Effects of Beraprost on Intestinal Microcirculation and Barrier Function in a Mouse Model of Renal Failure.

OBJECTIVE: Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI2), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI2 improves intestinal microcirculation and barrier function via endothelial protective effects. METHODS: ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI2 effects. Beraprost served as PGI2. PGI2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions. RESULTS: We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration. CONCLUSIONS: Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure.

Activation of the inflammasome drives peritoneal deterioration in a mouse model of peritoneal fibrosis.

During peritoneal dialysis (PD), the peritoneum is exposed to a bioincompatible dialysate, deteriorating the tissue and limiting the long-term effectiveness of PD. Peritoneal fibrosis is triggered by chronic inflammation induced by a variety of stimuli, including peritonitis. Exposure to PD fluid alters peritoneal macrophages phenotype. Inflammasome activation triggers chronic inflammation. First, it was determined whether inflammasome activation causes peritoneal deterioration. In the in vivo experiments, the increased expression of the inflammasome components, caspase-1 activity, and concomitant overproduction of IL-1ß and IL-18 were observed in a mouse model of peritoneal fibrosis. ASC-positive and F4/80-positive cells colocalized in the subperitoneal mesothelial cell layer. These macrophages expressed high CD44 levels indicating that the CD44-positive macrophages contribute to developing peritoneal deterioration. Furthermore, intravital imaging of the peritoneal microvasculature demonstrated that the circulating CD44-positive leukocytes may contribute to peritoneal fibrosis. Bone marrow transplantation in ASC-deficient mice suppressed inflammasome activation, thereby attenuating peritoneal fibrosis in a high glucose-based PD solution-injected mouse model. Our results suggest inflammasome activation in CD44-positive macrophages may be involved in developing peritoneal fibrosis. The inflammasome-derived pro-inflammatory cytokines might therefore serve as new biomarkers for developing encapsulating peritoneal sclerosis.

[Three Cases of Locally Advanced Breast Cancer with Skin Invasion Treated with Cadexomer Iodine for Local Control].

Advanced breast cancer with skin invasion are relatively often accompanied by bleeding, effusion, malodor, and pain, which reduce the quality of life(QOL)of the patients and their families. Therefore, local symptom control is as important as surgical treatment and chemotherapy. We control these symptoms by using cadexomer iodine, cadexomer iondine is expensive, but relatively easy for family to use and keep patients' QOL.

IL-1ß may be an indicator of peritoneal deterioration after healing of peritoneal dialysis-associated peritonitis.

BACKGROUND: Peritoneal dialysis (PD) is an essential lifesaving treatment for end-stage renal disease. However, PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure because of progressive peritoneal deterioration. Peritonitis is the most common complication in patients undergoing PD. Thus, elucidating the mechanism of chronic peritoneal inflammation after PD-associated peritonitis is an urgent issue for patients undergoing PD. This first case report suggests that an increased interleukin-1ß (IL-1ß) expression in the peritoneal dialysate after healing of peritonitis can contribute to peritoneal deterioration. CASE PRESENTATION: A 64-year-old woman was diagnosed with diabetes mellitus 10 years ago and had been started on PD for end-stage renal disease. One day, the patient developed PD-associated acute peritonitis and was admitted to our hospital for treatment. Thus, treatment with antimicrobial agents was initiated for PD-associated peritonitis. Dialysate turbidity gradually disappeared after treatment with antimicrobial agents, and the number of cells in the PD fluid decreased. After 2 weeks of antimicrobial therapy, peritonitis was clinically cured, and the patient was discharged. Thereafter, the patient did not develop peritonitis; however, residual renal function tended to decline, and peritoneal function also decreased in a relatively short period. We evaluated pro-inflammatory cytokine levels before and after PD-associated peritonitis; interestingly, the levels of IL-1ß remained high in the PD fluid, even after remission of bacterial peritonitis. In addition, it correlated with decreased peritoneal function. CONCLUSIONS: This case suggests that inflammasome-derived pro-inflammatory cytokines may contribute to chronic inflammation-induced peritoneal deterioration after PD-related peritonitis is cured.

