Pharmacist Interventions for Adverse Drug Reactions in Palliative Care: A Multicentre Pilot Study.

This study aimed to investigate adverse reactions to medications administered during palliative care and compare the responses of Board-Certified Pharmacists in Palliative Pharmacy (BCPPP) and non-BCPPP professionals. Methods: This multicentre prospective survey included hospital and community pharmacists who are members of the Japanese Society for Pharmaceutical Palliative Care and Sciences. Study participants included patients who experienced new drug reactions during the study period and responded to the requested survey items. The follow-up period for each eligible patient began on the day the pharmacists initiated the intervention and ended at discharge, death, or after one month of intervention. The primary endpoint was the impact of pharmacist intervention on adverse drug reactions. The pharmacists included in the study evaluated the severity of adverse drug reactions to assess the effect of their intervention using an integrated palliative care outcome scale before and after the intervention. Key findings: During the survey period, 79 adverse drug reaction intervention reports from 69 patients were obtained from 54 pharmacists (28 certified and 26 non-certified). The response rate was 1.62% (54/3,343). The management of palliative pharmacotherapy side effects by BCPPP and non-BCPPP significantly improved the patients' activities of daily living (P < 0.001). The BCPPP group intervened for significantly more patients with adverse drug reactions and overall adverse drug reactions than the non-BCPPP group (P < 0.023 and P < 0.013, respectively). Conclusion: BCPPP interventions can improve symptom management.

Egg laying performance and egg quality with Paracoccus carotinifaciens supplementation containing high astaxanthin levels.

1. This study assessed 1) the effects of Paracoccus carotinifaciens supplementation containing high astaxanthin levels on egg production performance and quality, 2) dynamics of carotenoids levels in the egg yolk and 3) taste of astaxanthin-rich egg yolk.2. Laying hens were fed diets containing different levels of P. carotinifaciens-derived astaxanthin (ASX; 0, 2, 4, 8, or 16 ppm) for 28 d (experiment 1) or a diet containing 16 ppm astaxanthin for 28 d followed by a 0 ppm astaxanthin diet for 28 days (experiment 2).3. Production performance, egg quality and egg yolk carotenoid levels were examined in experiment 1 (Ex1) and the dynamics of egg yolk carotenoid levels and egg yolk taste in experiment 2 (Ex2).4. ASX supplementation did not affect production performance or egg quality. ASX levels in the egg yolk became saturated after seven days of 16 ppm supplementation and decreased to less than one-tenth of the saturated levels seven days after supplementation cessation. Supplementation with 16 ppm ASX for 28 d did not affect egg yolk taste.5. Supplementation resulted in the production of ASX-rich eggs for a brief period without affecting production performance, egg quality or taste. Understanding the time taken for the incorporation of ASX into egg yolks is beneficial for value-added egg production and may help in minimising supplementation costs.

Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

First Description of the Fur of Two Cubs of Fossil Cave Lion Panthera spelaea (Goldfuss, 1810) Found in Yakutia in 2017 and 2018.

The first description of well-preserved fur of one male and one female cubs of the fossil cave lion Panthera spelaea (finds of 2017-2018, Semyuelyakh River, Yakutia, Russia) is presented in comparison with the fur of two cubs (a male and a female) of the extant African lion P. leo and adult lions of both species: the color, differentiation, configuration, microstructure, and internal design of hair of different categories are considered. The coat of the cave lion is similar but not identical to that of the African lion, because it contains a high thick undercoat of spiral-shaped thick and airy down hair. This difference is most pronounced in the cave lion cubs, in which, however, the fur is not differentiated to the same extent as in the adult. The microstructure of hair is species-specific and subject to intraspecific age-related variability. Adaptive features of the hair structure in the cave lion are noted.

Evaluation of an early-stage innovation for full-thickness excision of benign colonic polyps using the IDEAL framework.

