Patients triaged to neoadjuvant chemotherapy have higher rates of sarcopenia: An opportunity for prehabilitation.

OBJECTIVE: To compare baseline body composition measures (BCM), including sarcopenia, between patients with advanced epithelial ovarian cancer (EOC) undergoing primary cytoreductive surgery (PCS) versus neoadjuvant chemotherapy/interval cytoreductive surgery (NACT/ICS) and evaluate changes in BCM pre-NACT versus pre-ICS. METHODS: Patients with stage IIIC/IV EOC who underwent PCS or NACT with curative intent between 1/1/2012 and 7/31/2016 were included. Computed tomography scans were evaluated via a semi-automated program to determine BCM. Measures evaluated include skeletal muscle area (SMA), skeletal muscle density (SMD), skeletal muscle index (SMI), and skeletal muscle gauge (SMG). Sarcopenia was defined as SMI <39.0 cm2/m2. RESULTS: The study included 200 PCS patients and 85 NACT/ICS patients, of which 76 had both pre-NACT and pre-ICS scans. NACT patients were significantly more likely to be sarcopenic compared to PCS patients (40.0% vs 27.5%, p = 0.04). Mean SMA (107.3 vs 113.4 cm2, p = 0.004) and mean SMG (1344.6 vs. 1456.9 (cm2 x HU)/m2, p = 0.06) were lower in NACT patients. Among NACT/ICS patients, mean SMI significantly decreased -1.4 cm2/m2 (p = 0.005) at the time of surgery, resulting in a non-statistically significant increase in the percentage of sarcopenic patients from baseline (40.8% vs. 50.0%, p = 0.09). CONCLUSIONS: Sarcopenia is more common in patients with advanced EOC undergoing NACT compared to PCS when using an evidence-based triage system for triage decisions. Body composition changes significantly over the course of NACT. Sarcopenia may be an indicator of debility and another factor for consideration in treatment planning. Further research into body composition's effects on prognosis and altering sarcopenia is necessary.

Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment.

BACKGROUND: Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. OBJECTIVES: To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). METHODS: Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome. RESULTS: IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. CONCLUSIONS: Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.

The anti-inflammatory effect of 10-oxo-trans-11-octadecenoic acid (KetoC) on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide.

BACKGROUND: There is rapidly developing interest into the role of several anti-inflammatory agents to resolve inflammation in periodontal disease. A bioactive polyunsaturated fatty acid, 10-oxo-trans-11-octadecenoic acid (KetoC), is known to have various beneficial physiological effects; however, the effect of KetoC on inflammation remains unclear. Here, we investigated the effect of KetoC on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide, and explored the intracellular mechanism responsible for its anti-inflammatory effects. METHODS: RAW 264.7 cells were pre-treated with or without KetoC, and then stimulated with or without P. gingivalis lipopolysaccharide. Levels of tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-1ß were determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Specific antagonists for G protein-coupled receptor (GPR)40 and GPR120 were used to clarify the receptor for KetoC. The intracellular mechanism was investigated using western blotting analysis to separate nuclear and cytosolic NF-κB p65 protein. RESULT: KetoC (5 µmol/L) was not toxic to RAW 264.7 cells, and significantly reduced the expression of TNFα and IL-6 mRNA and protein, and IL-1ß mRNA. No protein production of IL-1ß was observed. Additionally, when bound to GPR120, KetoC trended to downregulate nuclear NF-κB p65 protein levels. However, the antagonist for GPR40 failed to diminish the action of KetoC. CONCLUSION: KetoC suppressed the proinflammatory cytokines TNFα, IL-6 and IL-1ß via NF-κB p65, by binding to its receptor GPR120. KetoC is a promising candidate in future studies as a bioactive anti-inflammatory agent in treating periodontal disease.

Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey.

