Molecular role of ascorbate in enhancement of NO production in activated macrophage-like cell line, J774.1

Ascorbate-enhanced nitric oxide (NO) production in lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-activated macrophage J774.1 cells through the inducible nitric oxide synthase (iNOS) pathway. The iNOS gene was synergistically induced by LPS and IFN-gamma. The inductive mechanism of ascorbate on the iNOS gene was studied by examining the degradation of I kappa B alpha by Western blotting, activation of the nuclear factor kappa B (NF-kappa B) by gel shift assays, and protein levels of interferon regulatory factor 1 (IRF-1) in LPS- and IFN-gamma-activated cells. Ascorbate had no effect on the onset of either I kappa B alpha degradation or the nuclear translocation of NF-kappa B, but it delayed the recovery of I kappa B alpha. The prolonged degradation of I kappa B alpha caused by ascorbate in LPS- and IFN-gamma-activated cells paralleled elevated NF-kappa B binding to DNA, which led to an increase in the iNOS protein level. Ascorbate alone did not induce I kappa B alpha degradation or NF-kappa B activation. Furthermore, ascorbate exerted no effect on the expression of I kappa B alpha and ubiquitin genes in the activated cells. Ascorbate could modulate NF-kappa B DNA binding activity in response to combined LPS and IFN-gamma activation, which increases NO production in activated macrophages.     

Examination of inhibitory effect, safety and usefulness of SN-307 (ondansetron) administered orally once daily for 3-5 consecutive days on nausea and emesis associated with non-platinum anti-cancer drugs]

We examined the anti-emetic effect, safety and usefulness of ondansetron hydrochloride, a selective 5-HT3 receptor antagonist, given orally once daily at the dosage of 4 mg, for 3 to 5 consecutive days to patients with nausea and emesis induced by non-platinum anti-cancer drugs such as cyclophosphamide, doxorubicin and carboplatin. Out of 84 cases where anti-emetic effects were evaluated, numbers of cases assessed as excellent and good were 36 (83.3%) and 34 (40.5%), respectively, the efficacy rate being 83.3% (70/84). Side effects, such as moderate constipation (3 cases) and mild headache (3 cases), were observed in 8/85 cases (9.4%). Abnormalities in clinical laboratory findings including elevation of hepatic function and uricacid values and increase in eosinocyte counts, were observed in 3/85 cases (3.5%). As to overall safety, 78/85 cases (91.8%) were evaluated as having no problem in safety, and 7/85 cases (8.2%), as having minor problem in safety. As to clinical usefulness based on anti-emetic effect and overall safety, out of 79 cases the drug was assessed as very useful in 29 cases (36.7%) and useful in 35 cases (44.3%), the rate of "useful" or above being 81.0% (64/79). Furthermore, when ondansetron was administered in 3 courses of chemotherapy, though the number of patients was small, it was shown that anti-emetic effect of ondansetron did not decline and no problem in safety was observed. From the above, ondansetron which exerted adequate anti-emetic effect in 4 mg once daily doses was considered as a useful and safe anti-emetic in treatment of nausea and emesis associated with cancer chemotherapy.     

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.     

Behavioral outcome including attention deficit hyperactivity disorder/hyperactivity disorder and minor neurological signs in perinatal high-risk newborns at 4−6 years of age with relation to risk factors

BACKGROUND: Diagnostic problems with the criteria of attention deficit hyperactivity disorder (ADHD) in the Diagnostic Statistical Manual, 4th edn, have been identified. The aim of this study was to clarify whether the minor neurological signs test (MNT) the authors had previously reported was a predictor for the criteria of ADHD or hyperactivity disorder (HD) in perinatal risk children at 4-6 years of age and what kind of risk factors related to MNT. METHODS: A total of 136 children discharged from neonatal intensive care units were examined at the age of 4-6 years by a developmental neuropediatrician using both MNT and diagnostic criteria of DSM-IV ADHD/ICD-10 (International Classification of Diseases, 10th edn) HD. SPSS base and professional were used for statistical analysis. RESULTS: On comparison of diagnostic criteria between ADHD (11.0%) and HD (27.5%), the incidence in the same subjects showed significant difference. MNT scores showed significant correlation with criteria of ADHD (P < 0.01) and HD (P < 0.05). Diagnostic validity of MNT for predicting ADHD was demonstrated with 78% sensitivity and 79% specificity. High positive rates on MNT did not show a significant difference between the very low birthweight (VLBW) and non-low birthweight (NLBW) groups. Behavioral outcome with relation to risk factors were analyzed using multiple regression analysis. Apgar 5 in the NLBW group and toxemia of pregnancy and small for gestational age (SGA) in VLBW group were highly correlated with behavioral outcome. CONCLUSIONS: Minor neurological signs test score was a significant predictor for criteria of ADHD and HD. High incidences of positive MNT were suspected in not only VLBW children but also NLBW children and Apgar 5 in NLBW children and toxemia of pregnancy and SGA in VLBW children influenced behavioral outcome.     

