Liquid-Crystalline Photonic Sandwich: Electroresponsive Colloids of Clay Nanosheets Loading Photofunctional Dyes.

Colloidal clay nanosheets obtained by the delamination of layered crystals of smectite-type clay minerals in water form liquid crystals because of their shape anisotropy. Loading of organic dyes onto the liquid crystalline clay nanosheets will enable novel photonic materials, where photofunctions of the loaded dye are controlled by the liquid crystallinity of the clay nanosheets. However, adsorption of organic dyes onto the nanosheets renders the nanosheet surfaces hydrophobic, and consequently, colloidal stability of the nanosheets is lost. In this study, this drawback is overcome by sandwiching cationic stilbazolium dyes between a pair of synthetic fluorohectorite nanosheets. This is realized by the preparation of stilbazolium-clay second-stage intercalation compounds characterized by intercalation of dye cations into every other interlayer space of the hectorite clay, where nonintercalated interlayer spaces are occupied by Na+ ions. The second-stage intercalation compounds are obtained by partial ion exchange of mother clay mineral incorporating Na+ ions in all of the interlayer spaces and delaminated from the Na+-containing interlayer spaces to form clay nanosheets sandwiching the dye molecules. Aqueous colloids of the dye-sandwiching clay nanosheets form colloidal liquid crystals, and the dye-sandwiching liquid crystalline clay nanosheets respond to an applied AC electric field to be aligned parallel to the electric field. The assembled structure of the dye-sandwiching clay nanosheets under the electric field is characterized by aligned discrete clay platelets, which is somewhat different from that of a colloidal liquid crystal of clay nanosheets without dye loading characterized by macroscopic liquid crystalline domains up to submillimeters. The electric alignment of the clay nanosheets induces alteration of light absorption of the sandwiched stilbazolium molecules, which verifies a strategy of constructing stimuli-responsive photonic materials of clay-organic hybrids.

Real-Time Monitoring of Adsorption-Induced Scrolling of Colloidal Inorganic Nanosheets.

Inorganic nanotubes have attracted much attention due to their unique physicochemical properties. Nanotubes can be prepared by scrolling exfoliated nanosheets under ambient conditions. However, how the nanosheet scrolled in its colloidal state has not been experimentally visualized. In this paper, we directly observed the scrolling process of nanosheets upon adsorption of organic cations. Exfoliated flat nanosheets of niobate and clay in aqueous colloids were found to scroll by adding organic cations, such as exfoliation reagents, to the colloids. Employment of cationic stilbazolium dye enabled in situ observation of the dye adsorption and scrolling by optical microscopy based on changes in color and morphology of the nanosheets. The scrolling was promoted for nanosheets adsorbed with a stilbazolium dye with a longer alkyl chain, suggesting that the interaction between the hydrophobic parts of the dye cations is the driving force of the scrolling. This finding should encourage research on the formation of nanotubes from nanosheets and also provides important guidelines for the selection of appropriate exfoliation reagents when exfoliating nanosheets from layered crystals.

Clinical Utility of the Combined Use of CA19-9 and DUPAN-2 in Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) patients with normal carbohydrate antigen (CA) 19-9 levels can have early-stage cancer or advanced cancer without elevation of CA19-9 level; estimating their malignant potential is difficult. This study investigated the clinical utility of the combined use of preoperative CA 19-9 and Duke pancreatic monoclonal antigen type 2 (DUPAN-2) levels in patients with PDAC. METHODS: Patients who underwent curative-intent surgery for PDAC between November 2005 and December 2021 were investigated. Eligible patients were classified into four groups based on these two markers. Among patients with normal CA19-9 levels, those with normal and high DUPAN-2 levels were classified into normal/normal (N/N) and normal/high (N/H) groups, respectively. Among patients with high CA19-9 levels, those with normal and high DUPAN-2 levels were classified into high/normal (H/N) and high/high (H/H) groups, respectively. Survival rates were compared between the groups. RESULTS: Among 521 patients, the N/N, N/H, H/N, and H/H groups accounted for 25.0%, 10.6%, 35.1%, and 29.4% of patients, respectively. The proportions of resectable PDAC in the N/N and H/N groups (71.5% and 66.7%) were significantly higher than those in the N/H and H/H groups (49.1% and 54.9%) (P < 0.01). The 5-year survival rates in the N/N, N/H, H/N, and H/H groups were 66.0%, 31.1%, 34.9%, and 29.7%, respectively; the rate in the N/N group was significantly better than those in the other three groups (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSIONS: Only patients with normal CA19-9 and DUPNA-2 values should be diagnosed with early-stage PDAC.

