Low Regional Homogeneity of Intrinsic Cerebellar Activity in Ankle Instability: An Externally Validated rs-fMRI Study.

PURPOSE: Joint deafferentation after post-ankle sprain ligament healing can disrupt sensory input from the ankle and induce maladaptive neuroplasticity, especially in the cerebellum. This study aimed to determine whether the regional homogeneity of intrinsic cerebellar activity differs between patients with ankle instability and healthy controls without a history of ankle injury. METHODS: The current study used a primary data set of 18 patients and 22 healthy controls and an external UK Biobank data set of 16 patients with ankle instability and 69 healthy controls for a cross-database, cross-sectional investigation. All participants underwent resting-state functional magnetic resonance imaging to calculate their regional homogeneity (ReHo) value. Between-group comparisons of the sensorimotor-related subregions of the cerebellum were first performed in the primary data set to identify low cerebellar ReHo in patients with multiple comparison corrections, and the surviving subregions were then externally validated in the UK Biobank data set. Correlation analyses between the ReHo values and clinical features were also performed. RESULTS: The ReHo value of cerebellar lobule VIIIb was significantly lower in the ankle instability group than in the controls (0.170 ± 0.016 vs 0.184 ± 0.019 in the primary data set, 0.157 ± 0.026 vs 0.180 ± 0.042 in the UK Biobank data set). The ReHo values of this subregion showed a significant positive correlation with the Cumberland Ankle Instability Tool scores in the ankle instability group (r = 0.553, P-corrected = 0.0348). CONCLUSIONS: Patients with ankle instability had lower intraregional coherence in cerebellar lobule VIIIb than that of controls, which was also positively correlated with the intensity of self-reported ankle instability.

[The impact of diabetic retinopathy on vision-related quality of life].

Objective: To assess the effect of diabetic retinopathy (DR) on vision-related quality of life (VRQoL) in patients with type 2 diabetes. Methods: In this cross-sectional study, patients with type 2 diabetes residing in 15 residency communities in Fushun, Liaoning province were enrolled from July 2012 to May 2013. We measured the VRQoL by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Patients were grouped according to their age, gender, presence of visual impairment, and affected eyes. NEI-VFQ-25 scores were compared between/among groups using the Wilcoxon rank-sum test or Kruskal-Wallis H test. The severity of DR in the eyes was graded into no DR, mild non-proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR). Severity scores from both eyes were then summarized to create a single per-person grade ranging from 1 (no DR in either eye) to 7 (bilateral PDR). Generalized linear models were used to assess the linear relationship between NEI-VFQ-25 scores and DR severity. Locally weighted scatterplot smoothing plots were generated to evaluate the possible nonlinear associations between concatenated severity of DR and VRQoL. Results: A total of 1 537 patients were recruited, including 836 (54.4%) with no DR, 479 (31.2%) with mild NPDR, 90 (5.9%) with moderate NPDR, 72 (4.7%) with severe NPDR and 60 (3.9%) with PDR. Compared with patients with unilateral DR, bilaterally involved subjects were statistically significantly compromised in general vision [70.2 (66.5, 72.5) vs. 68.9 (63.9, 71.6), Z=90.222, P=0.038], near activities [90.5 (85.8, 94.0) vs. 88.8 (84.5, 92.5), Z=114.942, P=0.005], dependency [91.1 (85.6, 96.5) vs. 89.3 (83.8, 94.5), Z=91.934, P=0.033], mental health [80.0 (73.4, 84.9) vs. 77.5 (70.8, 82.0), Z=118.388, P=0.003], role difficulties [76.8 (70.1, 82.4) vs. 74.5 (67.6, 80.6), Z =90.791, P=0.036] and NEI-VFQ-25 composite [88.3 (84.2, 91.0) vs. 86.9 (82.8, 90.1), Z=96.207, P=0.024]. Scores on general vision (χ2=85.665), near activities (χ2=78.462), distance activities (χ2=145.489), social function (χ2=53.629), dependency (χ2=86.710), mental health (χ2=68.281), role difficulties (χ2=45.357), color vision (χ2=68.176), peripheral vision (χ2=116.179) and NEI-VFQ-25 composite (χ2=133.291) decreased gradually as DR severity increased (all P<0.001). On role difficulties, locally weighted scatterplot smoothing plots showed significant"turning points"from bilateral mild NPDR to mild NPDR/>mild NPDR (slope m=-4.7) and from moderate NPDR/≥moderate NPDR to severe NPDR/≥severe NPDR (slope m=-12.6). Conclusion: Both greater severity and bilaterality of DR were associated with lower vision-specific VRQoL, particularly role difficulties and mental health.