AIMS: Colectomy is the current approach for patients with endoscopically unresectable benign polyps but risks considerable morbidity. Full-thickness laparoendoscopic excision (FLEX) is a novel procedure, specifically developed to treat endoscopically unresectable benign colonic polyps, which could reduce the treatment burden of the current approach and improve outcomes. However, traditional evaluations of surgical innovations lack methodological rigour. This study reports the development and feasibility of the FLEX procedure in selected patients. METHOD: A prospective development study using the Idea, Development, Evaluation, Assessment, Long-term study (IDEAL) framework was undertaken, by one surgeon, of the FLEX procedure in selected patients with endoscopically unresectable benign colonic polyps. Three-dimensional (3D)-CT colonography reconstructions were used preoperatively to rehearse patient-specific, critical manoeuvres. Targetted, full-thickness excision was performed: after marking the margin of the caecal polyp using circumferential endoscopic argon plasma coagulation, transmural endoscopic sutures were used to evert the bowel and resection was undertaken by laparoscopic linear stapling. Feasibility outcomes (establishing 'local success') included evidence of complete polyp resection without adverse events (especially safe closure of the excision site). RESULTS: Ten patients [median (interquartile range) age: 74 (59-78) years] with polyp median diameters of 35 (30-41) mm, were referred for and consented to receive the FLEX procedure. During the same time frame, no patient underwent colectomy for benign polyps. One further patient received FLEX for local excision of a presumed malignant polyp because severe comorbidity prohibited standard procedures. The FLEX procedure was successfully performed locally, with complete resection of the polyp and safe closure of the excision site, in eight patients. Three noncompleted procedures were converted to laparoscopic segmental colectomy under the same anaesthetic because of endoscopic inaccessibility (two patients) and transcolonic suture failure (one patient). CONCLUSIONS: The FLEX procedure is still under development. Early data demonstrate that it is safe for excision of selected benign polyps. Modifications to transcolonic suture delivery are now required and there is a need for wider adoption before more definitive evaluation can be performed.

Chemical properties of commercially available honey species and the functional properties of caramelization and Maillard reaction products derived from these honey species.

The chemical parameters and the functionalities of six monofloral honeys of different botanical and geographical origins were investigated. Vitamins B1, B2, and C and the protein content of majority of honeys were distinguishable from general honey. Honeys not only were rich in a variety of functional components like flavonoids but also had strong anti-oxidant activities, scavenging activities against ROS, and anti-hypertensive and anti-allergic activities. Honeys were heated at 100 °C for 24 h and their browning intensity during heating process was observed to vary with botanical origin. The functional properties of caramelization and maillard reaction (MR) products derived from honeys during heating were evaluated. The browning of honeys progressed regardless of honey species. Anti-oxidant activities and scavenging activities against superoxide and DPPH radicals of products drastically increased, but ACE and hyaluronidase activities gradually decreased with passage of heating time. It concluded that the products, mainly melanoidins, produced simultaneously to browning process in caramelization and MR contributed to the expression of its useful function.

Effects of peripheral administration of a Neuromedin U receptor 2-selective agonist on food intake and body weight in obese mice.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity. METHODS: Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain. RESULTS: We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS. CONCLUSION: Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.

Retrospective analysis of in vivo recovery and clearance during continuous infusion of recombinant factor VIII products: a single-institution study.

BACKGROUND: Continuous infusion (CI) of recombinant FVIII (rFVIII) concentrates has been reported as an effective and safe method to achieve haemostasis during major surgeries or severe bleeding events. For more effective and safer CI, better understanding of in vivo recovery (IVR) and clearance (CL) issues is imperative. OBJECTIVE: We investigated the following factors affecting IVR and CL using univariate and multivariate regression analyses during 47 CIs in 34 patients: rFVIII concentrate type, haemophilia severity, blood type, the presence of hepatitis C virus (HCV) or human immunodeficiency virus (HIV), age and body mass index (BMI). RESULTS: The mean IVR was 1.64 ± 0.49 IU dL-1 per IU kg-1 , and the mean CL during CI was 3.56 ± 1.57 mL h-1 kg-1 . The univariate and multivariate regression analyses showed that the CL of octocog alfa was significantly lower than that of rurioctocog alfa (P = 0.043 and 0.0034, respectively). There was a significant difference in BMI in the univariate and multivariate regression analyses (P = 0.0403 and 0.0376, respectively). CONCLUSIONS: This study indicated that CL during CI was potentially affected by the type of rFVIII concentrate used and BMI.