BACKGROUND AND OBJECTIVES: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. MATERIAL AND METHODS: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high-sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-α, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). RESULTS: The concentrations of PCSK9 and hs-CRP were increased (P = .001 and .042, respectively), and the concentration of TBIL was decreased (P = .046), in subjects with periodontal disease (determined as a probing depth of ≥4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P = .038, .007, .002, and .049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of ≥4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized ß = .243, P = .040; standardized ß = -.443, P = .0002; respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth ≥ 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. CONCLUSION: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL.

CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 'gene desert', serve as important prognostic biomarkers in colorectal cancer.

BACKGROUND: 8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a 'gene desert' due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogene MYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC. PATIENTS AND METHODS: A total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts. RESULTS: The expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P = 0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P = 0.049 and 0.022, respectively) and OS (P = 0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04-6.06, P = 0.042) and a poor OS (HR:8.38, 95%CI: 2.68-37.0, P < 0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P = 0.034) and stage III (P = 0.001) CRC patients. CONCLUSIONS: Several lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC.

Pancreatic cysts: Diagnostic accuracy and risk of inappropriate resections.

BACKGROUND: Pancreatic cystic neoplasms (PCN) frequently undergo surgery, given malignant potential. Pancreatic cyst surgery is associated with significant rates of morbidity and mortality. It is crucial to accurately characterize these lesions pre-operatively to avoid unnecessary surgery in patients with benign pancreatic cysts. AIM: We aimed to assess the correlation between pre-operative (pre-op) diagnosis based on imaging and clinical presentation, and post-operative (post-op) diagnosis based on histopathology in patients undergone pancreatic cyst surgery. METHODS: From January 2000 to January 2012, we randomly selected 2000 patients with ICD-9 code 211.6 and 577.2. Amongst these we identified 281 patients undergone pancreas surgery. Patients with no pre-op imaging or non-cyst indication for surgery were excluded (n = 107). Imaging details, demographics, pre-operative physician diagnosis and histopathologic details of pancreatic cysts were recorded in 174 patients. RESULTS: There was a discrepancy between the pre- and post-operative pancreatic cyst diagnosis in 54 (31%) patients. There was no difference in the proportion of various imaging studies (CT, EUS or MRI) between patients with a correct and patients with an incorrect pre-op diagnosis. The pre-op diagnosis was confirmed at pathology in 87.5% of the presumed SCNs, in 80% of the presumed pseudocysts, in 73.3% of the presumed BD-IPMNs, in 66.7% of the presumed MD/mixed-IPMNs and in 53.6% of the presumed MCNs. The accuracy of the pre-operative diagnosis of presumed MCN was significantly lower compared to the non-MCN cysts (53.6% vs. 75%; p = 0.037). Fourteen percent of resections were performed for asymptomatic benign cysts, preoperatively suspected to be potentially pre-malignant cysts. CONCLUSION: In nearly 1 out of 3 patients undergone pancreas cyst surgery, there is a discrepancy between pre- and post-op diagnosis. Pre-op diagnosis of presumed MCN is more likely to be incorrect, compared to the other cysts.

Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin.

The density of intraepidermal nerve fibres has been shown to be higher in itchy dry skin than in healthy skin, suggesting that epidermal hyperinnervation is at least partly involved in peripheral itch sensitization. We investigated whether oral administration of milk-derived phospholipids (MPLs) would inhibit epidermal hyperinnervation in a mouse model of dry skin. We found that the number of intraepidermal nerve fibres was significantly lower in the MPL group than in the control group. Expression of nerve growth factor (NGF) levels in the epidermis was significantly decreased by oral administration of MPLs, whereas expression of semaphorin (Sema)3A, a nerve repulsion factor, was increased in the MPL group. These results suggest that dietary MPLs attenuate the penetration of nerve fibres into the epidermis by reducing epidermal NGF levels and increasing Sema3A level. Thus, dietary MPLs may have beneficial effects in the prevention and/or alleviation of dry skin-induced itch by reducing intraepidermal nerve fibre density.

Should sexual intercourse be avoided during the embryo transfer cycle? Life-threatening ruptured heterotopic pregnancy after single thawed embryo transfer: case report and review of the literature.