A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

[Role of complement regulatory protein CD55 in the liver immune injury of trichloroethylene-sensitized mice].

Objective: To explore the expression of CD55 in liver tissue of trichloroethylene-sensitized mice and discuss the role of CD55 in the liver immune injury of trichloroethylene-sensitized mice. Methods: 6-8 weeks specific pathogen free female BALB/c were randomly divided into blank control group, solvent control group and TCE treatment group to establish BALB/c mice sensitized model. According to mouse skin sensitization reaction score, TCE treatment mice were divided into sensitized and non-sensitized group at 24 h after the last challenge. At 48 h after the last challenge, the blood and aseptic livers were collected. The level of serum ALT was tested by automatic biochemical analyzer and pathology of the liver was observed. C5b-9 deposition was studied by immunohistochemistry (IHC) . CD55 protein expression level in liver tissue was studied by immunohistochemistry and Western blotting. The expression of CD55 mRNA in liver tissue was detected by qRT-PCR. Results: Liver function test result showed level of serum ALT in TCE sensitized group was significantly higher than solvent control group and TCE non-sensitized group (P<0.05) . There was ballooning degeneration and necrosis of liver cells in TCE sensitized group. IHC demonstrated that TCE sensitized group had obviously increased content of C5b-9 but had reduced content of CD55 compared with solvent control group and TCE non-sensitized group (P<0.05) . Western blotting also showed that TCE sensitized group had lower expression of CD55 than solvent control group and TCE non-sensitized group (P<0.05) . qRT-PCR showed that CD55 mRNA expression level in liver tissue of TCE sensitized group was apparently lower than solvent control group and TCE non-sensitized group (P<0.05) . Conclusion: Complement activation may be involved in TCE-induced liver injury, and the expression change of complement regulatory protein CD55 may play essential role in the process.

[The effect of complement C3a receptor antagonist in the kidney immune injury in trichloroethylene-sensitized mice].

Objective: To explore the effect of complement C3 a-C3a receptor in the kidney immune inju-ry in trichloroethylene-sensitized mice by using C3a receptor specific antagonist C3aRA and discuss the patho-genesis of kidney injury in occupational dermatitis medicamentosa-like of trichloroethylene (ODMLT) . Methods: 42 female 6~8 weeks old BALB/c mice of specific pathogen free were randomly divided into blank control group (5) , solvent control group (5) , TCE treatment group (16) and TCE+C3aRA treatment group (16) . The TCE treat-ment group and TCE+C3aRA treatment group were further divided into the sensitized group and the non-sensi-tized group according to the skin sensitization test score. Renal function was detected by biochemical detection kit; expression of C3aR in kidney tissue was detected by qPCR; expression of IL-1ß and TNF-α protein were de-tected by immunohistochemical. Results: Compared with solvent control group and corresponding non-sensitized group, CRE and BUN in TCE sensitized group and TCE + C3aRA sensitized group were significantly increased (P<0.05) . Compared with TCE sensitized group, CRE and BUN in TCE+C3aRA sensitized group were signifi-cantly decreased (P<0.05) . Compared with solvent control group and TCE non-sensitized group, the expression level of C3aR gene in kidney tissue in TCE sensitized group was significantly increased (P<0.05) . There was a large number of IL-1ß and TNF-α protein expression in kidney tissue in TCE sensitized group and TCE+C3aRA sensitized group. Compared with the TCE sensitized group, the expression level of IL-1ß and TNF-α protein in kidney tissue in TCE+C3aRA sensitized group was significantly decreased (P<0.05) . Conclusion: C3a-C3aR may be involved in the kidney immune injury in TCE sensitized mice, C3aRA has a protective effect on the kid-ney immune injury in TCE sensitized mice.