Prognostic impact of peritoneal washing cytology in patients with biliary tract cancer.

PURPOSE: To elucidate the clinical significance of peritoneal washing cytology (PWC) in patients with resectable biliary tract cancer (BTC). METHODS: Clinical data of patients with BTC, who received PWC at curative intent surgery from March 2009 to December 2021, were retrospectively analyzed. Eligible patients were stratified into two groups according to positive or negative PWC. Recurrence-free survival and overall survival were compared between the two groups. Independent factors associated with positive PWC were investigated using multivariate analysis. RESULTS: Among the 284 patients analyzed, all 53 patients with ampullary carcinoma showed negative PWC and these patients were excluded. Among the remaining eligible 231 patients, 41 patients had intrahepatic cholangiocarcinoma, 55 had gall bladder carcinoma, 72 had hilar cholangiocarcinoma, and 63 had distal cholangiocarcinoma. Eleven (4.8%) patients had positive PWC, and 220 (95.2%) had negative PWC. The median recurrence-free survival in the positive and negative PWC groups were 12.0 vs. 60.7 months (p = 0.005); the median overall survival times were 17.0 vs. 60.6 months (p = 0.008), respectively. Multivariate analysis revealed that serum carbohydrate antigen 19-9 level over 80 U/mL and multiple lymph node metastasis were independently associated with positive PWC (odds ratio [OR]: 5.84, p = 0.031; OR: 5.28, p = 0.021, respectively). CONCLUSION: Patients with positive PWC exhibited earlier recurrence and shorter survival times compared with those with negative PWC.

Long-term outcomes of neoadjuvant gemcitabine, nab-paclitaxel, and S1 (GAS) in borderline resectable pancreatic cancer with arterial contact: Results from a phase II trial.

BACKGROUND/PURPOSE: This study reports the long-term results of a phase II trial evaluating the clinical efficacy of neoadjuvant gemcitabine, nab-paclitaxel, and S1 (GAS) in borderline resectable pancreatic cancer with arterial contact (BRPC-A). METHODS: A multicenter, single-arm, phase II trial was conducted. Patients received six cycles of GAS and patients without progressive disease were intended for R0 resection. RESULTS: Of the 47 patients, 45 (96%) underwent pancreatectomy. At the time of this analysis, all patients were updated with no loss to follow-up. A total of 30 patients died, while the remaining 17 patients were followed for a median of 68.1 months. The updated median overall survival (OS) was 41.0 months, with 2- and 5-year OS rates of 68.0% and 44.6%, respectively. Multivariate analysis in the preoperative model showed that a tumor diameter reduction rate ≥10% and a CA19-9 reduction rate ≥95% after neoadjuvant chemotherapy remained independently associated with favorable survival. In the postoperative multivariate model, no lymph node metastasis, no major surgical complications, and completion of adjuvant chemotherapy were independently associated with improved OS. CONCLUSIONS: This long-term evaluation of the neoadjuvant GAS trial demonstrated the high efficacy of the regimen, suggesting that it is a promising treatment option for patients with BRPC-A.

Difficulty of adjuvant chemotherapy administration in patients with biliary tract cancer.