[Adjuvant Capecitabine for Residual Disease after Standard Neoadjuvant Chemotherapy Among Patients with Triple-Negative Breast Cancer].

CREATE-X trial demonstrated the effectiveness of additional capecitabine therapy in prolonging disease-free survival among patients who are HER2 negative, especially those with triple-negative breast cancer who had residual invasive disease after standard neoadjuvant chemotherapy. We investigated our data regarding adjuvant capecitabine for residual disease. Ten patients were enrolled, and the average age of the patients was 54.2 years. All patients completed 8 courses of treatment; all adverse events were Grade 2 or lower. Five-year disease-free survival rate was 70.0% in an average observation period of 40.9 months. Three patients recurred within 2 years, and all patients had brain metastasis. In the CREATE-X trial, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group; our results were same as those of CREATE-X. Brain metastasis may be detected by the early phase of enhanced brain MRI.

[Uncertainty Evaluation and Internal Quality Control of ELISA Test for Food Allergens (in Egg and Milk) Using Control Samples].

We evaluated measurement uncertainty and performed internal quality control of an ELISA test for allergens in egg and milk, using control samples. For the evaluation of measurement uncertainty, the following three important factors were identified: 1) Differences in test-kit lots, 2) Different-day reproducibility, 3) Same-time reproducibility. A three-stage nested design was used, and the combined standard uncertainty of the three factors mentioned above was calculated based on the results obtained. Measurement uncertainty was defined as the expanded uncertainty obtained by multiplying the combined standard uncertainty by a coverage factor of two. As a result, the expanded uncertainty of egg was 1.9 µg/g when the total egg protein concentration was 13.4 µg/g, and the expanded uncertainty of milk was 1.8 µg/g when the total milk protein concentration was 13.5 µg/g. For the internal quality control, we first set the reference range of the measured value of the control sample, using the obtained combined standard uncertainty as an index. Each control sample was then measured for every test, and we concluded that the test was performed without any errors, when the result of the control sample was within the reference range. Second, the measured values of the control samples were plotted on a graph for continuous monitoring. This enabled us to check whether inspection accuracy was maintained. There were no large chronological changes and no major differences between the standard deviations of the control samples and the combined standard uncertainty in egg or milk. Therefore, it was determined that the dispersion was at an acceptable range and inspection accuracy was maintained.

[A Case of Breast Carcinoma with Cartilaginous Differentiation and Distant Metastasis with Complete Response to Post-Operative Chemotherapy].

We report a case of breast cancer with cartilaginous differentiation that responded well to chemotherapy, which completely eliminated distant metastasis. A 63-year-old woman visited our hospital complaining of a large hemorrhagic mass measuring 15 cm in diameter with ulceration of the left breast. Palpation revealed swelling of the left axillary and right supraclavicular (SC)lymph nodes, suggesting breast cancer metastasis. A CT scan revealed metastasis in the right lung measuring 2.5 cm in size. She underwent a total mastectomy with axillary dissection. The pathological findings were as follows; breast carcinoma with cartilaginous differentiation accompanied by a single lymph node metastasi(s 1/21)and skin involvement, ly0, v0, ER(-), PgR(-), HER2 0, Ki-67 80%. Four courses of AC therapy were administered as postoperative chemotherapy, which resulted in a decrease in the size of the SC lymph node to 1 cm. Subsequently, 12 courses of weekly paclitaxel yielded a complete response of the lung and SC lymph node metastasis. Oral administration of S-1 after paclitaxel therapy resulted in no recur- rence for 16 months after the operation.

[Ethinyl Estradiol Therapy for Postmenopausal Women with Heavily Pre-Treated Endocrine-Responsive Metastatic Breast Cancer].

Ethinyl estradiol(EE2)therapy has been reported to be an effective endocrine therapy for postmenopausal hormone receptor-positive advanced breast cancer, especially in the supposed acquired resistance state. The current study retrospectively investigated the efficacy and safety of EE2 therapy in postmenopausal women with hormone receptor-positive advanced breast cancer who had previously undergone multiple endocrine therapies. Twelve patients were enrolled; median lines of endocrine therapies were seven before EE2. Median PFS was 4.8 months and median overall survival was 10.0 months. Grade 3 adverse event comprised of anorexia in only one patient. EE2 therapy may be considered effective and safe in hormone receptor-positive advanced breast cancer even in late-stage endocrine therapy.