Elevated levels of ferritin in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

OBJECTIVES: The aim of the study was to detect changes in the levels of ferritin heavy chain (FHC), ferritin light chain (FLC), and transferrin in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients and to analyze the correlations between the levels of these proteins and various clinical parameters. METHODS: Cerebrospinal fluid and serum samples were obtained from 54 ALS patients and 46 non-inflammatory neurological disease control (non-INDC) patients. CSF and serum FHC, FLC, and transferring levels were measured via the enzyme-linked immunosorbent method using a commercial ELISA kit, and the times from onset (durations), ALS functional rating scale-revised (ALSFRS-r) scores, and disease progression rates (DPRs) were analyzed by registered neurologists. Statistical analysis was performed via Prism software. RESULTS: Compared with controls, ALS patients exhibited significantly increased FHC and FLC levels in CSF, which were positively correlated with DPR and negatively correlated with duration. Serum transferrin levels were significantly increased in ALS patients but were not correlated with disease progression. FHC and FLC in CSF rapidly increased as the disease worsened. CONCLUSIONS: This study demonstrated that the clinical measurement of FHC and FLC in CSF may be beneficial for disease differentiation and evaluating progression in patients with ALS. Compared with levels in serum, the levels of FHC and FLC in CSF might be more reliable for diagnosing and assessing the progression of ALS.

[Role of kallikrein kinin system activation in kidney injury induced by trichloroethylene sensitized mice].

OBJECTIVE: Through testing the expression of complement C3 fragment C3b and iC3b, C5b-9 as well as indexes of KKS before and after using kallikrein-kinin system inhibitor PKSI-527, observing the relevant between KKS and complement system, we preliminary study on the mechanism how KKS works on the renal injury of sensitized mice model induced by trichloroethylene. METHODS: Female BALB/c mice (6~8 weeks) were randomly divided into blank control group (5), TCE treated group (15), PKSI-527+TCE treated group (15). Mice were sensitized with TCE in the 1,3,7,10 days, the first and the last challenge were on day 17 and 19. 24h before every challenge, mice in PKSI-527+TCE group were treated with intraperitoneal injection of KKS inhibitor PKSI-527 inhibitor (50mg/kg). Mice were killed 72h after the last challenge. The function of kidney in mice were detected and kidney B1R, B2R expression were detected using real-time quantitative PCR, mice kidney complement C3 fragments C3b, iC3b and C5b-9 deposition were also detected by chemoimmunology. RESULTS: Compared with blank control group, all indexes expressions in the solvent control group have no significant change. Compared with the solvent control group, BUN、Cr level and B1R、B2R level have an significant increase (P< 0.05) in TCE sensitized group and PKSI-527+TCE sensitized group; There is a sharp decrease in PKSI-527+TCE sensitized group compared to TCE sensitized group(P< 0.05). CONCLUSION: The renal damage in the TCE sensitization mouse model may aggravated by upregulate complement system followed by the activation of kallikrein-kinin system.

A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.

Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.

Increased levels of MIP-1α in CSF and serum of ALS.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis. No effective diagnostic test and cure exists for the disease at present. We detected the levels of MIP-1α in cerebrospinal fluid (CSF) and serum and then further evaluated whether MIP-1α levels correlate with the severity and progression of ALS. METHODS: We used ELISAs to detect MIP-1α levels from 58 patients with ALS and 45 age- and gender-matched controls. The patients with ALS were also clinically evaluated with the revised ALS functional rating scale (ALSFRS-r). Moreover, we followed up with 40 cases of ALS by way of call or clinic visit 4 years after enrollment in this study. Finally, we assessed the correlations between MIP-1α levels and various clinical parameters. RESULTS: We found that the levels of MIP-1α in patients with ALS significantly increased compared to controls and they were positively correlated with duration. MIP-1α showed negative correlations with disease progression rate and the decrease in ALSFRS-r. Furthermore, the cumulative survival of patients with ALS with high levels of MIP-1α exceeded patients with low MIP-1α levels. CONCLUSIONS: MIP-1α levels increased in both CSF and serum of patients with ALS, and it may be a potential neuroprotective biomarker in ALS.

Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS).

BACKGROUND: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m(2)/day on days 1-14 and cisplatin 60 mg/m(2) on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m(2) on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). RESULTS: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68-0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81-1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. CONCLUSIONS: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.

bFGF in the CSF and serum of sALS patients.

OBJECTIVES: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by selective motor neuron loss in the brain and spinal cord. The cause of this selective death of motor neurons is still unclear, but among several pathomechanisms that have been discussed, the loss of neurotrophic factors is one hypothesis. Basic fibroblast growth factor 2 (bFGF) may be a potential neurotrophic factor for slowing various neurodegenerative diseases, but its potential role in the prognosis of ALS is not known. METHODS: To explore the role of bFGF in ALS, we investigated changes in bFGF in the CSF and serum from patients with sALS and from the control group. Furthermore, we analyzed the correlations between bFGF, disease duration, disease progression rate, ALSFRS-r score and survival. RESULTS: The level of bFGF increased in both the CSF and serum in sALS patients. It was higher in patients with longer durations. It was negatively correlated with disease progression rates, especially in the later stages of sALS, but showed no linear correlation with ALSFRS-r. In an analysis of the relationship between bFGF and survival, we found that sALS patients with high levels of bFGF had significantly higher cumulative survival rates than patients with low levels of bFGF. DISCUSSION AND CONCLUSION: In conclusion, endogenous bFGF increased both in the CSF and serum of sALS patients and it may be a useful biomarker that could predict disease progression and survival.

Comparison of RECIST 1.0 and RECIST 1.1 on computed tomography in patients with metastatic colorectal cancer.

OBJECTIVE: We conducted this study to compare tumor measurement by computed tomography (CT) and tumor response assessment between Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 and RECIST 1.1 in patients with metastatic colorectal cancer (CRC). METHODS: We reviewed the medical records of patients with metastatic CRC who received first-line chemotherapy between January 2004 and December 2012 and compared CT tumor measurement using two RECIST versions. RESULTS: A total of 58 patients who had target lesions according to RECIST 1.0 were included in the study. The number of target lesions recorded by RECIST 1.1 was significantly lower than that by RECIST 1.0, with a decrease experienced in 48 patients (82.7%). Six patients had no target lesions because of the new criteria of RECIST 1.1 for lymph node size. Out of 95 lymph nodes from 58 patients, only 40% were defined as target lesions according to RECIST 1.1. The overall response rate of first-line chemotherapy according to RECIST 1.0 and 1.1 was 41.5 and 40.4%, respectively. The best tumor responses showed almost perfect agreement between RECIST 1.1 and RECIST 1.0 (ĸ = 0.913). Three patients showed disagreement of the best responses between the two RECIST versions. CONCLUSION: RECIST 1.1 showed a highly concordant response assessment with RECIST 1.0 in metastatic CRC and its clinical impact on therapeutic decisions was minimal.

Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis.

BACKGROUND: Many patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. PATIENTS AND METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980-2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. RESULTS: The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52-0.79, P < 0.0001] was observed with salvage chemotherapy. When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40-0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56-0.90, P = 0.004) for docetaxel. CONCLUSION: This meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer.

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201).

BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89-1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients.

BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Viscoelastic properties of silica nanoparticle monolayers at the air-water interface.

