Real-world evidence of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer using an administrative claims database in Japan.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting. MATERIALS AND METHODS: This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI + BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment. RESULTS: Eligible population was 2369 for the FTD/TPI + BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI + BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR) = 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI + BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs = 0.68). Median TTD was 3.3 months for the FTD/TPI + BEV group and 1.8 months for the control group in the PSM population (P < 0.001). CONCLUSIONS: Real-world data showed that FTD/TPI + BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI + BEV can be a favorable regimen for refractory mCRC.

Unusual diagnosis of feline cardiac lymphoma using cardiac needle biopsy.

BACKGROUND: Cardiac tumors in cats are relatively rare, with lymphoma accounting for more than half of all cases. However, feline cardiac lymphoma is often diagnosed post-mortem, and it is difficult to diagnose while the cat is still alive. It is the first report of a direct, rather than estimative, diagnosis with cardiac needle biopsy of a living cat with cardiac lymphoma. CASE PRESENTATION: A 3-year-old domestic short-haired male cat experienced loss of energy and loss of appetite. Thoracic radiography and transthoracic echocardiography showed cardiomegaly with slight pleural effusion and cardiac tamponade due to pericardial effusion, respectively. In addition, partial hyperechoic and hypertrophy of the papillary muscle and myocardium were observed. Blood test showed an increase in cardiac troponin I levels. Pericardial fluid, removed by pericardiocentesis, was analyzed; however, the cause could not be determined. With the owner's consent, pericardiectomy performed under thoracotomy revealed a discolored myocardium. Cardiac needle biopsy was performed with a 25G needle, and a large number of large atypical lymphocytes were collected; therefore, a direct diagnosis of cardiac lymphoma was made. Pathological examination of the pericardium diagnosed at a later date revealed T-cell large cell lymphoma. The cat underwent chemotherapy followed by temporary remission but died 60 days after the diagnosis. Postmortem, two-dimensional speckle-tracking echocardiography (data when alive) revealed an abnormal left ventricular myocardial deformation, which corresponded to the site of cardiac needle biopsy. CONCLUSIONS: This rare case demonstrates that cardiac lymphoma should be added to the differential diagnosis in cats with myocardial hypertrophy and that the diagnosis can be made directly by thoracotomy and cardiac needle biopsy. In addition, the measurement of cardiac troponin I levels and local deformation analysis of the myocardium by two-dimensional speckle-tracking echocardiography may be useful in the diagnosis of cardiac tumors.

Effect of batch size on the granule properties in planetary centrifugal granulation.

A granulation method using a planetary centrifugal mixer, called planetary centrifugal granulation, has been developed for small-scale production, such as extemporaneous preparation in pharmacies. Although the impact of its operational parameters on granulation is described, the scale effect has not been investigated. Therefore, we aimed to reveal the effects of vessel size and vessel filling rate on granule properties. In this study, ibuprofen 20% granules consisting of lactose, cornstarch, sodium carmellose, and talc were used as model granules. Granulation was performed using geometrically similar containers, 6-58 mL, with a filling rate of 20-70%. After granulation, we monitored the granule properties, for example, median diameter (d50), span of particle size distribution, and sphericity. At filling rates of 40% and 50% in the 58-mL vessel, the granules grew larger in diameter, and at a rate of 30%, the granules showed a higher sphericity. When the filling rate was 30%, d50 became larger and the span decreased as the vessel size increased. The yields of the granules were higher than 95% when using the 12-58 mL vessel. Lastly, the drug content uniformity and drug dissolution behavior of the granules produced in different vessel size were examined. The granules showed similar drug consistencies and drug dissolution profiles. In conclusion, the quality of the products was not affected by changes in vessel size. Thus, pharmacists could prepare and compound the granule formulations with high yield and appropriate quality using an adequate vessel in the same manner.

Impact of the 12-gene recurrence score assay on deciding adjuvant chemotherapy for stage II and IIIA/B colon cancer: the SUNRISE-DI study.