PURPOSE: This study aimed to elucidate the difficulty of adjuvant chemotherapy administration in patients with biliary tract carcinoma (BTC). METHODS: Clinical data of patients with BTC who underwent curative-intent surgery were retrospectively analyzed. The eligible patients were stratified into two groups according to the presence or absence of adjuvant chemotherapy administration (adjuvant and non-adjuvant groups), and the clinicopathological features were compared between the two groups. The ratios of adjuvant chemotherapy administration were investigated in each surgical procedure. Independent factors associated with no administration of adjuvant chemotherapy were analyzed using multivariate analyses. RESULTS: Among 168 eligible patients, 141 (83.9%) received adjuvant chemotherapy (adjuvant group), while 27 (16.1%) did not (non-adjuvant group). The most common surgical procedure was pancreaticoduodenectomy in the adjuvant group, and it was hepatectomy with extrahepatic bile duct resection (BDR) in the non-adjuvant group, respectively. The rate of no adjuvant chemotherapy was significantly higher in patients who underwent hepatectomy with BDR than in those who underwent other surgeries (p < 0.001). The most common cause of no adjuvant chemotherapy was bile leak in 12 patients, which occurred after hepatectomy with BDR in ten patients. Multivariate analyses revealed that hepatectomy with BDR and preoperative anemia were independently associated with no adjuvant chemotherapy (p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Hepatectomy with BDR and subsequent refractory bile leak can be the obstacle to adjuvant chemotherapy administration in patients with BTC.

Increased plasma miR-370-3p expression in poor-outcome patients with pancreatic ductal adenocarcinoma.

OBJECTIVE: To determine whether circulating microRNAs (miRNAs) can be used as prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with PDAC (N = 120) who underwent surgical resection at Hiroshima University Hospital between November 2006 and January 2020 were enrolled in this study and grouped based on their overall survival (OS) into two groups: favorable prognosis group (F group; OS ≥ 18 months) and unfavorable prognosis group (U group; OS < 18 months). Blood plasma samples were collected prior to surgery. To identify candidate prognostic miRNAs, next-generation sequencing (NGS) analysis was used to evaluate the expression levels of miRNAs in seven of the plasma samples. Using quantitative real-time PCR (qRT-PCR), the expression levels of the selected miRNAs were determined in the remaining 113 patient plasma samples, and the relationship between miRNA expression and survival was statistically evaluated. RESULTS: NGS analysis and qRT-PCR revealed significantly upregulated plasma miR-370-3p expression in the U group compared to that in the F group (p = 0.028 and p = 0.005, respectively). Moreover, miR-370-3p expression and lymph node metastasis showed a statistically significant association (p = 0.028). In a multivariate analysis of OS and recurrence-free survival (RFS), the upregulation of miR-370-3p expression in plasma was identified as an independent risk factor for poor OS (HR2.13, p = 0.004) and RFS (HR1.84, p = 0.015). CONCLUSIONS: Plasma miR-370-3p expression upregulation correlates with poor prognosis in patients with PDAC.

Optimal Lymphadenectomy in Patients with Well-Differentiated Nonfunctioning Pancreatic Neuroendocrine Neoplasms.

This study aimed to evaluate the optimal extent of lymphadenectomy in patients with nonfunctioning pancreatic neuroendocrine neoplasms. We retrospectively analyzed the clinicopathological data of patients with nonfunctioning pancreatic neuroendocrine neoplasms who underwent surgical resection. We investigated the frequency of metastases at each lymph node station according to tumor location and analyzed the factors contributing to poor overall survival (OS) and disease-free survival (DFS). Overall, data of 84 patients were analyzed. Among patients with pancreatic head tumors, metastases at stations 8, 13, and 17 were found in one (3.1%), four (12.5%), and three (9.3%) patients, respectively. However, none of the other stations showed metastases. For pancreatic body and tail tumors, metastases only at station 11 were found in two (5.1%) patients. Additionally, multivariate DFS and OS analyses showed that lymph node metastasis was the only independent prognostic factor. In conclusion, lymph node metastasis near the primary tumor was the only independent factor of poor prognosis in patients with nonfunctioning pancreatic neuroendocrine neoplasms after undergoing curative surgery. Peri-pancreatic lymphadenectomy might be recommended for nonfunctioning pancreatic neuroendocrine neoplasms.

Left parietal involvement in motion sickness susceptibility revealed by multimodal magnetic resonance imaging.

