals may prevent early-onset starvation, and maintain nourishment in these patients. SUBJECTS: Twenty-one cirrhotic patients and 26 control subjects (Control) were recruited for this study. Patients were subsequently treated by LES (LC-LES) and by a non-LES regimen (LC-NLES). METHOD: Resting energy expenditure and respiratory quotient (RQ) were assessed by indirect calorimetry at 0830, 1130 and 1430. Blood glucose and non-esterified fatty acids (NEFA) were measured just before the energy metabolism measurements. The regular diet included three major meals and LES, at 0900, 1200, 1800 and 2100, respectively. The Control and LC-NLES groups received only the major meals, whereas the LC-LES group received three meals plus 200 kcal LES for 7 days. There was no difference in the total energy intake among Control, LC-NLES and LC-LES groups. RESULTS: Respiratory quotient in LC-NLES was significantly lower than that of Control at 0830. Respiratory quotient value in LC-LES significantly elevated from that in LC-NLES. The RQ values did not differ among Control, LC-NLES and LC-LES at 2 h after the meal (1130 and 1430). Non-esterified fatty acids in LC-LES were lower than that in LC-NLES after overnight fasting. CONCLUSIONS: The ingestion of a 200 kcal rice ball LES can improve the nutritional metabolism in cirrhotic patients.

The role of salvage surgery for recurrence of esophageal squamous cell cancer.

AIM: A consensus treatment strategy for recurrent esophageal squamous cell cancer (ESCC) has not been established. The purpose of the present study was to analyse the mode of recurrence, and evaluate the role of surgical salvage treatment in recurrence of ESCC. METHODS: Recurrence was detected in 131 of 367 consecutive patients with ESCC. We retrospectively analysed the mode of recurrence and treatment for recurrence. Recurrence was divided into four types; lymph node, hematogeneous, mixed and local. Treatments were classified into four groups; chemotherapy alone (C group), radiation therapy +/- chemotherapy (R group), surgery +/- other therapy (S group), and no therapy (N group). RESULTS: Of the 131 recurrences, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 43, 44, 40 and 4, respectively. The number of patients in the C, R, S, N groups was 35, 35, 24 and 37, respectively. Of the 24 patients who received surgical treatment for recurrence, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 11, 6, 6 and 1, respectively. The number of lesions in hematogeneous recurrence was 2 or less. The survival rate from recurrence to death in the C, R, S and N groups was 0, 3.9, 6.7 and 0%, respectively. A statistically significant difference was found in these groups (p < 0.0001). CONCLUSIONS: Salvage surgery is one of the useful treatment tools for resectable metastatic lesions. In such cases, the number of lesions, recurrent sites and effectiveness of chemotherapy and/or radiotherapy should be carefully evaluated.