BACKGROUND: Recent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection. PATIENTS AND METHODS: Patients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 : 1. RESULTS: Overall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P = 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001). CONCLUSION: Our study confirmed the usefulness of the 12-RS assay in aiding the physician-patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer.

Phase II study of trifluridine/tipiracil plus bevacizumab by RAS mutation status in patients with metastatic colorectal cancer refractory to standard therapies: JFMC51-1702-C7.

BACKGROUND: Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. PATIENTS AND METHODS: Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. RESULTS: Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. CONCLUSIONS: FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.

REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients.

BACKGROUND: The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. RESULTS: One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. CONCLUSIONS: The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.

Correction to: Age-related normative values of trabecular bone score (TBS) for Japanese women: the Japanese Population-based Osteoporosis (JPOS) study.

I have, as the Principal Investigator of this study, identified an error in the computation of TBS values in the JPOS cohort, which resulted in the publication of incorrect TBS absolute values [1]. This error was linked to the calibration process for calculating standardized TBS values in the R&D TBS.

PCR-based clonality analysis of antigen receptor gene rearrangements in canine cutaneous plasmacytoma.

Plasmacytomas are discrete, B cell-derived, round cell tumours that sometimes are difficult to distinguish from canine cutaneous histiocytomas or T cell lymphosarcomas (lymphomas). Diagnosis of plasmacytomas relies on morphological observations and immunohistochemistry for multiple myeloma oncogene-1 (MUM-1) and cluster of differentiation 3 (CD3). Clonality testing often is used as an adjunct diagnostic tool to examine lymphoproliferative diseases. In this study, the sensitivity of PCR-based clonality analysis of antigen receptor gene rearrangements in canine cutaneous plasmacytomas was determined. Formalin-fixed paraffin-embedded sections of 29 canine plasmacytomas, 23 diffuse large B cell lymphomas (DLBCLs) and 23 lymph nodes without lymphoma were used for clonality analysis. New oligonucleotide primers for the framework (FR)2 and FR3 regions of the immunoglobulin heavy chain (IGH) V gene subgroup 3 were designed and used with previously reported FR3 primers. Although plasma cells are of B cell lineage, the detected frequency of IGH clonality in plasmacytoma was 0-34.5% with the seven primers used, whereas in DLBCLs it was 8.7-78.3%. In 23 lymph nodes without lymphoma, IGH clonality was detected in only one case with two out of the seven primers used. Sequence analysis of PCR products from plasmacytomas revealed mismatches in the annealing region of the FR3 primers. The sensitivity of detecting IGH clonality in canine plasmacytomas was lower than in DLBCLs. The low detection rate of IGH clonality in canine plasmacytoma may be due to somatic hypermutation of the variable region.

Evaluation of the molecular lipid organization in millimeter-sized stratum corneum by synchrotron X-ray diffraction.

BACKGROUND: The aim of this study was to investigate whether the lamellar and lateral structure of intercellular lipid of stratum corneum (SC) can be evaluated from millimeter-sized SC (MSC) by X-ray diffraction. MATERIALS AND METHODS: A 12 mm × 12 mm SC sheet from hairless mouse was divided into 16 pieces measuring 3 mm × 3 mm square. From another sheet, 4 pieces of ultramillimeter-sized SC (USC:1.5 mm × 1.5 mm square) were prepared. Small and wide-angle X-ray diffraction (SAXD and WAXD) measurements were performed on each piece. For MSC and USC, changes in the lamellar and lateral structure after the application of d-limonene were measured. RESULTS: The intensity of SAXD peaks due to the lamellar phase of long periodicity phase (LPP) and WAXD peaks due to the lateral hydrocarbon chain-packing structures varied in MSC and USC pieces, although over the 12 mm × 12 mm SC sheet. These results indicated that the intercellular lipid components and their proportion appeared nearly uniform. Application of d-limonene on MSC and USC piece with strong peaks in SAXD and the WAXD resulted in the disappearance of peaks due to the lamellar phase of LPP and decrease in peak intensity for the lateral hydrocarbon chain-packing structures. These changes are consistent with normal-sized sample results. CONCLUSION: We found that the selection of a sample piece with strong diffraction peaks due to the lamellar and lateral structure enabled evaluation of the SC structure in small-sized samples by X-ray diffraction.