[HER2-Positive Breast Cancer with Severe Infusion Reaction to Pertuzumab plus Trastuzumab-A Case Report].

A 64-year-old woman detected a tumor in her left breast in July 2015, and the tumor became exposed and ulcerated in January 2016. Subsequently, the tumor began to bleed, and the patient was admitted to our hospital on an emergency basis in March 2016. A CT scan revealed the presence of a giant tumor in the left breast, accompanied by chest wall infiltration, left axillary lymph node metastasis, and multiple liver and bone metastases. Following needle biopsy, the specimen was diagnosed as Luminal-HER2-type invasive ductal carcinoma, and pertuzumab plus trastuzumab plus docetaxel was administered. Upon administration of 2/3 of the pertuzumab, the patient developed chills. Therefore, the administration rate was reduced; however, the patient experienced palpitations, nausea, tachycardia, and decreased blood pressure at the end of the administration. Pertuzumab was temporarily discontinued, a replenisher was infused, and the symptoms improved within approximately 20 minutes. However, the patient again experienced chills, tachycardia, and decreased blood pressure immediately after reinitiating trastuzumab administration and complained of strong pain at the tumor site. Continuation of chemotherapy was deemed dangerous, and administration was discontinued. It has been reported that infusion reactions to trastuzumab are associated with clinical stage. In this case, the symptoms of the infusion reaction were severe because of the large tumor volume. It is necessary to consider administration of premedication and the administration time of anti-HER2 drugs in cases with high tumor burden such as the current case.

[Bevacizumab plus Paclitaxel Therapy Was Effective for Metastatic Breast Cancer with Dysphagia Due to Mediastinal Lymph Node Metastasis-A Case Report].

A 69-year-old woman noticed a tumor of the right breast, and presented to our hospital with dysphagia. A tumor of size 10 cm exposed to the skin and swollen axillary lymph node were observed. She was diagnosed with invasive ductal carcinoma, luminal-B by core-needle biopsy. CT scan revealed primary breast cancer with lung, bone, and lymph node metastasis. Endoscopic and fluoroscopic findings of the esophagus showed severe stenosis by extrinsic compression. In order to improve the quality of life(QOL)immediately, bevacizumab plus paclitaxel therapy was initiated. After the first course, the dysphagia improved, and she was able to take normal meals after 2 courses of treatment. Primary tumor and metastatic lesions had remarkably shrunk on CT scan. After 4 courses of treatment, we changed to endocrine therapy and continued outcome treatment. Bevacizumab was effective for immediate improvement of QOL in such as an oncologic emergent case of metastatic breast cancer.

[Treatment Out Come of Eribulin in Patients with Advanced or Metastatic Breast Cancer Who Resistant to Anthracycline and Taxane].

PATIENTS AND METHODS: This retrospective observational study contains advanced or metastatic breast cancer female patients who pretreated with anthracycline and/or taxane received eribulin(ERI)mesylate. The primary endpoint was the progressionfree survival(PFS)and secondary endopoints were objective response rate(ORR), clinical benefit rate(CBR), overall survival (OS), and post-progression survival(PPS). RESULTS: A total of 32 patients underwent chemotherapy cycles(median 3; range 1-9 cycles). The ORR was 15.6% and the CBR was 31.3%. The median PFS, OS and PPS were 2.9 months, 8.5 months, 5.6 months respectively. The OS, PPS for relative dose intensity(RDI)<85% and RDI≥85% were 7.2 months, 3.4 months and 14.5 months, 11.4 months, respectively(p=0.005, 0.004). In multivariate analysis for OS and PPS, the visceral disease, total dose of ERI and RDI correlated with OS and PPS. The most frequent treatment-related Grade 3/4 adverse events was neutropenia( 56%). No Grade 3 and 4 peripheral sensory neuropathy was occurred. CONCLUSIONS: ERI exhibited efficacy and tolera- bility in patients with heavily pretreated A/MBC. The total dose and RDI of ERI would induce favorable effect for prognosis.

