Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

Three-dimensional reversed fast imaging with steady-state precession diffusion-weighted imaging for the detection of middle ear cholesteatoma.

AIM: To determine the usefulness of three-dimensional reversed fast imaging with steady-state precession diffusion-weighted imaging (3D-PSIF DWI) for the detection of middle ear cholesteatoma. MATERIALS AND METHODS: The study population consisted of 81 patients who underwent 3D-PSIF-DWI at 3 T. They included cholesteatoma in 73 cases, otitis media in five, and cholesterol granuloma in three. Two observers independently performed qualitative evaluations for the detection of cholesteatoma and measured apparent diffusion coefficient (ADC) values and ADC ratios of the lesions. Kappa (κ) statistics, the intraclass correlation coefficient (ICC), the independent t-test, and receiver operating characteristic (ROC) analysis were used for statistical analysis. Pair-wise comparison of the ROC curves was performed using the area under the ROC curve (AUC). RESULTS: Interobserver agreement and ICC for the qualitative and quantitative evaluations were excellent (κ=0.92 and ICC=0.90-0.92, respectively). The ADC value and the ADC ratio were significantly lower for cholesteatoma than non-cholesteatoma lesions (p<0.0001). In <5 mm cholesteatoma group, the diagnostic performance of the ADC value (AUC=0.97) and the ADC ratio (AUC=1) was significantly superior to qualitative 3D-PSIF-DWI (AUC=0.76; p=0.0001 and <0.0001, respectively). For ≥5 mm cholesteatoma group, there were no significant differences in diagnostic performance among the three parameters. CONCLUSION: 3D-PSIF-DWI sequence is useful for the detection of middle ear cholesteatomas, especially <5 mm lesions.

Analysis of masticatory muscle coordination during unilateral single-tooth clenching using muscle functional magnetic resonance imaging.

In a previous study, we used muscle functional magnetic resonance imaging to show that the anterior movement of the occlusal point increased the activity of the superior head of the ipsilateral lateral pterygoid muscle (ipsilateral SHLP) during unilateral single-tooth clenching. The purpose of this study was to verify the hypothesis that the increased activity of the ipsilateral SHLP described above serves to antagonise the occlusal force acting on the condyle. In total, 9 healthy volunteers were requested to perform left unilateral clenching at the first molar or first premolar region for 1 minute at 20% or 40% maximum voluntary clenching force. Changes in the mean proton transverse relaxation time (∆T2) were examined from the magnetic resonance images obtained before and after each clenching act as an index of the activity in all masticatory muscles. Correlation analyses of the mean ΔT2 for each volume of interest were performed with the first molar or premolar clenches to analyse the correlation between the activities in each muscle. A statistically significant correlation was exhibited between the ipsilateral temporal and ipsilateral SHLP (r = .651, P = .003) during first premolar clenching. However, no significant correlations were observed in the ipsilateral SHLP during first molar clenching. The results of this study suggest that the ipsilateral SHLP may contribute to the pulling of the mandibular condyle forward against the occlusal force generated by the ipsilateral temporal muscle.

Evaluation of masticatory activity during unilateral single tooth clenching using muscle functional magnetic resonance imaging.

Masticatory muscle activity during teeth clenching is affected by occlusal pattern. However, few studies have performed simultaneous evaluation of all masticatory activities during teeth clenching under various occlusal conditions. The aim of this study was to use muscle functional magnetic resonance imaging (mfMRI) to evaluate the effects of changes in occlusal point on masticatory activity during single tooth clenching. Changes in mean proton transverse relaxation time (∆T2) as an index of activity in all masticatory muscles during left unilateral clenching at the first molar or first premolar for 1 min were examined in nine healthy volunteers. Bite force was maintained at 40% of the maximum voluntary clenching force. The ∆T2 values of the masseter and lateral pterygoid muscles were analysed separately for superficial and deep layers, and for superior and inferior heads. The ∆T2 values for the ipsilateral deep masseter were significantly lower, and for the superior head of the ipsilateral lateral pterygoid muscles were significantly higher, after left first premolar clenching compared to left first molar clenching. These results quantitatively demonstrate a significant increase in activity of the superior head of the ipsilateral lateral pterygoid muscle and a significant decrease in activity of the ipsilateral deep masseter muscle with forward displacement of the occlusal contact point during unilateral tooth clenching.

Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits.

OBJECTIVE: To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. MATERIAL AND METHODS: Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. RESULTS: Participants with a GG genotype tended to have less teeth than those with CC; ß = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). CONCLUSION: The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals.

Phase II study of brigatinib in patients with ROS1 fusion-positive non-small-cell lung cancer: the Barossa study.