Susceptibility to motion sickness varies greatly across individuals. However, the neural mechanisms underlying this susceptibility remain largely unclear. To address this gap, the current study aimed to identify the neural correlates of motion sickness susceptibility using multimodal MRI. First, we compared resting-state functional connectivity between healthy individuals who were highly susceptible to motion sickness (N = 36) and age/sex-matched controls who showed low susceptibility (N = 36). Seed-based analysis revealed between-group differences in functional connectivity of core vestibular regions in the left posterior Sylvian fissure. A data-driven approach using intrinsic connectivity contrast found greater network centrality of the left intraparietal sulcus in high- rather than in low-susceptible individuals. Moreover, exploratory structural connectivity analysis uncovered an association between motion sickness susceptibility and white matter integrity in the left inferior fronto-occipital fasciculus. Taken together, our data indicate left parietal involvement in motion sickness susceptibility.

Hepatitis B virus DNA in the fingernails and hair of children with acute hepatitis B.

Hepatitis B virus (HBV) DNA is detectable in the nails and hair of patients with chronic HBV infection. However, it remains unclear whether HBV DNA can be detectable in the nails and hair of patients with acute HBV infection. We encountered two cases of children with acute HBV infection. HBV DNA in the nails and hair from the two children was evaluated by real-time PCR. To clarify the characteristics of HBV DNA, full-length HBV genome sequencing and phylogenetic tree analysis were performed. The levels of serum HBV DNA in children of cases 1 and 2 at day 0 were 7.6 Log IU/mL and 7.4 Log IU/mL, respectively. Nail HBV DNA was detected in both children (case 1: 4.6 Log IU/mL at day 0, case 2: 5.5 Log IU/mL at day 14). Moreover, hair HBV DNA was detectable in case 2 (4.0 Log IU/mL at day 14). Serum HBV DNA became undetectable within approximately 3-4 months after the first hospital visit. After the resolution of HBV viremia, nail and hair HBV DNA became undetectable. The sequence analysis of serum, nail and hair HBV DNA showed the same HBV genotype in each case (case1: genotype C, case 2: genotype A). In case 1, 3 nucleotides were different in the full-genome HBV sequence between the serum and nails. In case 2, the full-genome HBV sequences were identical among the serum, nails and hair. In conclusion, HBV DNA was detectable in nails and hair of children with acute HBV infection.

Vestibular Morphological Asymmetry Associated With Motion Sickness Susceptibility.

Sensory conflicts leading to motion sickness can occur not only between but also within sensory modalities. The vestibular organs are located in both left and right inner ears, and their misalignment can be a source of self-motion related sensory conflicts. In the current study, using inner ear magnetic resonance imaging, we examined whether morphological asymmetry of the bilateral vestibular organs was associated with motion sickness susceptibility. The results showed a larger position asymmetry of bilateral vestibular organs in individuals with high rather than low susceptibility. In addition, vestibular position asymmetry was associated with reciprocal interaction (negative resting state functional connectivity) between vestibular and visuocortical regions in lowly, but not highly, susceptible individuals. In conclusion, these findings suggest that vestibular morphological asymmetry can be a source of sensory conflicts in individuals with dysfunctional reciprocal visuo-vestibular interactions, a putative neural mechanism for resolving sensory conflicts.

The prognostic impact of peritoneal washing cytology for otherwise resectable extrahepatic cholangiocarcinoma patients.

The clinical importance of peritoneal washing cytology (PWC) for cholangiocarcinoma patients remains unclear. The clinical data of 137 extrahepatic cholangiocarcinoma patients who received PWC and curative surgery were retrospectively analyzed. Among the 137 patients analyzed, five (3.6%) had positive PWC, and 132 (96.4%) had negative PWC. The median survival time in patients with negative PWC was 6.45 years, and the overall 1-, 2-, and 5-year survival rates were 86.5%, 75.3%, and 51.6%, respectively. The median survival time in patients with positive PWC was 2.56 years, and the overall 1-, 2-, and 5-year survival rates were 60.0%, 60.0%, and 40.0%, respectively. A multivariate analysis revealed that positive lymph node metastasis (P < 0.001), positive perineural invasion (P = 0.014) and no use of adjuvant chemotherapy (P < 0.001), but not positive PWC were independently associated with a worse overall survival. In conclusion, surgery and subsequent chemotherapy might be a therapeutic option for cholangiocarcinoma patients with positive PWC.