BACKGROUND: To report the life-threatening complication of a raptured heterotopic pregnancy occurring from thawed single embryo transfer. CASE REPORT: A 33-year-old woman underwent in vitro fertilization (IVF) under a step-up regimen. After oocyte collection, blastocysts were frozen, and a single frozen-thawed blastocyst was then transferred according to the natural cycle. On day 17 after embryo transfer, an intrauterine pregnancy was confirmed. On day 28, she complained of sudden abdominal pain and ultrasonography revealed marked fluid retention in the peritoneal cavity. Emergency laparoscopy was performed, revealing hemoperitoneum and a ruptured interstitial heterotopic pregnancy (HP), which was then resected laparoscopically. Because sexual intercourse had occurred shortly before the transfer, a HP comprising a spontaneous pregnancy and a pregnancy achieved by assisted reproductive technology was assumed. The fetus in the uterus survived and was delivered. CONCLUSION: In this case, however, despite the single embryo transfer during the natural-cycle frozen-thawed embryo transfer process, the risk of life-threatening complication as a HP as a consequence of spontaneous pregnancy after sexual intercourse remained.

Ligature-induced periodontitis in mice induces elevated levels of circulating interleukin-6 but shows only weak effects on adipose and liver tissues.

BACKGROUND AND OBJECTIVES: Our previous study demonstrated using an oral gavage model that Porphyromonas gingivalis could induce various inflammatory changes linked to periodontitis-associated systemic diseases by altering gut microbiota. A ligature-induced periodontitis model is similar to human periodontitis in various aspects: in both cases, alveolar bone resorption depends on oral bacterial load, and gingival tissue becomes infiltrated with inflammatory cells. Therefore, this model may be suitable for the analysis of bacterial burden and gingival tissue inflammation with changes related to systemic diseases. MATERIAL AND METHODS: Periodontal tissue destruction was induced by a 2 wk ligature placement around the bilateral maxillary second molar. We analyzed the expression profile of various genes in several tissues, levels of systemic inflammatory markers and induction of insulin resistance. In addition, we studied changes in gut microbiota composition and bacterial load in the oral cavity. RESULTS: Two weeks after ligature placement gingival inflammation was significantly induced with a disrupted gingival epithelial barrier and alveolar bone resorption accompanied by increased bacterial burden in the oral cavity. Gene expression analysis of the gingival tissue of ligated mice demonstrated that interleukin (Il)1b was significantly elevated and Il6 and Il17a tended to be higher in ligated mice than in untreated mice. Although serum IL-6 was significantly elevated and serum amyloid A tended to be higher in ligated compared to untreated mice, endotoxin levels did not differ between the two groups. Among the genes whose expressions are closely related to glucose and lipid metabolisms, only phosphoenolpyruvate carboxykinase 1 (Pck1) and acetyl-coenzyme A carboxylase alpha (Acaca) showed significant changes following ligature placement in the liver, with the former upregulated and the latter downregulated. However, insulin sensitivity did not change following ligature placement. Furthermore, ligature placement weakly affected the composition of gut microbiota and gene expression in the intestines. CONCLUSION: The results suggest that increased oral commensals and gingival inflammation have limited roles in the pathological changes to adipose and liver tissues, which are important organs whose dysfunctions contribute to the development of periodontitis-related systemic diseases.

The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-α or isoproterenol.

BACKGROUND: A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear. OBJECTIVE: We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation. METHODS: C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays. RESULTS: The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The ß-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes. CONCLUSION: Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.

ABCB1 polymorphisms predict imatinib response in chronic myeloid leukemia patients: a systematic review and meta-analysis.