[Ethinylestradiol Following Everolimus plus Exemestane Was Effective in Postmenopausal Endocrine-Responsive Metastatic Breast Cancer - A Case Report].

A 71-year-old woman diagnosed with left breast cancer underwent mastectomy and axillary dissection in 1987. Pathological findings showed invasive ductal carcinoma that was ER and PgR positive and HER2 negative.5 -FU and tamoxifen were administered for 2 years as adjuvant therapy.Bone metastasis was found in 2002, and endocrine therapy was started, using anastrozole, exemestane, letrozole, medroxyprogesterone acetate, and fulvestrant.However, liver, lung, pleural, penetiral, and lymph-node metastases were observed, and the following chemotherapy regimen was administered: CAF, capecitabine, paclitaxel, vinorelbine, gemcitabine, methotrexate plus mitomycin C, and eribulin.Then, estrogen therapy with ethinylestradiol( EE2)was started in December 2013.T he pleural effusion disappeared and the liver metastases were reduced.After 11 months of progression-free survival(PFS), regrowth of the liver metastases was seen.Thus, everolimus plus exemestane was administered, and approximately 8 months of PFS was obtained.Therefore, both EE2 and everolimus are effective therapy even for heavily pretreated metastatic breast cancer.

Advantages of IP over elastic optical networks using multi-flow transponders from cost and equipment count aspects.

To evaluate the cost efficiency of IP over elastic optical network architectures, we use a multi-layer network design scheme that covers network to node equipment level. An evaluation in a static traffic environment shows that the multi-flow optical transponder-based elastic optical network reduces total cost as well as equipment counts compared to other elastic network models based on fixed-rate, mixed-line-rate and bandwidth-variable transponders.

A novel elastic optical path network that utilizes bitrate-specific anchored frequency slot arrangement.

We propose a novel elastic optical path network where each specific bitrate signal uses its own dedicated fixed grid and one edge of its frequency grid is anchored at a specific frequency. Numerical evaluations using various bitrate signal patterns and network topologies show that the network proposal can almost match the performance of conventional flexible grid networks, while greatly mitigating the hardware requirements: it allows the use of the tunable filters for the fixed grid systems.

Determination of hydrophobicity of dry-heated wheat starch granules using sucrose fatty acid esters (SFAE).

Sucrose fatty acid esters (SFAE) were adsorbed onto dry-heated (120 °C for 10, 20, 40, 60, and 120 min) wheat starch granules and extracted with ethyl ether in a Soxhlet apparatus without gelatinization of the starch granules. The amount of sucrose in the extracted SFAE was determined by the phenol sulfate method. A gradual increase of the sucrose from 159 to 712 µg, in SFAE per gram of starch, occurred with increasing dry-heating time and demonstrated the increased hydrophobicity of the starch granules. Increase of the SFAE was highly correlated (r = 0.9816) to increase of the oil-binding capacity of the dry-heated wheat starch granules. Non-waxy rice, waxy rice, sweet potato, and potato starch granules also showed higher hydrophobicity after dry-heating by this method.

Theobromine enhances absorption of cacao polyphenol in rats.

Several concentrations of theobromine (TB) and (-)-epicatechin (EC) were coadministered to rats, and plasma EC and its metabolites were determined using ultra-high-performance liquid chromatography-tandem mass spectrometry. It has been demonstrated that TB increases the absorption of EC in a dose-dependent manner. Cocoa powder had a similar effect, and the mechanism involved is not thought to depend on tight junctions.

Usefulness of the Palliative Prognostic Index in Predicting Prognosis when Considering the Transition from Hospital to Home Care in Patients with Terminal Stage Cancer.

