Effects of butyrate supplementation on blood glucagon-like peptide-2 concentration and gastrointestinal functions of lactating dairy cows fed diets differing in starch content.

The objective of this study was to evaluate effects of butyrate supplementation on plasma concentration of glucagon-like peptide-2 (GLP-2), apparent total-tract digestibility, and responses to a grain challenge of lactating dairy cows fed diets differing in starch content. Eight Holstein cows averaging 58.6 ± 9.96 d in milk (4 primiparous cows fitted with rumen cannula and 4 multiparous intact cows) were blocked by parity and assigned to one of two 4 × 4 Latin squares balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments were dietary starch content [20.6 vs. 27.5%, respectively, for low starch (LS) and high starch (HS)] and butyrate supplementation (butyrate vs. control) with 21-d periods. Butyrate was provided as Gustor BP70 WS (Norel, S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary dry matter (providing butyrate at 1.1% of dietary dry matter), and control premix contained 70% wheat bran and 30% fatty acid mixture. Feeds, orts, and fecal samples were collected from d 17 to 19 to determine apparent total-tract nutrient digestibility. Blood and rumen fluid samples were collected on d 19. The baseline of dry matter intake (DMI) was determined as average DMI from d 17 to 19 for each cow, and cows were feed-restricted at 60% of the baseline DMI on d 20, and a grain challenge was conducted by providing steam-flaked corn grain at 0.6% of body weight, on an as-fed basis, in addition to each treatment diet on d 21, and blood and ruminal fluid samples were collected. The interaction of dietary starch content by butyrate supplementation was significant for plasma GLP-2 concentration, being greater for cows fed butyrate with the HS diet than those fed the other 3 diets. Cows fed butyrate increased n-butyrate concentration in the ruminal fluid and tended to increase dry matter and organic matter digestibility compared with the control. During the grain challenge, rumen endotoxin concentration increased over time and was higher for cows fed the HS diets compared with those fed LS diets. However, response variables related to inflammation were not affected by the grain challenge. However, serum haptoglobin, lipopolysaccharide-binding protein, and serum amyloid-A concentrations were greater for cows fed butyrate with the LS diet, but not for those fed the HS diet. These results indicate that butyrate supplementation may increase plasma GLP-2 concentration for cows fed HS diets, and total-tract digestibility regardless of dietary starch content. However, butyrate supplementation did not mitigate inflammation in this study.

Relationship between the length of the forefoot bones and performance in male sprinters.

Although recent studies have reported that the forefoot bones are longer in sprinters than in non-sprinters, these reports included a relatively small number of subjects. Moreover, while computer simulation suggested that longer forefoot bones may contribute to higher sprint performance by enhancing plantar flexor moment during sprinting, the correlation between forefoot bone length and sprint performance in humans has not been confirmed in observational studies. Thus, using a relatively large sample, we compared the length of the forefoot bones between sprinters and non-sprinters. We also examined the relationship between forefoot bone length and performance in sprinters. The length of forefoot bones of the big and second toes in 36 well-trained male sprinters and 36 male non-sprinters was measured using magnetic resonance imaging. The length of forefoot bones in the big and second toes was significantly longer in sprinters than in non-sprinters. After dividing the sprinters into faster and slower groups according to their personal best time in the 100-m sprint, it was found that the forefoot bone length of the second toe, but not that of the big toe, was significantly longer in faster group than in slower group. Furthermore, the forefoot bone length of the second toe correlated significantly with the personal best time in the 100-m sprint. This study supported evidence that the forefoot bones are longer in sprinters than in non-sprinters. In addition, this is the first study to show that longer forefoot bones may be advantageous for achieving superior sprint performance in humans.

Patient preference: a comparison of electronic patient-completed questionnaires with paper among cancer patients.

In this study, we compared cancer patients preference for computerised (tablet/web-based) surveys versus paper. We also assessed whether the understanding of a cancer-related topic, pharmacogenomics is affected by the survey format, and examined differences in demographic and medical characteristics which may affect patient preference and understanding. Three hundred and four cancer patients completed a tablet-administered survey and another 153 patients completed a paper-based survey. Patients who participated in the tablet survey were questioned regarding their preference for survey format administration (paper, tablet and web-based). Understanding was assessed with a 'direct' method, by asking patients to assess their understanding of genetic testing, and with a 'composite' score. Patients preferred administration with tablet (71%) compared with web-based (12%) and paper (17%). Patients <65 years old, non-Caucasians and white-collar professionals significantly preferred the computerised format following multivariate analysis. There was no significant difference in understanding between the paper and tablet survey with direct questioning or composite score. Age (<65 years) and white-collar professionals were associated with increased understanding (both P = 0.03). There was no significant difference in understanding between the tablet and print survey in a multivariate analysis. Patients overwhelmingly preferred computerised surveys and understanding of pharmacogenomics was not affected by survey format.

Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites.

BACKGROUND: Epstein-Barr virus (EBV)-associated T/natural-killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors. OBJECTIVES: To elucidate the prognostic factors of HV and HMB. METHODS: We studied clinicopathological manifestations, routine laboratory findings, anti-EBV titres, EBV DNA load and EBV-encoded gene expression, including expression of BZLF1, in 50 patients with classical HV (cHV), sHV, HMB only and HMB with HV (HMB + HV), and further analysed 30 patients who were available for follow-up. RESULTS: The median age of disease onset was 5 years (range 1-74). A follow-up study indicated that fatal outcomes were observed in three of eight patients with sHV, two of six patients with HMB only, and two of five patients with HMB + HV. The main causes of death were complications from haematopoietic stem-cell transplantation and multiorgan failure. There were no fatalities among the 11 patients with cHV. Univariate analysis revealed two poor prognostic indicators: (i) onset age > 9 years and (ii) the expression of an EBV-encoded immediate-early gene transcript, BZLF1 mRNA, in the skin lesions (P < 0·001 and P = 0·003, respectively). CONCLUSIONS: No prognostic correlation was observed in EBV-infected lymphocyte subsets, anti-EBV antibody titres or EBV DNA load. Late onset and EBV reactivation are both related to more severe phenotypes of the disease, and thus may predict a poor prognosis.

Strontium hydroxyapatite in situ gel-forming system - a new approach for minimally invasive bone augmentation.

OBJECTIVES: To achieve ideal functional and aesthetic requirements, ridge augmentation is often required before dental implant placement. Bone augmentation (especially vertical), which normally consists of complex and invasive surgeries, still remains challenge. This study seeks to investigate the feasibility of an injectable in situ gel-forming system containing strontium hydroxyapatite (SrHA) and alginate for minimally invasive bone augmentation in a rat calvarial model. MATERIAL AND METHODS: SrHA-alginate solution was prepared by mixing SrHA powder with alginate solution (20 mg/mL) to the final concentration of 0.5% (w/v). Each animal received a 200-µL single subperiosteal injection of either SrHA-alginate solution or alginate solution. The new bone formation was assessed at 0, 4, and 8 weeks histologically and radiologically. RESULTS: The SrHA-alginate solution materials could form solid gel once injected. As such, no sutures were required to close the injection site. Significantly greater amount of new bone formation was observed in the SrHA-alginate group compared with the alginate group both by micro-CT and by histological section. The newly formed bone in the SrHA-alginate group originated both from the underlying original bone and from the elevated periosteum. A 2.3-fold increase of the vertical bone height was observed in the SrHA-alginate group compared with 1.3-fold increase in the alginate group. CONCLUSIONS: Rat calvarial bone augmentation was achieved by a single subperiosteal injection of SrHA-alginate solution without any administration of stem cells or growth factors. The in situ gel-forming material may hold potential therapeutic benefits for local bone augmentation in a minimally invasive manner.

Phorbol ester stimulates ethanolamine release from the metastatic basal prostate cancer cell line PC3 but not from prostate epithelial cell lines LNCaP and P4E6.