We have investigated the rheological behaviour of silica nanoparticle layers at the air-water interface. Both compressed and deposited layers have been studied in Langmuir troughs and with a bicone rheometer. The compressed layers are more homogeneous and rigid, and the elastic response to continuous, step and oscillatory compression are similar, provided the compression is fast enough and relaxation is prevented. The deposited layers are less rigid and more viscoelastic. Their shear moduli deduced from the oscillatory uniaxial compression are much smaller than those deduced from pure shear deformation suggesting that the effective shear rate is smaller than expected in the compression measurements.

Phase II study with oxaliplatin and S-1 for patients with metastatic colorectal cancer.

BACKGROUND: To evaluate the efficacy and safety of the combination of oxaliplatin and S-1 (OS) in treating metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients were those with measurable lesions, no previous history of chemotherapy (except adjuvant chemotherapy), an age of 18-70 years, and an Eastern Cooperative Oncology Group performance status of zero to two. Oxaliplatin 130 mg/m(2) was administered i.v. on day 1, and S-1 40 mg/m(2) b.i.d. was administered orally on days 1-14, every 3 weeks. RESULTS: Forty-eight patients (median age, 56 years) were enrolled: 23 had colon cancer, seven rectosigmoid colon cancer; and 18 rectal cancer. Of the 48 patients, 31 were diagnosed with metastatic cancer and 17 had relapsed cancer after surgery, with adjuvant chemotherapy or chemoradiotherapy. In total, 413 cycles were administered (median 6 per patient; range 2-24). Toxicity was evaluated in 48 patient and response in 46. Major toxic effects were grade 3/4 thrombocytopenia (13%) and neutropenia (10%). The overall response rate was 54% [95% confidence interval (CI) 40% to 68%]. The median time to progression and median survival time were 8.5 (95% CI 6.2-10.9) months and 27.2 (95% CI 20.3-34.0) months, respectively. CONCLUSIONS: These data indicate that the OS regimen is effective and well tolerated in patients with advanced colorectal cancer.

A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer.

This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (>or=65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m(-2) two times daily on days 1-14 every 3 weeks or S-1 40-60 mg two times daily according to body surface area on days 1-28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1-40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6-42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3-4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3-4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand-foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.

Incomplete Freund's adjuvant enhances locomotor performance following spinal cord injury.

Following spinal cord injury (SCI), the pathological sequelae which ensue through the secondary mechanisms of degeneration produce myelin deposits which are potent inhibitors of endogenous neuroregeneration. We have enhanced the immune-mediated response following a hemisection lesion by immunizing adult C57Bl/6 female mice against the inhibitor of neurite outgrowth Nogo-A(623-640) peptide. Moderate anti-Nogo-A(623-640) antibody titre levels were obtained by using Montanide as the adjuvant. However, this antibody response was not obtained using incomplete Freund's adjuvant (IFA). Significant benefit in locomotor performance was demonstrated only in animals which were vaccinated with IFA and not with Montanide. No further benefit could be demonstrated with the Nogo-A(623-640) peptide beyond that seen for adjuvant alone. These data imply that generating antibodies against Nogo-A(623-640) in vivo alone is not sufficient to enhance locomotor recovery and that subcutaneous injection of IFA prior to SCI can enhance locomotor performance.

Induction of endogenous neural precursors in mouse models of spinal cord injury and disease.

Adult neural precursor cells (NPCs) in the mammalian central nervous system (CNS) have been demonstrated to be responsive to conditions of injury and disease. Here we investigated the response of NPCs in mouse models of spinal cord disease [motor neuron disease (MND)] with and without sciatic nerve axotomy, and spinal cord injury (SCI). We found that neither axotomy, nor MND alone brought about a response by Nestin-positive NPCs. However, the combination of the two resulted in mobilization of NPCs in the spinal cord. We also found that there was an increase in the number of NPCs following SCI which was further enhanced by systemic administration of the neuregulatory cytokine, leukaemia inhibitory factor (LIF). NPCs were demonstrated to differentiate into astrocytes in axotomized MND mice. However, significant differentiation into the various neural cell phenotypes was not demonstrated at 1 or 2 weeks following SCI. These data suggest that factors inherent to injury mechanisms are required for induction of an NPC response in the mammalian spinal cord.