BACKGROUND: Brigatinib is a next-generation tyrosine kinase inhibitor (TKI) targeting ALK and ROS1. The Barossa study is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. ROS1 TKI-naive patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) were enrolled in cohort 1, and ROS1-rearranged NSCLC patients treated previously with crizotinib were enrolled in cohort 2. Patients with ROS1-rearranged solid tumors other than NSCLC were enrolled in cohort 3. PATIENTS AND METHODS: Eligible patients received brigatinib at the dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary endpoint was the objective response rate (RECIST 1.1) assessed by independent central review in cohorts 1 and 2. RESULTS: Between July 2019 and June 2021, 51 patients were enrolled into the study. Of the 51, 47 patients had ROS1-rearranged NSCLC; 28 and 19 of these patients were enrolled in cohort 1 and cohort 2, respectively. The remaining four patients had other ROS1-rearranged solid tumors, including rectal, brain, and pancreas tumor in one patient each, and primary unknown tumor in one patient. The confirmed objective response rate was 71.4% [95% confidence interval (CI) 51.3% to 86.8%] in cohort 1 (TKI-naive NSCLC patients) and 31.6% (95% CI 12.6% to 56.6%) in cohort 2 (NSCLC patients treated previously with crizotinib). The median progression-free survival was 12.0 months (95% CI 5.5-22.9 months) in cohort 1 and 7.3 months (95% CI 1.3-17.5 months) in cohort 2. None of the patients in cohort 3 showed any treatment response. Pneumonitis was observed in 9.8% of all the patients. CONCLUSIONS: Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.

Endogenous memory CD8 T cells are activated within cardiac allografts without mediating rejection.

Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 12-24 h posttransplant in mice and are activated to proliferate and produce IFN-γ. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti-LFA-1 mAb given to allograft recipients on days 3 and 4 posttransplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG-treated recipients on day 7 posttransplant, allografts from anti-LFA-1 mAb-treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor-reactive CD8 T cells producing IFN-γ. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti-LFA-1 mAb continued to proliferate up to day 7 posttransplant and did not upregulate expression of the exhaustion marker LAG-3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection.

Ambulatory sagittal split ramus osteotomy: strategy for enhanced recovery after surgery.

The sagittal split ramus osteotomy (SSRO) has been performed mainly on an inpatient basis because of the duration of anaesthesia and the potential risk of postoperative complications, such as bleeding, pain, nausea, and vomiting. However, advances in both surgical and anaesthetic management have enabled the reduction of these risks and shortened the length of hospital stay. Thus, the SSRO may be feasible even in the ambulatory setting in elective cases. The clinical records of all patients who underwent an outpatient SSRO between August 2011 and September 2020 at Lilla Craniofacial Clinic were reviewed retrospectively. Data on age, sex, duration of surgery, operative procedures, intraoperative bleeding, and admission status were investigated. In total, 143 patients underwent a bilateral SSRO. The SSRO was performed as an isolated procedure in 73 patients and concomitantly with other surgical procedures in the remaining 70 patients. Overall, 142 of the 143 patients were discharged on the day of surgery (99.3%); only one (0.7%) required an overnight stay because of a submental haemorrhage after genioplasty. No emergency hospitalizations or readmissions occurred after discharge. Multimodal perioperative management, both surgical and anaesthetic, facilitated enhanced patient recovery after surgery, and SSRO was performed successfully and safely as an ambulatory procedure.

Antibody-mediated rejection of single class I MHC-disparate cardiac allografts.

Murine CCR5(-/-) recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2(b)) and B6.CCR5(-/-) recipients. Donor-specific antibody titers in CCR5(-/-) recipients were 30-fold higher than in wild-type recipients. B6.K(d) allografts survived longer than 60 days in wild-type recipients whereas CCR5(-/-) recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils and macrophages, and C4d deposition in the graft capillaries. B6.K(d) allografts were rejected by CD8(-/-)/CCR5(-/-), but not µMT(-/-)/CCR5(-/-), recipients indicating the need for antibody but not CD8 T cells. Grafts recovered at day 10 from CCR5(-/-) and CD8(-/-)/CCR5(-/-) recipients and from RAG-1(-/-) allograft recipients injected with anti-K(d) antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of antidonor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity.

LFA-1 antagonism inhibits early infiltration of endogenous memory CD8 T cells into cardiac allografts and donor-reactive T cell priming.