Effectiveness of continuous unsupervised exercise therapy after above-knee femoropopliteal bypass.

OBJECTIVE: Exercise therapy has acceptable outcomes for patients with intermittent claudication, although few reports exist regarding the results of continuous exercise therapy after surgical reconstruction for intermittent claudication. This study aimed to analyze the long-term outcomes of unsupervised exercise therapy for patients after above-knee femoropopliteal bypass. MATERIAL AND METHODS: We retrospectively analyzed 69 patients (69 limbs, 69 grafts) who underwent above-knee femoropopliteal bypass from April 2009 to March 2018 in our hospital. At six months after above-knee femoropopliteal bypass, we evaluated the maintenance of unsupervised exercise therapy. Patients who continued unsupervised exercise therapy or discontinued unsupervised exercise therapy were assessed via 1:1 propensity matching. Long-term outcomes such as patency, survival, and major adverse cardiovascular events were compared between the groups after matching. We also analyzed the maintaining rate of unsupervised exercise therapy in a study cohort. RESULTS: Twenty-nine (42%) patients continued unsupervised exercise therapy until six months after above-knee femoropopliteal bypass. The discontinued unsupervised exercise therapy had higher proportions of female sex (p = 0.015) and cerebrovascular disease (p = 0.025) than did the continued unsupervised exercise therapy. The mean follow-up period was 65 ± 36 months. After propensity matching, the rates of the following factors were significantly higher in the continued unsupervised exercise therapy than in the discontinued unsupervised exercise therapy: primary patency (97% vs. 61%, p = 0.0041), secondary patency (100% vs. 69%, p = 0.0021), and freedom from major adverse cardiovascular events (61% vs. 24%, p = 0.0071) at five years. Both groups had a similar survival rate. The maintaining rate of unsupervised exercise therapy in the study cohort was 44% at six months, 41% at one year, 36% at three years, 25% at five years, and 25% at seven years. CONCLUSION: The findings of this study suggested superior long-term outcomes, including graft patency and freedom from major adverse cardiovascular events, with unsupervised exercise therapy after open bypass than with the usual therapy. Unsupervised exercise therapy may be recommended for the patients after open bypass.

Long-Term Results and Risk Analysis of Redo Distal Bypass for Critical Limb Ischemia.

BACKGROUND: Distal bypass is the optimal treatment for patients with critical limb ischemia (CLI). However, effectiveness of redo distal bypass (rDB) after failed initial distal bypass (iDB) remains uncertain. This study aimed to analyze long-term results of rDB for CLI. METHODS: Patients undergoing rDB for CLI from 2009 to 2018 at a single institute were retrospectively reviewed. Operative details, primary and secondary patency, survival rate, major amputation-free rate, and risk factors affecting patency were analyzed. The distal runoff was evaluated using the infrapopliteal Global Limb Anatomic Staging System (GLASS) grade (0 to 4: 0 represents good runoff and 4 represents the poorest runoff). RESULTS: Of 310 iDB (251 patients), 46 rDB were performed in 44 patients: 27 men, mean age 75 ± 10 years, diabetes mellitus 77%, chronic renal failure with hemodialysis 45%. Only the autologous veins were used in distal bypasses: a great saphenous vein (GSV) in 28 (57%), a small saphenous vein in 13 (27%), an arm vein in 6 (12%), and a superficial femoral vein in 2 (4%). The GSV was used less frequently for rDB than for iDB (57% vs. 90%, P < 0.0001). The infrapopliteal GLASS grade 4 was recognized more in rDB than iDB (76% vs. 60%, P = 0.04). Primary and secondary patency of rDB was 25% and 44% at 1 year and 14% and 29% at 3 years, respectively, which were significantly lower than those of iDB (P < 0.0001). The survival rate after rDB was 68% at 1 year and 53% at 3 years. Freedom from major amputation rate in rDB was 83% at 1 year and 66% at 3 years. Multivariate analysis showed the risk factor influencing on secondary patency was patent duration of the iDB graft (P = 0.012). Secondary patency of rDB was higher in the group of late graft occlusion ≥6 months after iDB (late group) than in the group of early graft occlusion < 6 months after iDB (early group) (94% vs. 9% at 1 year and 75% vs. 5% at 3 years, P < 0.0001). However, freedom from major amputation rate at 3 years was comparable between both groups (71% in the late group vs. 61% in the early group). CONCLUSIONS: Patency of rDB was significantly lower than that of iDB partly because of less use of the GSV and poorer runoff. Because survival and graft patency after rDB was low, rDB should be a suboptimal treatment especially in patients with early graft occlusion within 6 months after iDB.