Gallbladder Agenesis in 17 Dogs: 2006-2016.

BACKGROUND: Gallbladder agenesis (GBA) is extremely rare in dogs. HYPOTHESIS/OBJECTIVES: To describe the history, clinical signs, diagnosis, treatment, and outcomes of dogs with GBA. ANIMALS: Seventeen client-owned dogs with GBA. METHODS: Medical records from 2006 through 2016 were retrospectively reviewed. Dogs were included when GBA was suspected on abdominal ultrasonography and confirmed by gross evaluation. Signalment, clinical signs, clinicopathological data, diagnostic imaging, histopathology, treatment, and outcome were recorded. RESULTS: Dogs were of 6 different breeds, and Chihuahuas (10 of 17) were most common. Median age at presentation was 1.9 (range, 0.7-7.4) years. Clinical signs included vomiting (5 of 17), anorexia (2 of 17), ascites (2 of 17), diarrhea (1 of 17), lethargy (1 of 17), and seizures (1 of 17). All dogs had increased serum activity of at least 1 liver enzyme, most commonly alanine aminotransferase (15 of 17). Fifteen dogs underwent computed tomography (CT) cholangiography; common bile duct (CBD) dilatation was confirmed in 12, without evidence of bile duct obstruction. Gross evaluation confirmed malformation of the liver lobes in 14 of 17 dogs and acquired portosystemic collaterals in 5 of 17. Ductal plate malformation was confirmed histologically in 16 of 17 dogs. During follow-up (range, 4-3,379 days), 16 of 17 dogs remained alive. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with GBA exhibit clinicopathological signs of hepatobiliary injury and hepatic histopathological changes consistent with a ductal plate abnormality. Computed tomography cholangiography was superior to ultrasound examination in identifying accompanying nonobstructive CBD distention. Computed tomography cholangiography combined with laparoscopic liver biopsy is the preferable approach to characterize the full disease spectrum accompanying GBA in dogs.

Impact of surgical margins on survival of 37 dogs with massive hepatocellular carcinoma.

AIMS: To compare the survival of dogs with completely resected massive hepatocellular carcinoma (HCC) with that of dogs in which HCC were incompletely excised. METHODS: A retrospective cohort study was conducted. Dogs that underwent surgical excision of massive HCC between November 2006 and April 2015 were included. Dogs that died in the perioperative period or were lost to follow-up within 2 months after surgery were excluded. Data were collected from the medical records and a single pathologist examined all available histology slides to confirm the diagnosis of HCC. Surgical margins were defined as complete if no neoplastic cells were seen at the edge of excised tissues, based on original histopathology reports. Progression-free survival (PFS) and overall survival (OS) were compared between dogs with complete surgical margins (CM) and those with incomplete margins (IM) using a log-rank test. RESULTS: Of the 37 dogs included in the study, 25 were allocated to the CM group and 12 to the IM group. Progressive local disease developed after surgery in three dogs in the CM group and seven dogs in the IM group. Three dogs in the CM group and five dogs in the IM group died due to tumour progression. Median PFS was longer for dogs in the CM group (1,000 (95% CI=562-1,438) days) compared to dogs in the IM group (521 (95% CI=243-799) days; p=0.007). OS was also longer for dogs in the CM group (>1,836 days) compared to those in the IM group (median 765 (95% CI=474-1,056) days; p=0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with complete resection, incomplete resection decreased PFS and OS in dogs with massive HCC. Dogs with incompletely excised HCC should be closely monitored for local recurrence, although median OS was >2 years following incomplete excision. Further prospective studies are warranted to confirm these findings.

Localization of Toll-like Receptor (TLR) 2 and TLR4 mRNA in the Colorectal Mucosa of Miniature Dachshunds with Inflammatory Colorectal Polyps.