Imatinib mesylate, a competitive tyrosine kinase inhibitor, is considered the first-line therapy drug for Ph+ chronic myeloid leukemia (CML). Three single-nucleotide polymorphisms (SNPs) in the ATP-binding cassette, subfamily B (MDR/TAP), member 1 gene (ABCB1/MDR1), c.1236C>T, c.2677G>T/A and c.3435C>T, have been shown to affect cellular transport/metabolism of imatinib. The associations between these SNPs and imatinib response in CML patients have been widely evaluated, but the results were inconsistent. To derive a conclusive assessment of the associations, we performed a meta-analysis by combining data from a total of 12 reports including 1826 patients. The results showed that the 2677G allele or 3435T allele predicted a worse response to imatinib in CML patients, whereas 1236CC genotype was associated with better response in CML patients from Asian region. In conclusion, this meta-analysis suggests that c.1236C>T, c.2677G>T/A and c.3435C>T can be served as predictive markers for the therapeutical use of imatinib in CML patients.

Atomic layer deposition of Y2O3 on h-BN for a gate stack in graphene FETs.

The combination of h-BN and high-k dielectrics is required for a top gate insulator in miniaturized graphene field-effect transistors because of the low dielectric constant of h-BN. We investigated the deposition of Y(2)O(3) on h-BN using atomic layer deposition. The deposition of Y(2)O(3) on h-BN was confirmed without any buffer layer. An increase in the deposition temperature reduced the surface coverage. The deposition mechanism could be explained by the competition between the desorption and adsorption of the Y precursor on h-BN due to the polarization. Although a full surface coverage was difficult to achieve, the use of an oxidized metal seeding layer on h-BN resulted in a full surface coverage.

Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner.

BACKGROUND AND OBJECTIVE: In periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism. MATERIAL AND METHODS: We stimulated the HGEC line, epi 4, with live or heat-killed P. gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1ß genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-κB (NF-κB). RESULTS: Resveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-κB translocation when cells were stimulated with heat-killed P. gingivalis. CONCLUSION: Resveratrol suppressed the inflammatory responses of P. gingivalis-stimulated HGECs, probably by inhibiting NF-κB signaling but independent of SIRT1.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing. RESULTS: A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients. CONCLUSIONS: Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects.

Blocking the CD40-CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.

The pharmacokinetics and safety profiles of belimumab after single subcutaneous and intravenous doses in healthy Japanese volunteers.

WHAT IS KNOWN AND OBJECTIVES: Belimumab is a recombinant human monoclonal antibody that binds and antagonizes the biological activity of soluble B-lymphocyte stimulator (BLyS) protein. BLyS appears to play a role in the pathogenesis of systemic lupus erythematosus, and the biological profile of belimumab suggests that it may have a therapeutic benefit in the treatment for the disease. In this healthy Japanese subjects study, we investigated the pharmacokinetics and safety of a single subcutaneous and intravenous injection of belimumab administered as a 200 mg/mL liquid formulation. METHODS: This was an open-label, randomized, parallel-group, single-dose study in healthy Japanese subjects. Each subject received a single intravenous infusion or a subcutaneous injection of 200 mg belimumab. The pharmacokinetic parameters and safety parameters including local tolerance (injection site), biomarkers, immunogenicity and adverse events were evaluated up to 70 days post-dosing. RESULTS: After a single intravenous or a subcutaneous administration of 200 mg belimumab, all 16 subjects completed the study. There were no serious adverse events or adverse events related to injection site reactions. All seven adverse events were considered mild or moderate in intensity and deemed unrelated to belimumab except for cellulitis following intravenous administration. The bioavailability of the single subcutaneous dose of 200 mg belimumab in the subjects was estimated to be 77·5%. Time to the maximum serum concentration after subcutaneous injection was 6·5 days (median). The geometric mean terminal half-life was comparable between the two administration routes (17·7 days intravenous and 15·9 days subcutaneous). Serum immunoglobulin G level decreased slightly after each treatment. No subjects were found to produce antibelimumab antibodies. WHAT IS NEW AND CONCLUSIONS: A favourable absolute bioavailability in healthy Japanese subjects was seen following a subcutaneous injection of 200 mg belimumab. Considering the intersubject variability, exposures were consistent with those previously observed in healthy non-Japanese subjects. Safety and biomarker data were also consistent with previous non-Japanese clinical studies.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Dental caries from a molecular microbiological perspective.