Daily Meal Supplemented with Astaxanthin-Enriched Yolk Has Mitigative Effects against Hypertension in Spontaneously Hypertensive Rats.

The aim of this study was to investigate the effects of egg yolk powder enriched with astaxanthin (ASX-E) on blood pressure in spontaneously hypertensive rats (SHR) and to verify the benefits of ASX-E as a functional food. To investigate the antihypertensive effect, SHR were fed with an ASX-E mixed diet before hypertension development. Blood pressures were determined periodically during the study by the tail-cuff method. At the end of the study, animals were euthanized, and their thoracic aortas were collected to determine vascular conductance. The thoracic aorta tension was measured with a force displacement transducer. Concentration-dependent response relationships were determined by cumulative addition of 10-9-10-4 M Carbamoylcholine (Cch). Blood pressures of the SHR in the ASX-E mixed diet group were ASX-dose-dependently lower than that of those in the control group. In SHR fed with an ASX-E mixed diet, Cch induced vasorelaxation in the thoracic aorta with endothelium lining but not without endothelium. However, the antihypertensive effect of ASX-E was not observed on blood pressures in SHR that were fed with ASX-E only after the development of hypertension. Results suggest that ASX-E protects endothelial function and thereby prevents the development of hypertension. Hence, the results of our research indicate that daily consumption of ASX-E has a potential benefit on human health.

Antimutagenic components in Spatholobus suberectus Dunn against N-methyl-N-nitrosourea.

BACKGROUND: An extract from Spatholobus suberectus (S. suberectus) Dunn has been reported to show potent antimutagenic effects against N-alkyl-N-nitrosoureas in umu screening. The aim of this study was to identify the antimutagenic components from extracts of S. suberectus against N-methyl-N-nitrosourea (MNU) in the Ames assay with Salmonella typhimurium strain TA1535 and to elucidate the antimutagenic mechanism of the flavonoids. RESULTS: From the ethyl acetate fraction obtained from fractionation of the methanol extract of S. suberectus Dunn, medicarpin, formononetin and isoliquiritigenin were successfully isolated through a combination of normal- and reversed-phase chromatography. Genistein and naringenin, which were already reported to be contained in S. suberectus Dunn, were also tested for their antimutagenicity towards MNU, along with formononetin, isoliquiritigenin and medicarpin. Our results demonstrated that genistein, isoliquiritigenin, medicarpin and naringenin were antimutagenic against MNU without showing cytotoxicity. MNU is reported to cause not only DNA alkylation but also induce reactive oxygen species. The hydroxyl radical scavenging capacity of the flavonoids was correlated with the antimutagenic capacity, indicating that the hydroxyl radical scavenging activity was involved in their antimutagenicity towards MNU. CONCLUSIONS: It is important to prevent DNA damage by N-nitrosamines for cancer chemoprevention. Genistein, isoliquiritigenin, medicarpin and naringenin were demonstrated to possess an antigenotoxic effects against carcinogenic MNU due to their radical scavenging activity.

Simulation study on compressive laminar optical tomography for cardiac action potential propagation.