Inflammatory colorectal polyps (ICRPs) are characterized by the formation of multiple or solitary polyps with marked neutrophil infiltration in the colorectal area, and are speculated to be a novel form of breed-specific canine idiopathic inflammatory bowel disease (IBD). In human IBD, toll-like receptor (TLR) 2 and TLR4 have been reported to be involved in the pathogenesis of the disease. The aim of this study was to evaluate the expression of TLR2 and TLR4 mRNA in the colorectal mucosa of dogs with ICRPs by in-situ hybridization using an RNAscope assay. Samples of inflamed colorectal mucosa (n = 5) and non-inflamed mucosa (n = 5) from miniature dachshunds (MDs) with ICRPs and colonic mucosa from healthy beagles (n = 5) were examined. TLR2 and TLR4 hybridization signals were localized to the colorectal epithelium, inflammatory cells and fibroblasts in the inflamed colorectal mucosa of affected dogs. The signals were significantly greater in inflamed colorectal epithelium compared with non-inflamed epithelium of MDs with ICRPs and healthy beagles (P <0.05). These results suggest that increased expression of TLR2 and TLR4 mRNA in the inflamed colorectal mucosa results from not only inflammatory cell infiltration, but also the upregulation of TLR2 and TLR4 mRNA in the colonic epithelium.

Amyloid-Producing Odontogenic Tumors of the Facial Skin in Three Cats.

Amyloid-producing odontogenic tumors (APOTs) of the facial skin were diagnosed in 3 domestic cats. The neoplasms had the histopathological characteristics of the odontogenic tumor. The neoplastic cells were present in irregular islands, strands, and sheets. The peripheral neoplastic cells of the islands and strands were arranged in a palisading fashion, while the central cells were polyhedral to stellate and randomly arranged. Multiple spherules of homogeneous eosinophilic material were closely apposed to the neoplastic epithelial cells. The spherules stained with Congo red and produced an apple green birefringence under polarization microscopy, indicative of amyloid. Immunohistochemically, amyloid materials of the neoplasms reacted with polyclonal antibodies for ameloblastin, amelogenin, and sheathlin antibodies. Neoplastic epithelial cells also reacted with antiameloblastin, amelogenin, and sheathlin antibodies, with varied intensity. The histopathological and immunohistochemical characteristics of dermal neoplasms of the 3 cats were analogous to those of APOTs reported in the dog and the cat.

Effect of hypoxia on UDP-glucuronosyl transferase mRNA expression in human hepatocarcinoma functional liver celL4 cell line.

Although hypoxic conditions have been reported to affect the expression levels of various enzymes like cytochrome P450, the effect of hypoxia for UDP-glucuronosyl transferase (UGT) expression has been unclear. We evaluated the mRNA expression of UGTs (UGT1A1·1A6·1A9·2B7) in a functional liver cell-4 (FLC-4) cell line by three-dimensional culture under hypoxic conditions (37 °C, 1% O2, 5% CO2) fo 7 days. The mRNA expression of UGT1A1·1A6·1A9·2B7 decreased significantly after 3 days and that of UGT1A1·1A6·1A9 decreased significantly after 7 days. Hypoxic conditions affect the expression levels of UGT enzymes, thus the adjustment of dosage and interval should be considered in drug therapy that metabolized by UGT.

Analysis of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours.

The aim of this study was to determine the type and frequency of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours (GISTs) and investigate the association between the c-KIT mutation status and KIT immunohistochemical staining pattern. Mutations in exon 11 of c-KIT were examined in 46 formalin-fixed paraffin-embedded canine GISTs using PCR of genomic DNA and reverse transcription-PCR (RT-PCR) of cDNA. Exon 11 c-KIT mutations were detected in 15/46 (32.6%) cases by conventional PCR and 34/46 (73.9%) cases by RT-PCR; the mutation detection rate was significantly higher for RT-PCR (P = 0.004, Fisher's exact test). Ten different mutations, including deletion, internal tandem duplication and point mutations, were identified by RT-PCR. Immunohistochemistry was performed using an anti-KIT antibody; diffuse KIT staining was detected in the tumour cell cytoplasm in 32/46 (69.6%) cases and partial or stippled cytoplasmic staining of KIT was observed in 14/46 (30.4%) cases. Neither pattern was significantly associated with c-KIT exon 11 mutation status (P = 1.000, chi-square test). These data indicate that c-KIT exon 11 mutations occur frequently in canine GISTs, similar to human GISTs; however, there is no association between c-KIT mutations and the KIT expression pattern in canine GISTs. This study suggests that RT-PCR is more sensitive than conventional PCR for the detection of c-KIT mutations in canine GISTs.