18F]fluorodeoxyglucose uptake by positron emission tomography predicts outcome of non-small-cell lung cancer.

PURPOSE: To determine whether the standardized uptake value (SUV) of [(18)F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. RESULTS: There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs ( 5.0; surgery group, P = .02; radiotherapy group, P = .0005). Low SUVs ( 5.0; stage I or II, P = .02; stage IIIa or IIIb, P = .004). However, using the same cutoff point of 5, the SUV for regional lymph nodes was not a significant indicator for DFS (P = .19), LRC (P = .97), or DMFS (P = .17). The multivariate analysis showed that the SUV for the primary tumor was a significant prognostic factor for OS (P = .03) and DFS (P = .001). CONCLUSION: The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.     

Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma.

PURPOSE: The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is much better in patients with pathologic complete response than those with residual tumor. Some adenocarcinomas have mixed patterns, including signet-ring cell and mucinous histology, but the clinical significance of these subtypes is unknown. EXPERIMENTAL DESIGN: We studied 412 consecutive patients with esophageal or EGJ adenocarcinoma treated with chemoradiation followed by esophagectomy (193 patients) or surgery alone (219 patients). We evaluated signet-ring cell and mucinous histology in the resection and pretherapy biopsy specimens and compared clinicopathologic features with overall survival. RESULTS: The fraction of signet-ring cell and mucinous histology was similar in evaluated specimens of patients treated with preoperative chemoradiation or surgery alone (17% and 18%, respectively). The overall survival rate at 5 years of patients treated with preoperative chemoradiation was significantly better if residual signet-ring cell or mucinous histology was present in the esophagectomy specimen (63% versus 28%; P = 0.02). All 13 patients with acellular mucin pools and no residual carcinoma are still alive after an average follow-up time of 36 months. By contrast, in patients treated with surgery alone, overall survival rate was significantly worse if signet-ring cell or mucinous histology was present (14% versus 30%; P = 0.05). In multivariate analysis, overall survival was independently predicted by presence of signet-ring cell or mucinous histology (P = 0.04). CONCLUSIONS: Our study showed that patients with esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from preoperative chemoradiation and esophagectomy.     

Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01.

PURPOSE: To test the ability of the cytoprotectant, amifostine, to reduce chemoradiotherapy-induced esophagitis and evaluate its influence on quality of life (QOL) and swallowing symptoms. PATIENTS AND METHODS: A total of 243 patients with stage II to IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m(2) intravenously (IV) days 1 and 22 and carboplatin area under the curve (AUC) days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m(2) IV) and carboplatin (AUC 2), and hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy bid). Patients were randomly assigned at registration to amifostine (AM) 500 mg IV four times per week or no AM during chemoradiotherapy. Beyond standard toxicity end points, physician dysphagia logs (PDLs), daily patient swallowing diaries, and QOL (EORTC QLQ-C30/LC-13) were also collected. Swallowing AUC analyses were calculated from patient diaries and PDLs. RESULTS: A total of 120 patients were randomly assigned to receive AM, and 122, to receive no AM (one patient was ineligible); 72% received AM per protocol or with a minor deviation. AM was associated with higher rates of acute nausea (P = .03), vomiting (P = .007), cardiovascular toxicity (P = .0001), and infection or febrile neutropenia (P = .03). The rate of >/= grade 3 esophagitis was 30% with AM versus 34% without AM (P = .9). Patient diaries demonstrated lower swallowing dysfunction AUC with amifostine (z test P = .025). QOL was not significantly different between the two arms, except for pain, which showed more clinically meaningful improvement and less deterioration at 6 weeks follow-up (v pretreatment) in the AM arm (P = .003). The median survival rates for both arms were comparable (AM, 17.3 v no AM, 17.9 months; P = .87). CONCLUSION: AM did not significantly reduce esophagitis >/= grade 3 in patients receiving hyperfractionated radiation and chemotherapy. However, patient self-assessments suggested a possible advantage to AM that is being explored with modified dosing route strategies.     