To measure the activity of tissue at the microscopic level, laminar optical tomography (LOT), which is a microscopic form of diffuse optical tomography, has been developed. However, obtaining sufficient recording speed to determine rapidly changing dynamic activity remains major challenges. For a high frame rate of the reconstructed data, we here propose a new LOT method using compressed sensing theory, called compressive laminar optical tomography (CLOT), in which novel digital micromirror device-based illumination and data reduction in a single reconstruction are applied. In the simulation experiments, the reconstructed volumetric images of the action potentials that were acquired from 5 measured images with random pattern featured a wave border at least to a depth of 2.5 mm. Consequently, it was shown that CLOT has potential for over 200 fps required for the cardiac electrophysiological phenomena.

Application of Akaike information criterion to evaluate warfarin dosing algorithm.

INTRODUCTION: Several factors responsible for inter-individual differences in response to warfarin have been confirmed; however, unidentified factors appear to remain. The purpose of this study was to examine a simple method to evaluate whether optional variables are appropriate as factors to improve dosing algorithms. MATERIALS AND METHODS: All patients were Japanese. Genotyping of selected genes was conducted, and other information was obtained from medical record. Dosing algorithms were constructed by multivariate linear regression analyses and were evaluated by the Akaike Information Criterion (AIC). RESULTS AND CONCLUSIONS: Multivariate analysis showed that white blood-cell count (WBC), concomitant use of allopurinol, and CYP4F2 genotype are apparently involved in warfarin dose variation, in addition to well-known factors, such as age and VKORC1 genotype. We evaluated the adequacy of these variables as factors to improve the dosing algorithm using the AIC. Addition of WBC, allopurinol administration and CYP4F2 genotype to the basal algorithm resulted in decreased AIC, suggesting that these factor candidates may contribute to improving the prediction of warfarin maintenance dose. This study is the first to evaluate the warfarin dosing algorithm by AIC. To further improve the dosing algorithm, AIC may be a simple and useful tool to evaluate both the model itself and factors to be incorporated into the algorithm.

Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules.

Polarised cell migration is required for various cell behaviours and functions. Actin and microtubules are coupled structurally and distributed asymmetrically along the front-rear axis of migrating cells. CLIP-associating proteins (CLASPs) accumulate near the ends of microtubules at the front of migrating cells to control microtubule dynamics and cytoskeletal coupling. Regional inhibition of GSK-3beta is responsible for this asymmetric distribution of CLASPs. However, it is not known how GSK-3beta regulates the activity of CLASPs for linkage between actin and microtubules. Here we identified IQGAP1, an actin-binding protein, as a novel CLASP-binding protein. GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules. At the leading edges of migrating fibroblasts, CLASP2 near microtubule ends partially colocalises with IQGAP1. Expression of active GSK-3beta abrogates the distribution of CLASP2 on microtubules, but not that of a nonphosphorylatable CLASP2 mutant. The phosphorylated CLASP2 does not accumulate near the ends of microtubules at the leading edges. Thus, phosphorylation of CLASP2 by GSK-3beta appears to control the regional linkage of microtubules to actin filaments through IQGAP1 for cell migration.

IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth.

Rac1 and Cdc42, members of the Rho family GTPases, control diverse cellular processes such as cell migration and morphogenesis through their effectors. Among the effectors, IQGAP1 plays pivotal roles in the establishment of cytoskeletal architecture and intercellular adhesions in various cells. However, its roles remain to be clarified, especially in neuronal cells. We have identified IQGAP3 as a novel member of the IQGAP family, which is highly expressed in brain. We found that IQGAP3, an effector of Rac1 and Cdc42, associates directly with actin filaments and accumulates asymmetrically at the distal region of axons in hippocampal neurons. The depletion of IQGAP3 impairs neurite or axon outgrowth in neuronal cells with the disorganized cytoskeleton, but depletion of IQGAP1 does not. Furthermore, IQGAP3 is indispensable for Rac1/Cdc42-promoted neurite outgrowth in PC12 cells. Taken together, these results indicate that IQGAP3 can link the activation of Rac1 and Cdc42 with the cytoskeletal architectures during neuronal morphogenesis.