BACKGROUND: Malignancy alters cellular complex lipid metabolism and membrane lipid composition and turnover. Here, we investigated whether tumorigenesis in cancer-derived prostate epithelial cell lines influences protein kinase C-linked turnover of ethanolamine phosphoglycerides (EtnPGs) and alters the pattern of ethanolamine (Etn) metabolites released to the medium. METHODS: Prostate epithelial cell lines P4E6, LNCaP and PC3 were models of prostate cancer (PCa). PNT2C2 and PNT1A were models of benign prostate epithelia. Cellular EtnPGs were labelled with [1-(3)H]-Etn hydrochloride. PKC was activated with phorbol ester (TPA) and inhibited with Ro31-8220 and GF109203X. D609 was used to inhibit PLD (phospholipase D). [(3)H]-labelled Etn metabolites were resolved by ion-exchange chromatography. Sodium oleate and mastoparan were tested as activators of PLD2. Phospholipase D activity was measured by a transphosphatidylation reaction. Cells were treated with ionomycin to raise intracellular Ca(2+) levels. RESULTS: Unstimulated cell lines release mainly Etn and glycerylphosphorylEtn (GPEtn) to the medium. Phorbol ester treatment over 3h increased Etn metabolite release from the metastatic PC3 cell line and the benign cell lines PNT2C2 and PNT1A but not from the tumour-derived cell lines P4E6 and LNCaP; this effect was blocked by Ro31-8220 and GF109203X as well as by D609, which inhibited PLD in a transphosphatidylation reaction. Only metastatic PC3 cells specifically upregulated Etn release in response to TPA treatment. Oleate and mastoparan increased GPEtn release from all cell lines at the expense of Etn. Ionomycin stimulated GPEtn release from benign PNT2C2 cells but not from cancer-derived cell lines P4E6 or PC3. Ethanolamine did not stimulate the proliferation of LNCaP or PC3 cell lines but decreased the uptake of choline (Cho). CONCLUSIONS: Only the metastatic basal PC3 cell line specifically increased the release of Etn on TPA treatment most probably by PKC activation of PLD1 and increased turnover of EtnPGs. The phosphatidic acid formed will maintain a cancer phenotype through the regulation of mTOR. Ethanolamine released from cells may reduce Cho uptake, regulating the membrane PtdEtn:PtdCho ratio and influencing the action of PtdEtn-binding proteins such as RKIP and the anti-apoptotic hPEBP4. The work highlights a difference between LNCaP cells used as a model of androgen-dependent early stage PCa and androgen-independent PC3 cells used to model later refractory stage disease.

Quantitative determination of lattice fluoride effects on the solubility and crystallinity of carbonated apatites with incorporated fluoride.

The purpose of this study was to evaluate quantitatively the effects of fluoride on the solubility and crystallinity of carbonated apatites (CAPs) after its incorporation into the crystal lattice using the metastable equilibrium solubility (MES) distribution method. Fluoride-incorporated CAPs (F-CAPs) of two different carbonate levels (3 and 5%) and fluoride contents from 0 to 20,000 µg/g were synthesized. X-ray diffraction experiments and Rietveld analysis were conducted to obtain crystallite microstrain and unit cell parameters. Acetate buffer MES solution media were prepared at two solution fluoride concentrations (0.2 and 2.0 mg/l) and at two pHs (5.0 and 5.7). The unit cell a-axis values of the F-CAPs were found to decrease as the fluoride content increased, consistent with the fluoride being incorporated into the crystal lattice. The fluoride concentrations in the MES solution media were high enough to provide a 'swamping' effect such that the fluoride released from the F-CAPs during dissolution was minimal in changing the solution fluoride concentration. Employing the MES distribution superposition method, it was shown that the surface complex possessing the fluorapatite (FAP) stoichiometry [Ca10(PO4)6F2] accounted for the MES distribution behavior of all experiments. In addition, the mean pIFAP [the value of -log(aCa(10)aPO4(6)aF(2)) calculated from the ionic activity product based on FAP stoichiometry of the MES dissolution media in which 50% of the F-CAPs had dissolved] correlated well with the crystallite microstrain parameters of the F-CAPs. The incorporated fluoride in the F-CAPs showed only modest effects on F-CAP crystallinity and solubility.

MicroRNAs and liver function.

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression post-transcriptionally through complementary base pairing with thousands of messenger RNAs. Although the target genes and precise biological functions of individual miRNAs remain largely unknown, miRNAs are speculated to play important roles in diverse biological processes in both normal and pathological states. The liver is a vital organ that plays major roles in a number of physiological functions. Recent advances in the study of liver miRNAs using gene-modified mice or in vivo nucleic acid delivery to overexpress specific miRNAs or inhibit miRNA functions have revealed the crucial biological roles of individual miRNAs in physiologically essential liver functions in vivo. Because miRNA-based strategies are being applied to clinical therapeutics, the importance of precise knowledge of miRNA functions cannot be underestimated, not only from a scientific point of view, but also from a clinical perspective to make the most of such drugs and avoid unexpected harmful effects. The aims of this review are to describe current knowledge regarding both known and as-yet-undiscovered molecular aspects of the biological roles of miRNAs in the liver, with a special emphasis on lipid, glucose, drug, and iron metabolism as vital functions of the liver as well as important therapeutic targets.

Associations of time to return to performance following acute posterior thigh injuries with running biomechanics, hamstring function, and structure in collegiate sprinters: A prospective cohort design.