Combined effects of starvation and butyrate on autophagy-dependent gingival epithelial cell death.

BACKGROUND AND OBJECTIVE: Bacteria in the dental biofilm surrounding marginal gingival grooves cause periodontal diseases. Numerous bacteria within the biofilm consume nutrients from the gingival crevicular fluid. Furthermore, some gram-negative bacteria in mature dental biofilms produce butyrate. Thus, gingival epithelial cells in close proximity to mature dental biofilms are at risk of both starvation and exposure to butyrate. In the present study, we determined the combined effects of starvation and butyrate exposure on gingival epithelial cell death and the underlying mechanisms. MATERIAL AND METHODS: The Ca9-22 cell line was used as an in vitro counterpart of gingival epithelial cells. Cell death was measured as the amount of total DNA in the dead cells using SYTOX Green dye, which penetrates through membranes of dead cells and emits fluorescence when it intercalates into double-stranded DNA. AMP-activated protein kinase (AMPK) activity, the amount of autophagy, and acetylation of histone H3 were determined using western blot. Gene expression levels of microtubule-associated protein 1 light chain 3b (lc3b) were determined using quantitative reverse transcription-polymerase chain reaction. RESULTS: Butyrate-induced cell death occurred in a dose-dependent manner whether cells were starved or fed. However, the induction of cell death was two to four times higher when cells were placed under starvation conditions compared to when they were fed. Moreover, both starvation and butyrate exposure induced AMPK activity and autophagy. While AMPK inactivation resulted in decreased autophagy and butyrate-induced cell death under conditions of starvation, AMPK activation resulted in butyrate-induced cell death when cells were fed. Combined with the results of our previous report, which demonstrated butyrate-induced autophagy-dependent cell death, the results of this study suggest that the combination of starvation and butyrate exposure activates AMPK inducing autophagy and subsequent cell death. Notably, this combination markedly induced LC3B production and the induction was attenuated by AMPK inhibition. LC3B knockdown, in turn, significantly decreased butyrate-induced cell death. Therefore, AMPK-dependent LC3B induction apparently plays an important role in butyrate-induced cell death. There was a lack of correspondence between the levels of AMPK activation and LC3B induction; this may reflect the histone deacetylase-inhibitory capacity of butyrate on histone proteins. CONCLUSION: Taken together, starvation and butyrate exposure promote autophagy via AMPK signaling, while the histone deacetylase-inhibitory effects of butyrate alter chromatin to transcriptionally active state, resulting in strong LC3B induction and subsequent cell death. These findings may help improve the understanding of the cellular processes underlying periodontal disease initiation.

Compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis.

BACKGROUND: Mutations in FLG, which encodes profilaggrin, cause ichthyosis vulgaris (IV) and are an important predisposing factor for atopic dermatitis (AD). IV shows autosomal hemidominant (semidominant) inheritance, and patients with bi-allelic FLG mutations tend to have severe IV phenotypes. However, the effect of bi-allelic FLG mutations on AD incidence and severity remains a subject of controversy. OBJECTIVE: In this study, we studied individuals with bi-allelic null FLG mutations to elucidate the effect of bi-allelic FLG mutations on AD incidence and severity. METHODS: Six individuals with bi-allelic FLG null mutations from three families of IV/AD were investigated. We report the detailed clinical features of the individuals. The phenotype was confirmed by the clinical examinations and the severity of IV and AD was scored using ichthyosis score and Eczema Area and Severity Index (EASI). RESULT: It was found that five of the six patients had severe IV, and the remaining patient showed moderate IV. Two of the six had moderate AD and three of the six had mild AD. The remaining patient had no AD. CONCLUSION: Our results suggest that individuals with bi-allelic FLG mutations do not always have severe AD and confirm that not all individuals with bi-allelic FLG mutations have AD.

Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Investigation of in vitro parameters and fertility of mouse ovary after storage at an optimal temperature and duration for transportation.