Age-related normative values of trabecular bone score (TBS) for Japanese women: the Japanese Population-based Osteoporosis (JPOS) study.

UNLABELLED: Trabecular bone score (TBS), a surrogate measure of bone microarchitecture, represents fracture risk independently of bone density. We present normative TBS values from a representative population study of Japanese women. This database would enhance our understanding of trabecular bone microarchitecture and improve osteoporosis management. INTRODUCTION: TBS is a texture parameter that quantifies local variation in gray level distribution within dual-energy X-ray absorptiometry (DXA) images of the lumbar spine. While TBS is associated with fracture risk independently of areal bone mineral density (aBMD), normative TBS values have only been reported for Caucasian women. This study provides age-specific normative values of TBS from a representative sample of Japanese women. METHODS: We randomly selected 4,550 women aged 15-79 years from 7 areas throughout Japan. Women younger than 20 years and those with any medical history which might affect bone metabolism were excluded, and the remaining 3,069 with at least two assessable vertebrae from the first to the fourth vertebrae were subjected to analysis. TBS values were calculated from spine DXA images using TBS iNsight software (Med-Imaps, France). Age-related models of TBS were constructed using piecewise linear regression analysis. RESULTS: Participant age, body mass index (BMI), spine aBMD, and TBS (mean ± SD) were 48.7 ± 16.8 years, 22.9 ± 3.4, 0.888 ± 0.169 g/cm(2), and 1.187 ± 0.137, respectively. A three-piece linear regression model of TBS on age explained 70.7% of the total variance in TBS and comprised very small age-related changes in the youngest segment of the regression line, rapid loss in the middle segment, and small loss in the oldest segment. TBS was lower in Japanese women than in Caucasian women across all age ranges, with the difference increasing with age up through 65 years. CONCLUSIONS: The normative values of TBS for Japanese women presented here would enhance our understanding of trabecular bone microarchitecture and help improve the management of osteoporosis.

Modeling the nutrient removal process in aerobic granular sludge system by coupling the reactor- and granule-scale models.

We developed a model for nutrient removal in an aerobic granular sludge system. This model can quantitatively describe the start-up of the system by coupling a model for studying the population dynamics of the granules in the reactor (reactor-scale model) and a model for studying the microbial community structure in the granules (granule-scale model). The reactor-scale model is used for simulation for 10 days from the start, during which the granule size is relatively small; the granule-scale model is used after Day 10. The present approach proposes the output data of the reactor-scale model after 10 days as initial conditions for the granule-scale model. The constructed model satisfactorily describes experimental data in various spatial and temporal scales, which were obtained in this study by performing the anaerobic-aerobic-anoxic cycles using a sequencing batch reactor. Simulations using this model quantitatively predicted that the stability of nutrient removal process depended largely on the dissolved oxygen (DO) concentration, and the DO setpoint adaptation could improve the nutrient removal performance.

Mathematical modelling of spatio-temporal cell dynamics in colonic crypts following irradiation.