Cell-killing Activity and Kinetic Analysis of a Novel Antitumor Compound NC-190, a Benzo[a]phenazine Derivative

A novel antitumor compound, N-β-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190), was evaluated for antitumor activity in vitro against cultured tumor cell lines, and the kinetics of cell killing was elucidated. NC-190 strongly inhibited the growth of all of 3 murine tumor cell lines, 7 human tumor cell lines and 2 normal cell lines. With continuous exposure, the 50% inhibition concentrations were in the range of 0.005–0.06 μg/ml, except for KATO-III (2.15 μ g/ml). By colony-forming assay, concentrations of NC-190 giving 90% cell kill (IC₉₀) at various exposure times were obtained with HeLa S3 cells. The plot of IC₉₀exposure time on a log-log scale was linear for NC-190 with a slope of -1, which is typical for cell cycle phase-nonspecific agents. A 2 h treatment with NC-190 induced a rapid reduction in cell viability at doses of more than 3 μ g/ml. At the dose where colony formation was completely inhibited, cell viability was persistently reduced to below 20% during the cell culture period. NC-190 cauced a dose- and time-dependent reduction in DNA synthesis. The inhibitions of RNA and protein synthesis were less than that of DNA synthesis. Spectroscopic studies of NC-190 mixed with calf thymus DNA demonstrated that NC-190 was capable of interacting with DNA. However, DNA thermal denaturation studies suggested that intercalation of NC-190 was weak in comparison with those of classical intercalating drugs.     

Concurrent deletion of BMP4 and OTX2 genes,two master genes in ophthalmogenesis

BMP4 and OTX2 are master genes in ophthalmogenesis. Mutations of BMP4 and OTX2 often lead to eye defects, including anophthalmia–microphthalmia. A significant degree of variable expressivity has been reported in heterozygous individuals with BMP4 or OTX2 mutation. Interestingly, both BMP4 and OTX2 reside on 14q22, being only 2.8 Mb apart. Previous studies reported that among three patients with 14q22 deletion involving BMP4 and OTX2, all had severe eye defects. The minimal degree of variable expressivity among these individuals who were doubly deleted for BMP4 and OTX2 could be attributed to the combinatorial relationship of the two genes observed in animal models. We herein report a patient with a concurrent deletion of BMP4 and OTX2 who exhibited bilateral microphthalmia, more specifically, anterior segment dysgenesis with microcornea. Evolutionarily conserved physical linkage of Bmp4 and Otx2 loci may suggest an advantage of the proximal alignment of the two genes. Another striking feature in the propositus was the progressive white matter loss observed by serial neuroimaging. A review of twelve previously reported patients with 14q22 microdeletion revealed decreased white matter volume in half of the patients. It remains to be elucidated whether the white matter lesion is age-dependent and progressive. In conclusion, anterior segment defects of the eyes, especially when accompanied by decreased white matter volume on neuroimaging, should raise the clinical suspicion of 14q22 microdeletion.     

Study of the distribution by age group of serum cross-linked C-terminal telopeptide of type I collagen and procollagen type I N-propeptide in healthy Japanese women to establish reference values

Osteoporosis prevention is an important public health goal. Bone turnover markers are clinically measured to assess bone strength. C-terminal telopeptide of type I collagen (CTX) is released when collagens degrade and serves as an indicator of bone resorption. Simple CTX immunoassays are now available. However, serum CTX (sCTX) reference ranges for Japanese women are lacking. Procollagen type I N-propeptide (intact P1NP) reflects osteoblast activity, serving as a marker of bone formation. Because sCTX and intact P1NP are clinically applied as bone turnover markers, we determined reference ranges for both sCTX and intact P1NP in healthy Japanese women. We collected 228 blood samples from healthy Japanese women aged 19–83 years, grouped by age and menopausal status. We measured sCTX and intact P1NP and examined their correlation. sCTX values differed significantly between the two consecutive decade groups encompassing 19–39 years of age, intact P1NP values between 20 and 30 s, between post-menopausal 50 and 60 s, and between pre-and post-menopausal women in their 50 s. The mean sCTX of 91 healthy pre-menopausal women was 0.255 (0.100–0.653) ng/mL, the intact P1NP in 90 women 33.2 (17.1–64.7) μg/L. Corresponding values for post-menopausal women were 0.345 (0.115–1.030) ng/mL and 41.6 (21.9–79.1) μg/L. sCTX correlated with intact P1NP. Bone resorption markers are measured to assess anti-resorption agents, bone formation markers to assess the effects of bone-forming agents. The sCTX and intact P1NP reference values determined herein, in healthy Japanese women, are expected to be useful for osteoporosis treatment, assessment of fracture risk, and other clinical applications.