BACKGROUND: The time to return to sport from acute hamstring strain injuries is associated with several functional and structural impairments. However, not all previous studies assessed the preinjury level before acute hamstring strain injuries directly. The purpose of this study was to examine the associations of the time to return to performance following acute hamstring strain injuries with deficits in running biomechanics, hamstring function and structure in collegiate sprinters by a prospective study. METHODS: Using a prospective cohort design, 72 participants were recruited from a collegiate track and field team. At the preinjury assessment, a 60-m running-specific test, passive straight leg raise test and isometric knee flexion strength test were assessed at the beginning of the competitive season for three consecutive years (2017-2019). Afterwards, postinjury examinations were performed only in sprinters with acute hamstring strain injuries. FINDINGS: Twelve sprinters strained their hamstring muscle (incidence rate of hamstring strain injuries: 16.7%); the majority (n = 10) were classified as grades 0-2. The running speed deficit of the running-specific test was associated with the time to return to performance as well as the passive straight leg raise test deficit. In the running-specific test, lower-limb kinetic deficits were more strongly associated with the time to return to performance compared to lower-limb kinematic deficits. INTERPRETATION: A running-specific test may be considered one of the most convenient and valid tests for assessing rehabilitation progress after acute hamstring strain injuries.

Endotoxin activity and leukocytic STAT3 mRNA alterations differ according to age in lipopolysaccharide-challenged calves.

The objective of this study was to investigate the age difference in the response to endotoxin in calves related to the plasma endotoxin activity and mRNA expression of cytokines. Fifteen calves were divided into three groups: control (191 ± 21 days), weaning (162.4 ± 17.5 days), and calf (22.4 ± 8.2 days). The weaning and calf groups received 2.5 µg/kg of ultrapure O111:B4 LPS in 10 mL of each autologous serum, whereas the control calves received a similar volume of saline. Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 h. Liver samples were collected by ultrasound-guided liver biopsy at 0, 2, 4, and 24 h. Plasma endotoxin activity was measured by the limulus amebocyte lysate kinetic turbidimetric assay. The mRNA expression level of GAPDH, TLR-4, NF-κB2, TNF-α, IL-6, and STAT3 in leukocytes and the liver was measured by real-time PCR. Following LPS challenge, the maximal plasma endotoxin activity, and leukocytic expression of TLR4, NF-κB2, TNF-α, and STAT3 were reached at 0.5, 4, 2-4, 2-4, and 4 h, respectively, in weaning and calf groups. The endotoxin activity in calf remained high until 2 h. Furthermore, the expression of leukocytic STAT3 mRNA in calf was not significantly different from the pre-value. In contrast, STAT3 mRNA in weaning markedly increased at 2 and 4 h. Therefore, this study provides new information to the literature of immune and inflammatory responses in calves.

Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Evaluation of allergenicity of constituents of myoga using the murine local lymph node assay.

Myoga (Zingiber Myoga Roscoe) is a perennial plant with a pungent smell from its flower buds. It is native to East Asia and has been reported to cause allergic contact dermatitis. The purpose of this study is to assess the allergenicity of myoga related to its major chemical components, alpha-pinene, beta-pinene, limonene, limonene oxide and beta-phellandrene, which are supposed to be the causative agents of contact dermatitis among myoga cultivators. We performed a toxicity study of the volatile constituents of myoga using the local lymph node assay (LLNA), in which limonene, limonene oxide and beta-phellandrene had positive responses and the EC3 was 35.8%, 8.22%, and 0.54%, respectively. EC3 for both alpha-pinene and beta-pinene was over 100%. Both chemicals failed to induce positive responses in the LLNA. While the maximization rating of limonene, limonene oxide and phellandrene were evaluated as moderate, extreme, and extreme respectively, alpha-pinene and beta-pinene were evaluated as weak in the previously reported GPMT. The usage of LLNA was also confirmed by comparing with previously reported GPMT results to detect the allergenicity of myoga constituents. The actual risk of humans developing an allergy to myoga constituents depends on many factors. The concentration of the compounds, the frequency and duration of exposure and the condition of the skin are supposed to be important factors.

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients.

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.

Poor postoperative blood glucose control increases surgical site infections after surgery for hepato-biliary-pancreatic cancer: a prospective study in a high-volume institute in Japan.