Dental caries results from an imbalance of the metabolic activity in the dental biofilm. The microbial communities of teeth have traditionally been studied by standard cultural approaches. More recently, cloning and sequencing of the 16S rRNA gene have been used to characterize the microbial composition of the oral biofilm, but the methodological limitations of this approach have now been recognized. Next-generation high-throughput sequencing methods have the potential to reveal the composition and functioning of the biofilm by means of metagenomic and metatranscriptomic analyses. Currently available high-throughput sequencing approaches are reviewed and discussed in relation to studying the biofilm associated with dental caries. Important in understanding the dynamic processes in caries is the metabolic activity of the biofilm; metabolome analysis is a new tool that might enable us to assess such activity. As caries is a localized disease, it is essential that biofilm samples are taken from precisely determined tooth sites; pooling samples is not appropriate. This paper presents the case that culture-based studies are important, but that the fullest understanding of the role of the biofilm in the caries process will only come from an integrated approach determining biological function and metabolic output.

Divalent cations enhance fluoride binding to Streptococcus mutans and Streptococcus sanguinis cells and subsequently inhibit bacterial acid production.

One preventive effect of topical fluoride application is derived from the fact that fluoride can inhibit bacterial acid production. Furthermore, divalent cations such as Ca(2+) and Mg(2+) increase the binding of fluoride to bacterial cells. These findings suggest that exposure of oral bacteria to fluoride in the presence of divalent cations increases fluoride binding to bacterial cells and subsequently enhances fluoride-induced inhibition of bacterial acid production. This study investigated the effects of fluoride exposure (0-20,000 ppm F) in the presence of Ca(2+) or Mg(2+) prior to glucose challenge on pH fall ability by bacterial sugar fermentation, as well as fluoride binding to bacterial cells by exposure to fluoride, and fluoride release from bacterial cells during bacterial sugar fermentation, using caries-related bacteria, Streptococcus mutans and Streptococcus sanguinis. The pH fall by both streptococci was inhibited by exposure to over 250 ppm F in the presence of Ca(2+) (p < 0.01), whereas in the presence of Mg(2+), the pH fall by S. mutans and S. sanguinis was inhibited after exposure to over 250 and 950 ppm F, respectively (p < 0.05). The amounts of fluoride binding to and released from streptococcal cells increased with the concentration of fluoride the cells were exposed to in the presence of Mg(2+), but were high enough even after 250 ppm F exposure in the presence of Ca(2+). The enhanced inhibition of acid production in the presence of divalent cations is probably due to the improved efficiency of fluoride binding to bacterial cells being improved via these divalent cations.

An observational, prospective study of monthly adalimumab therapy for disease maintenance in psoriasis patients: a possible new therapeutic option for good responders to the initial induction treatment.

BACKGROUND: While adalimumab is a mainstay of treatment for moderate to severe chronic plaque psoriasis, the data regarding optimal treatment intervals for therapeutic maintenance are limited. OBJECTIVE: We compared the clinical efficacy of biweekly maintenance administration of adalimumab with that of monthly treatment. METHODS: 17 psoriasis patients treated with adalimumab 40 mg every other week with initial loading dose of 80 mg until week 24 were assigned to the maintenance therapy with adalimumab 40 mg either every other week (n = 7), or every month (n = 10). The treatment efficacy was evaluated by the proportion of patients who achieved PASI 75 from the baseline at weeks 36, 48 and 60. There was no selection bias between the two groups. RESULTS: At week 24, all the patients except for one in each group achieved PASI 75. In both groups, all the patients who achieved PASI 75 at week 24 maintained PASI 75 responses at week 60. Regarding two patients who did not achieve PASI 75 at week 24, one biweekly treated patient experienced a gradual increase in therapeutic response while one monthly treated patient showed exacerbation after week 24. CONCLUSION: Monthly adalimumab treatment seems to be a reasonable treatment option for patients who responded well to initial standard adalimumab treatment for 24 weeks. Since there are several limitations in this study, including the number of patients, observation period, and patients' characteristics, large randomized controlled trials are needed to confirm these results.