OBJECTIVES: Modelling the apoptotic process is essential for simulating and understanding tumour growth, as most tumour tissues carry mutations in apoptotic signalling pathways. Thus here, we have aimed to construct a mathematical model of colonic crypts that explicitly incorporates the apoptotic mechanism. METHODS: A murine colonic crypt was described as being a two-dimensional rectangular surface model. In this system, three types of cells with different proliferating and differentiating potentials migrate. Apoptosis was described as a process activated by irradiation that progresses in a stepwise manner. Parameter values in the model were determined to be consistent with experimental data for changes in the apoptotic cell ratio within murine transverse colonic crypts following irradiation. RESULTS: First, we constructed a model reproducing cell proliferation dynamics in normal murine colonic crypts; next, we applied the apoptotic mechanism to this model. As a result, we succeeded in simultaneous reproduction of both spatial and temporal changes in distribution of apoptotic cells in murine colonic crypts by determining parameter values in numerical simulations. Through this adjustment process, we were able to predict that stem cells and transit amplifying (TA) cells in each generation must react distinctly from each other, to apoptosis-inducing stimuli. CONCLUSIONS: We constructed a mathematical model with which we could quantitatively describe cell proliferative and apoptotic dynamics in a murine colonic crypt. Using this model, we were able to make novel predictions that sensitivity to apoptosis-inducing stimuli is dependent on cell type.

The effect of storage time on the release profile of dexamethasone dipropionate from admixtures of steroid and heparinoid ointments.

We examined the stability and release profiles of dexamethasone dipropionate (DDP) from admixtures by using an innovator ointment (Methaderm [IM]), two generic ointments (Promethasone [GP] and Mainvate [GM]), and a heparinoid ointment. The admixtures were prepared using a spatula and an ointment slab and were stored at room temperature. Microscopic and Fourier transform-Raman spectrometric analyses showed that crystallization of DDP in admixtures of IM after 1 week of storage occured. And DDP crystals in all admixtures of GP and GM were observed. DDP was not decomposed in the admixtures after storage. Cumulative DDP permeation across a silicone membrane in a 1-week storage sample of the IM system decreased with DDP crystallization and reached a plateau after 2 weeks. In the GP and GM systems, DDP permeation decreased after 1 week of storage and increased again after 2 and 4 weeks. Each admixture was separated into 3 phases (liquid, lower, and upper solid phases) by ultracentrifugation to determine the apparent solubility of DDP. The DDP contents in the upper solid phase of the IM admixtures at 1, 2, and 4 weeks were lower than that in the 0-week sample. No significant differences were observed in the DDP content between the liquid phases throughout the storage period. Therefore, the amount of DDP dissolved in the upper solid phase may influence DDP release from the IM admixtures. The GP and GM systems showed no significant differences in the apparent DDP solubility. These results indicate that the dispersion state of DDP in the tested admixtures may be altered with storage.

The clinical efficacy of dietary fat restriction in treatment of dogs with intestinal lymphangiectasia.

BACKGROUND: Intestinal lymphangiectasia (IL), a type of protein-losing enteropathy (PLE), is a dilatation of lymphatic vessels within the gastrointestinal tract. Dietary fat restriction previously has been proposed as an effective treatment for dogs with PLE, but limited objective clinical data are available on the efficacy of this treatment. HYPOTHESIS/OBJECTIVES: To investigate the clinical efficacy of dietary fat restriction in dogs with IL that were unresponsive to prednisolone treatment or showed relapse of clinical signs and hypoalbuminemia when the prednisolone dosage was decreased. ANIMALS: Twenty-four dogs with IL. METHODS: Retrospective study. Body weight, clinical activity score, and hematologic and biochemical variables were compared before and 1 and 2 months after treatment. Furthermore, the data were compared between the group fed only an ultra low-fat (ULF) diet and the group fed ULF and a low-fat (LF) diet. RESULTS: Nineteen of 24 (79%) dogs responded satisfactorily to dietary fat restriction, and the prednisolone dosage could be decreased. Clinical activity score was significantly decreased after dietary treatment compared with before treatment. In addition, albumin (ALB), total protein (TP), and blood urea nitrogen (BUN) concentration were significantly increased after dietary fat restriction. At 2 months posttreatment, the ALB concentrations in the ULF group were significantly higher than that of the ULF + LF group. CONCLUSIONS AND CLINICAL IMPORTANCE: Dietary fat restriction appears to be an effective treatment in dogs with IL that are unresponsive to prednisolone treatment or that have recurrent clinical signs and hypoalbuminemia when the dosage of prednisolone is decreased.