STUDY QUESTION: How do the temperature and duration of storage affect ovaries during transportation? SUMMARY ANSWER: Fertility is reduced with the extension of the storage duration. WHAT IS KNOWN ALREADY: Live birth has been reported after ovarian transport overnight on ice before freezing ovarian tissue, but there have been no basic investigations of ovarian storage conditions focused on fertility. There are no guidelines on optimal ovarian storage conditions and the maximum storage time during transportation. STUDY DESIGN, SIZE AND DURATION: Experiments were performed using C57BL/6J mice. Ovaries of 4-week-old mice were harvested, stored at 4, 14, 37 °C or room temperature (RT) for 24 h, and subjected to histological examination. Next, ovaries were stored at 4 °C for 4, 8 or 24 h and subjected to histological examination. Then orthotopic transplantation of ovaries, stored at 4 °C for 4, 8 or 24 h, was performed in 6-week-old C57BL/6J mice, and fertility was assessed by in vitro fertilization and embryo transfer. Freshly harvested ovaries were used as controls for comparison with ovaries stored under the above-mentioned conditions and experiments were repeated at least three times. PARTICIPANTS/MATERIALS, SETTING AND METHODS: In experiments on the ovarian storage temperature, haematoxylin-eosin (HE) staining was performed for histological examination. In experiments on the storage duration, HE staining, the terminal deoxynucleotidyl transferase dUTP nick end labelling assay, Ki-67 staining and electron microscopy were performed, and the numbers of follicles were counted. Fertility was assessed from the number of oocytes, and the rates of fertilization, embryo development, implantation and live birth. MAIN RESULTS AND THE ROLE OF CHANCE: Histological changes were minimal after storage of ovaries at 4 °C for up to 24 h. At 4 °C, there were no significant changes in the number of MII oocytes, fertilization rate or blastocyst development rate with storage up to 24 h. The implantation rate was 82.7 ± 17.3% in the control group, while it was 82.2 ± 7.7, 14.6 ± 14.6 and 4.4 ± 4.4% after storage for 4, 8 or 24 h, respectively. After 8 or 24 h of storage, the implantation rate was significantly lower in than in the control group (P< 0.05). The rate of live pups was 24.8 ± 13.2% in the control group, while it was 23.9 ± 6.6, 4.2 ± 4.2 and 4.4 ± 4.4% after storage for 4, 8 or 24 h, respectively. After 8 or 24 h of storage, the rate of live pups was significantly lower than in the control group (P< 0.05). LIMITATIONS, REASONS FOR CAUTION: Further investigations are needed in mammals with ovaries of a similar size to human ovaries, and should include the assessment of fertility following transplantation of frozen and thawed ovaries. WIDER IMPLICATION OF THE FINDINGS: The present results suggest that prolonging the ovarian storage time reduces fertility in mice. Thus, ovaries should be frozen immediately after harvesting or transported as rapidly as possible to minimize damage. To allow young cancer patients to preserve fertility, regional medical centres need adequate ovarian tissue cryopreservation techniques. STUDY FUNDING/COMPETING INTERESTS: This study supported by Department of Obstetrics and Gynecology, St. Marianna University School of Medicine. The authors have no competing interests to declare.

Bombyx mori E26 transformation-specific 2 (BmEts2), an Ets family protein, represses Bombyx mori Rels (BmRels)-mediated promoter activation of antimicrobial peptide genes in the silkworm Bombyx mori.

E26 transformation-specific (Ets) family transcription factors are known to play roles in various biological phenomena, including immunity, in vertebrates. However, the mechanisms by which Ets proteins contribute to immunity in invertebrates remain poorly understood. In this study, we identified a cDNA encoding BmEts2, which is a putative orthologue of Drosophila Yan and human translocation-ets-leukemia/Ets-variant gene 6, from the silkworm Bombyx mori. Expression of the BmEts2 gene was significantly increased in the fat bodies of silkworm larvae in response to injection with Escherichia coli and Staphylococcus aureus. BmEts2 overexpression dramatically repressed B. mori Rels (BmRels)-mediated promoter activation of antimicrobial peptide genes in silkworm cells. Conversely, gene knockdown of BmEts2 significantly enhanced BmRels activity. In addition, two κB sites located on the 5' upstream region of cecropin B1 were found to be involved in the repression of BmRels-mediated promoter activation. Protein-competition analysis further demonstrated that BmEts2 competitively inhibited binding of BmRels to κB sites. Overall, BmEts2 acts as a repressor of BmRels-mediated transactivation of antimicrobial protein genes by inhibiting the binding of BmRels to κB sites.