Alloreactive memory T cells are present in virtually all transplant recipients due to prior sensitization or heterologous immunity and mediate injury undermining graft outcome. In mouse models, endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-γ in response to donor class I MHC within 24 h posttransplant. The current studies analyzed the efficacy of anti-LFA-1 mAb to inhibit early CD8 T cell cardiac allograft infiltration and activation. Anti-LFA-1 mAb given to C57BL/6 6 (H-2(b)) recipients of A/J (H-2(a)) heart grafts on days -1 and 0 completely inhibited CD8 T cell allograft infiltration, markedly decreased neutrophil infiltration and significantly reduced intragraft expression levels of IFN-γ-induced genes. Donor-specific T cells producing IFN-γ were at low/undetectable numbers in spleens of anti-LFA-1 mAb treated recipients until day 21. These effects combined to promote substantial prolongation (from day 8 to 27) in allograft survival. Delaying anti-LFA-1 mAb treatment until days 3 and 4 posttransplant did not inhibit early memory CD8 T cell infiltration and proliferation within the allograft. These data indicate that peritransplant anti-LFA-1 mAb inhibits early donor-reactive memory CD8 T cell allograft infiltration and inflammation suggesting an effective strategy to attenuate the negative effects of heterologous immunity in transplant recipients.

A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. METHODS: Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor kappaB (NF-kappaB) activation was assessed by reporter gene assay. RESULTS: Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-kappaB activation. We therefore examined the effect of liraglutide on TNFalpha-induced NF-kappaB activation and NF-kappaB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-kappaB activation and TNFalpha-induced IkappaB degradation. It also reduced TNFalpha-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-kappaB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. CONCLUSIONS/INTERPRETATION: Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-kappaB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.

Increase in tumour permeability following TGF-beta type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI.

BACKGROUND: To enhance the success rate of nanocarrier-mediated chemotherapy combined with an anti-angiogenic agent, it is crucial to identify parameters for tumour vasculature that can predict a response to the treatment of the anti-angiogenic agent. METHODS: To apply transforming growth factor (TGF)-beta type I receptor (TbetaR-I) inhibitor, A-83-01, to combined therapy, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was carried out in mice bearing colon 26 cells using gadolinium (Gd)-DTPA and for its liposomal formulation to evaluate changes in tumour microvasculature following A-83-01. Tumour vascular parameters from DCE-MRI were compared with histological assessment and apparent diffusion coefficient of water in tumour generated by diffusion-weighted MRI. RESULTS: Contrary to evaluations reported for anti-angiogenic agents, A-83-01 treatment increased the initial area under the Gd concentration-time curve (IAUGC60), volume transfer constant (K(trans)) and fractional plasma volume (v(p)) significantly within 24 h, that was positively related to alpha-smooth muscle actin-positive pericyte coverage and tumour cell proliferation, and was correlated inversely with the apparent diffusion coefficient. The vascular function of the tumour improved by A-83-01 treatment was well assessed on post-liposomal Gd-DTPA-enhanced MR images, which predicted delivery of a liposomal drug to the tumour. CONCLUSION: These findings suggest that DCE-MRI and, in particular, K(trans) and v(p) quantitation, provide important additional information about tumour vasculature by A-83-01 treatment.

Glimepiride upregulates eNOS activity and inhibits cytokine-induced NF-kappaB activation through a phosphoinoside 3-kinase-Akt-dependent pathway.

AIMS: Several studies suggest increased mortality postcoronary angioplasty in patients on sulphonylureas. However, a theoretical reduction in cardiac risk has been suggested with the newer sulphonylurea agents, which differ from the first-generation agents. In the present study, we investigated whether a third generation of sulphonylurea, glimepiride, might stimulate nitric oxide (NO) production and thereby inhibit cytokine-induced nuclear factor (NF)-kappaB activation in endothelial cells compared with the classical sulphonylurea glibenclamide. METHODS AND RESULTS: We demonstrated that glimepiride, but not glibenclamide, induces NO production in human umbilical vein endothelial cells (HUVEC). A significant increase in endothelial NO synthase (eNOS) activity, measured in terms of citrulline production, was observed with glimepiride treatment. Akt phosphorylation followed by phosphorylation of eNOS (Ser1177) was observed with glimepiride treatment in HUVEC. Moreover, two phosphoinoside 3-kinase inhibitors, wortmannin and LY294002, significantly inhibited glimepiride-induced NO production. We also demonstrated inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation in HUVEC treated with glimepiride, which was attenuated by pretreatment with N(omega)-nitro-L-arginine methyl ester. We also demonstrated a marked increase in p65 in nuclear extracts from untreated HUVEC following stimulation with TNFalpha, which was dose dependently inhibited by glimepiride, but not by glibenclimide in association with NF-kappaB levels. CONCLUSION: These data suggest that glimepiride might be a preferable sulphonylurea agent in the setting of type 2 diabetes and vascular disease because it may have protective effects on vascular endothelial cells.