Two hundred and sixty-five consecutive patients awaiting hepato-biliary-pancreatic surgery were prospectively observed for surgical site infections (SSIs). SSI rates differed according to type of hepato-biliary-pancreatic surgery. Multivariate analysis identified enteric anastomoses, poor postoperative blood glucose control and type of cancer as independent risk factors. SSI rates were directly correlated with the degree of hyperglycaemia encountered during the postoperative period. In particular, SSI rates were 5/25 (20%) among patients in whom a blood glucose level of <200mg/dL was maintained by insulin infusion therapy, which was significantly better than the rates of 49/94 (52%) among patients in whom a blood glucose level of <200mg/dL was not maintained despite insulin infusion therapy (P<0.01). It is necessary to maintain postoperative blood glucose levels of <200mg/dL in order to reduce SSI rates.

Studies on inhibition mechanism of transcription factor NF-kappaB and DNA binding by chelator pyrogallol red on the basis of its interaction with metal ions.

Recent studies have shown that the zinc influences the DNA binding of transcription factor NF-kappaB. So the zinc-interaction of pyrogallol red (PR) an inhibitor of NF-kappaB-DNA binding was studied by isolating the zinc-PR complex. The complex was characterized using IR, UV-visible, 1H NMR, and thermal studies. Binding sites of PR were investigated by molecular modeling using MM+ and PM3 methods and by generating molecular electrostatic map. These studies have confirmed the role of metal ion chelation in the inhibition of NF-kappaB-DNA binding by PR.

Effects of bead size and polymerization in PMMA bone cement on vancomycin release.

Polymethylmethacrylate (PMMA) bone cement loaded with antimicrobial agents is used for the treatment and prevention of infections in orthopaedic surgery. The use of antimicrobial-loaded bone cement allows for high local doses while avoiding systemic toxicity. The release of vancomycin (VCM) from bone cement has been reported. However, the exact mechanism behind the release is unknown. We studied the influence of bead size and polymerization time on elution, and considered the release mechanism for VCM. We used CMW Endurance Bone Cement. Cements were prepared by mixing 6 g of VCM with 40 g of polymer, and then 10 g of liquid monomer was added. We kneaded and shaped the preparation into spheres containing 10.7 w/w% VCM. We measured the release of VCM from PMMA beads of three different sizes. Average weights of the beads were 0.96 g (SB) (n = 6), 2.86 g (MB) (n = 2) and 5.65 g (LB) (n = 1). Additionally, we studied beads made with different polymerization times. The polymerization time was taken as the period from the making of the beads until the start of the study, and was 15 min (B15), 20 min (B20), 60 min (B60) or 180 min (B180). The release of VCM showed a bimodal curve with a high initial release followed by a sustained release. Regarding the size of the beads, SB released 7.2%, MB released 4.3% and LB released 3.1%. Regarding polymerization time, B15 released 10.0%, B20 released 6.5%, B60 released 6.3% and B180 released 4.3%, respectively. The release of VCM from PMMA beads was influenced by bead size and polymerization time. Those beads which were smaller and had a shorter polymerization time released more VCM. Total pore volume of beads that polymerization time was 30 min after drug-release test was 1.33 times grater than that of control beads that polymerization time was one week before drug-release test. This suggested that the short polymerization time caused the beads to leak more VCM. We proposed a model with four kinds of the dissolution from bone cement. (A) Dissolution from drug particles on the cement surface. This type shows the burst effect of release curve. (B) Dissolution from micropores near the cement surface. It is responsible the grater part of the curve based on Higuchi's equation. (C) Dissolution from ink-bottle-neck-type micropores. It causes a release based on a non-Higuchi's equation. (D) No dissolution from Encapsulation micropores.It can be concluded that the release of VCM from bone cements is controlled by a combination of surface area and polymerization time. PMMA beads loaded with VCM should be used carefully in orthopaedic surgery, taking into consideration the influence of bead size and polymerization time.

Confinement effects, surface effects, and transport in Bi and Bi1-x Sb x semiconducting and semimetallic nanowires.

Hicks and Dresselhaus predicted that quantum well and nanowire thermoelectric materials could show a meaningful enhancement of the heat-to-electricity conversion efficiency compared to their bulk counterparts. The unique transport properties of bismuth, specifically the low effective mass, high mobility, and large Bohr radius of its charge carriers, enabled the study of size-quantization effects in Bi nanowires following those theoretical predictions. In this review, the band structure of Bi and Bi1-x Sb x alloys is discussed as a function of their composition, temperature, and size-quantization effects. Further, the theoretical basis of the thermoelectric performance enhancement in Bi nanowires is reviewed and compared to experimental data. Single-wire conductivity and Hall data are reviewed. Finally, several synthesis routes for Bi1-x Sb x nanowire samples are discussed, including liquid pressure impregnation, vapor impregnation, electrochemical deposition and wet chemistry impregnation in a template.

Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients.

Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.

Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation.

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.