Resting salivary flow independently associated with oral malodor.

BACKGROUND: Dryness of the oral cavity is considered one cause of oral malodor. However, it is unclear which of the factors regulating the wetness of the oral cavity are involved in oral malodor development. This study investigated the effects of salivary flow and oral mucosal moisture on oral malodor. METHODS: The study population comprised 119 patients (48 men and 71 women, mean age of 50.6 ± 15.4 years) with complaint of oral malodor. After the oral malodor level had been evaluated by the organoleptic test and gas chromatography, the rates of stimulated saliva and resting saliva and the moisture levels of the tongue and buccal mucosa were measured. The plaque index, bleeding on pocket probing, probing pocket depth, and tongue coating score were also assessed. Strong oral malodor was defined as an organoleptic test score of ≥3. RESULTS: The flow rate of resting saliva in women was significantly lower than in men. The flow rate of resting saliva and the moisture levels of the tongue and buccal mucosa showed significant negative correlations with age. The flow rate of resting saliva was significantly lower in patients with strong oral malodor than in those with no or weak oral malodor. The flow rate of stimulated saliva and the moisture levels of the tongue and buccal mucosa had no relationship with strong oral malodor. Logistic regression analysis showed that a ≥5-mm probing pocket depth with bleeding on pocket probing, an increased tongue coating score, and decreased resting salivary flow were strong explanatory factors in clinical findings for oral malodor. CONCLUSION: This study suggests that the flow rate of resting saliva is a significant modulating factor for oral malodor.

The features of clearance in recombinant factor IX (BeneFIX(®) ).

INTRODUCTION: Dosage adjustment is very important to perform continuous infusion (CI) of recombinant factor IX (rFIX) concentrates more effectively and economically, and clearance (CL) is strongly related to the infusion rate. However, previous reports have shown that the CL of rFIX concentrates varies widely (4.2-11.4 mL kg(-1) h(-1) ). AIM: The goal of this study was to gain a better understanding of the CL of the rFIX concentrate (BeneFIX(®) ) to precisely set the infusion rate of rFIX concentrates. METHODS: We estimated CLs by five different calculation approaches: from area under the blood concentration-time curve (AUC), from in vivo recovery (IVR) and half-life, from actual FIX activity value during CI, and from the simulation by one-compartment model in seven patients with haemophilia B. RESULTS: The mean CL calculated from AUC was 3.8 ± 0.4 mL kg(-1) h(-1) (range = 3.3-4.3 mL kg(-1) h(-1) ). CONCLUSION: The mean CL calculated from IVR and distribution half-life was 4.4 ± 0.4 mL kg(-1) h(-1) (range = 4.0-5.1 mL kg(-1) h(-1) ). The mean CL calculated from IVR and terminal half-life was 2.1 ± 0.5 mL kg(-1) h(-1) (range = 1.7-2.8 mL kg(-1) h(-1) ). The mean CL during CI was 4.9 ± 0.6 mL kg(-1) h(-1) (range = 4.2-5.6 mL kg(-1) h(-1) ). In addition, when we simulated the theoretical CL using a one-compartment model, the adjusted mean CL during CI was 4.8 ± 0.5 mL kg(-1) h(-1) (range = 4.0-5.4 mL kg(-1) h(-1) ). The CL obtained from distribution half-life was comparable to the CL during CI, while the CL calculated from terminal half-life did not reflect actual CL. Further, the rFIX concentrate was characterized by a one-compartment model under certain conditions.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.

Expression of B7-H3, a potential factor of tumor immune evasion in combination with the number of regulatory T cells, affects against recurrence-free survival in breast cancer patients.

BACKGROUND: In the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients. METHODS: We immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer. RESULTS: Positive B7-H3 expression was associated with shorter recurrence-free survival (RFS) (p = 0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS (p = 0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade (p = 0.003, p < 0.001, p = 0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs. CONCLUSIONS: B7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.