BACKGROUND: No accurate prognostic tool is available for patients with cancer who spend their final days at home. In this study, we examined whether performance status (PS) and the palliative prognostic index (PPI), a well-known prognostic tool in palliative care units, could be used to predict prognosis in the home care setting at the time of intervention by home physicians. SUBJECTS AND METHODS: Using medical records, we conducted a retrospective analysis of 132 patients who were referred to the Home Clinic Naginoki for home care for terminal stages of carcinoma in situ. Based on the status at the time of the first visit, the PPI-Low group was defined as those scoring six or below and the PPI-High group as those scoring greater than six. RESULTS: The PPI-high group had a significantly poorer prognosis within 21 days than the PPI-low group (21-day-OS; Low 71.4% vs. High 13.2%; p<0.001). The Eastern Cooperative Oncology Group (ECOG) PS alone predicted better prognosis in the group with PS of one or two (21-day survival 90.1%), and the PPI score further significantly stratified the prognosis for patients with PS three or four, with a trend toward poor prognosis (p ≤ 0.005). CONCLUSION: ECOG PS 1 or 2 has a favorable prognosis and that using PPI in ECOG PS 3 or 4 leads to a more accurate prognosis prediction. PPI evaluated during the hospital-based treatment of patients with terminal cancer can also be used to predict prognosis if the patient is transitioned to a home care environment.

ASK-1 activation exacerbates kidney dysfunction via increment of glomerular permeability and accelerates cellular aging in diabetic kidney disease model mice.

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD.

Metastable atomic-ordered configurations for Al1/2Ga1/2N predicted by Monte-Carlo method based on first-principles calculations.

Metastability of Aln/12Ga1-n/12N (n= 2-10: integer) with the 1-2 monolayer (ML) in-plane configuration towards thec[0001] direction has been demonstrated recently. To theoretically explain the existence of these metastable structures, relatively large calculation cells are needed. However, previous calculations were limited to the use of small calculation cell sizes to estimate the local potential depth (Δσ) of ordered Al1/2Ga1/2N models. In this work, we were able to evaluate large calculation cells based on the interaction energies between proximate Al atoms (δEAl-Al) in AlGaN alloys. To do this,δEAl-Alvalues were estimated by first-principles calculations (FPCs) using a (5a1× 5a2× 5c) cell. Next, a survey of the possible ordered configurations using various large calculation cell models was performed using the estimatedδEAl-Alvalues and the Monte-Carlo method. Then, various Δσvalues were estimated by FPCs and compared with the configurations previously reported by other research groups. We found that the ordered configuration obtained from the (4a1× 2a2× 1c) calculation cell (C42) has the lowest Δσof -9.3 meV/cation and exhibited an in-plane configuration at thec(0001) plane having (-Al-Al-Ga-Ga-) and (-Al-Ga-) sequence arrangements observed along them11-00planes. Hence, we found consistencies between the morphology obtained from experiment and the shape of the primitive cell based on our numerical calculations.

A comparison of indocyanine green fluorescence imaging plus blue dye and blue dye alone for sentinel node navigation surgery in breast cancer patients.

PURPOSE: To evaluate two methods of sentinel node navigation surgery (SNNS) using blue dye with and without indocyanine green (ICG) fluorescence imaging (FI) to determine the usefulness of combined ICG and blue dye. METHODS: Between 2005 and 2010, a total of 501 patients underwent SNNS in our hospital. Detection of sentinel lymph node (SLN) was performed with sulfan blue (SB) alone until 2008 and with a combination of SB and ICG-FI since 2009. ICG 5 mg and SB 15 mg were injected in the subareolar region, and FI was obtained by a fluorescence imaging device. RESULTS: We attempted to identify SLNs in 393 patients by SB alone and in 108 patients by a combination of SB and FI. The mean number of SLNs detected was 1.6 (0-5) for SB alone and 2.2 (1-6) for the combination method. The SLN identification rate was 95.7 % for SB alone and 100 % for the combination method so that the combination was significantly superior to SB in terms of the identification rate (p = 0.0037). In patients who received the combination method, detection of SLN was made through only SB in 1 patient, only ICG in 8 patients, and both in 99 patients. Lymph node metastasis was found in 56 patients with SB alone and in 16 patients with the combination method. Recurrence of an axillary node was observed in 3 patients (0.8 %) with SB alone and in no patients with the combination method. CONCLUSIONS: ICG-FI is a useful method and is especially recommended in cases where no radiotracers are available.