Gastric emptying rate in subjects with experimentally shortened dental arches: a pilot study.

Although a shortened dental arch has been reported to provide sufficient subjective chewing ability, the loss of molar occlusion significantly reduces trituration ability, and may result in an impaired digestive function including delayed gastric emptying. This study investigated the effect of the experimental loss of molar occlusion on gastric emptying rate. Thirteen healthy dentate males underwent two sessions of gastric emptying rate measurement after ingestion of the same test meal that contained ham, bread and an egg mixed with carbon-labelled octanoic acid. A test food was divided into nine equal portions, and each was consumed in 60 cycles of chewing. In one of the two sessions, the subjects wore an intraoral appliance devised to simulate the occlusal conditions of the shortened dental arches. Two parameters of gastric emptying; namely, the lag phase (T(lag)) and gastric half-emptying time (T(1/2)), were evaluated by means of a (13)C-octanoic acid breath test. Following the measurement of gastric emptying in each session, masticatory performance was evaluated by a conventional sieve test. Masticatory performance decreased significantly in case of loss of molar occlusion (78.1 +/- 11.1% versus 33.4 +/- 18.2%, P <0.001); however, no significant changes were observed in terms of the gastric emptying parameters (T(lag): 99 +/- 19 versus 105 +/- 34 min; T(1/2): 168 +/- 32 versus 178 +/- 48 min). Within the limitations of this study, it was concluded that reduction in food trituration caused by shortening of the dental arch does not significantly affect gastrointestinal digestive function.

Maximum Occlusal Force and Incident Functional Disability in Older Adults: The Tsurugaya Project.

The purpose of the current study was to investigate the association between maximum occlusal force, which is an objective predictor of masticatory performance, and incident functional disability in an elderly Japanese population. A prospective cohort study was conducted targeting 815 (51.7% female) community-dwelling older adults aged ≥70 y residing in the Tsurugaya district, Sendai, Japan. The outcome measurement was incident functional disability, defined as a first certification of long-term care insurance in Japan, which is determined on the basis of a strictly established, uniform, nationwide standard. During a median follow-up of 7.9 y (interquartile range, 4.8-7.9 y), information on long-term care insurance was obtained from the Sendai Municipal Authority. Bilateral maximum occlusal forces of the participants were measured using a horseshoe-shaped pressure-indicating film, and the participants were categorized into quartiles based on occlusal force. Adjusted hazard ratios for functional disability were estimated with Cox proportional hazard models, adjusted for age, sex, body mass index, medical history, smoking status, alcohol consumption, duration of education, depressive symptoms, cognitive impairment, physical functioning, marital status, history of falls, and number of remaining teeth. The multiple-adjusted hazard ratios and 95% confidence intervals (CIs) for incident functional disability compared to the greatest occlusal force quartile were 1.53 (95% CI, 1.02-2.33), 1.64 (95% CI, 1.06-2.55), and 1.64 (95% CI, 1.01-2.68) for the third, second, and first quartiles, respectively ( P for trend = 0.011). A lower maximum occlusal force was significantly associated with an increased risk of functional disability independently of possible confounders, including the number of remaining teeth. Occlusal force may be a useful indicator of the relationship between oral function and geriatric health. Knowledge Transfer Statement:This prospective cohort study demonstrated that lower maximum occlusal force was associated with an increased risk of functional disability in older adults, even after adjustment for possible confounding factors, including the number of remaining teeth. This strengthens the rationale regarding the association between oral function and geriatric health. Particularly in older adults, occlusal force is reduced by several factors other than tooth loss, such as the absence of a dental prostheses, sarcopenia in the masticatory muscle, poor periodontal condition, and orofacial pain. Our findings suggest that maximum occlusal force may be a useful biomarker associated with diverse parameters aside from the number of remaining teeth.

Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion.

Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.

Slow relaxation mode in concentrated oil-in-water microemulsions consisting of repulsive droplets.

The present contribution reports on the observation of two diffusive relaxation modes in a concentrated microemulsion made of repulsive droplets. These two modes can be interpreted in the frame of Weissman's and Pusey's theoretical pioneering works. The fast mode is associated to the collective diffusion of droplets whereas the slow one corresponds to the relaxation of droplet concentration fluctuations associated with composition and/or size. We show that (i) repulsive interactions considerably slow down the latter and (ii) a generalized Stokes Einstein relationship between its coefficient of diffusion and the Newtonian viscosity of the solutions, similar to the Walden's rule for electrolytes, holds for concentrated microemulsion systems made of repulsive droplets.

CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients.

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients' immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38- cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.