Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

Clinical efficacy and safety of monthly oral ibandronate 100 mg versus monthly intravenous ibandronate 1 mg in Japanese patients with primary osteoporosis.

UNLABELLED: The MOVEST study evaluated the efficacy and safety of monthly oral ibandronate versus licensed monthly IV ibandronate in Japanese osteoporotic patients. Relative BMD gains after 12 months were 5.22 % oral and 5.34 % IV, showing non-inferiority of oral to IV ibandronate (primary endpoint). No new safety concerns were identified. INTRODUCTION: The randomized, phase 3, double-blind MOVEST (Monthly Oral VErsus intravenouS ibandronaTe) study evaluated the efficacy and safety of monthly oral ibandronate versus the licensed monthly intravenous (IV) ibandronate regimen in Japanese patients with osteoporosis. METHODS: Ambulatory patients aged ≥ 55 years with primary osteoporosis were randomized to receive oral ibandronate 100 mg/month plus monthly IV placebo, or IV ibandronate 1 mg/month plus monthly oral placebo. The primary endpoint was non-inferiority of oral versus IV ibandronate with respect to bone mineral density (BMD) gains at the lumbar spine after 12 months of treatment. RESULTS: Four hundred twenty-two patients were enrolled with 372 patients in the per-protocol set (183 and 189 in the oral and IV ibandronate groups, respectively). The relative change from baseline in lumbar spine BMD values for the oral and IV ibandronate groups, respectively, was 5.22 % (95 % confidence interval [CI] 4.65, 5.80) and 5.34 % (95 % CI 4.78, 5.90). The least squares mean difference between the two groups was -0.23 % (95 % CI -0.97, 0.51), showing non-inferiority of oral ibandronate to IV ibandronate (non-inferiority limit = -1.60). Changes in BMD values at other sites, and bone turnover marker levels in the oral ibandronate group, were comparable with those of the IV group. The safety profile was similar to that previously demonstrated; no new safety concerns were identified. CONCLUSIONS: This study demonstrated the non-inferiority of oral ibandronate 100 mg/month to IV ibandronate 1 mg/month (licensed dose in Japan) in increasing lumbar spine BMD in Japanese patients with primary osteoporosis.

A theory of the spin-crossover phenomena in the rare earth perovskite LaCoO3induced by temperature or a magnetic field.

Published magnetic data for LaCoO3are successfully analyzed with coexisting5Dand low-spin (LS) cobalt states. Energy levels of the two states are derived in analytic forms. To this end, fictitious orbital angular momentumlof magnitude one defines the Γ5(5D) state. Our Hamiltonian includes the spin-orbit interaction, and a cubic crystal field embellished by a trigonal distortion9B20(lz2-2/3)-80B40(lz2-9/10). A singlet ground state with an energy gap to the first excited doublet is realized for certain values of the parameters. The temperature-independent paramagnetic susceptibility (TIPS) of the5Dstate has a finite value, which accords with the observation. Whereas, TIPS is symmetry forbidden in the LS state. A rigorous calculation is made of the excitation spectrum in the LS state. The elementary excitation is modeled as a creation of an electron-hole pair that results in an energy level scheme in which the first excited quartet lies above the singlet ground state. The electron spin resonance data are successfully equated with transitions within the excited quartet. Available magnetization data delineate parameters in the5DHamiltonian. The temperature dependence of the susceptibility of our coexisting model is qualitatively reasonable. To improve on a quantitative outcome, we are led to introduce a temperature dependent concentration for the5Dand LS states. Calculated Bragg diffraction patterns gathered with x-rays tuned to the CoK-edge reveal potential to refine the current crystal structure and to shed light on the origin of the coexisting states.

A study of the incidence of implantation cyst at anastomotic sites after low anterior resection of the rectum with the double stapling technique.

BACKGROUND: The incidence of implantation cyst occurring at sites of anastomosis after low anterior resection of the rectum were studied in two different periods depending on the type of surgical devices used to close the rectal stump. SUBJECTS: The study included 361 patients undergoing the surgery during the first 8-year period between 1996 and 2003 and 87 patients undergoing the surgery during the second 3-year period between 2004 and 2006. RESULTS: Implantation cysts were found in nine (2.5%) of the patients undergoing the surgery during the first period and one of them also had local recurrence. Implantation cysts occurred 9 to 31 months postoperatively (mean, 17.1 +/- 6.9 months). Clinical symptoms were noted in one patient and treatment of the cysts, including local recurrence, was given to two patients. Anastomosis of the distal rectum was performed with the Roticulator or the Access 55 in all patients. Although implantation cysts were found in any patient undergoing surgery during the second period, no statistically significant difference was recognized (p = 0.217). Anastomosis of the distal rectum was performed with the TX30 in all patients. CONCLUSION: The pathogenesis of implantation cysts may be explained by the production of mucus when the mucosal epithelium of the colon is caught under the submucosa, forming a cyst after closure of the rectal stump, and the difference in the incidence rates of implantation cyst was presumably due to the characteristics of the device used and progress of the operative procedure.

Analysis of autonomic nerve preservation and pouch reconstruction influencing fragmentation of defecation after sphincter-preserving surgery for rectal cancer.

Our questionnaire survey on defecation disorders after rectal cancer surgery revealed that 66.7% of postoperative patients were most annoyed with fragmentation of defecation. Therefore, we performed a change-over-time analysis on the relationship of fragmentation and factors including location of rectal cancer, surgical technique, anastomosis method, pouch reconstruction, extent of lymph node dissection, and degree of pelvic and colonic nerve preservation surrounding the superior mesenteric artery. The fragmentation decreased over time at the postoperative time points of 6 months, 2 and 5 years. A statistical analysis of factors influencing fragmentation revealed that location of cancer, reconstruction technique, anastomosis method and degree of pelvic nerve preservation were significant factors for the entire patient population and that colonic nerve preservation was a significant factor 5 years after surgery. Analysis of patients with lower rectal cancer only showed that in addition to surgical technique and anastomosis method, pouch reconstruction was effective and autonomic nerve preservation was effective 5 years after surgery. As a result, when the anastomotic site was closer to the anus, the frequency of fragmentation increased; we concluded that pouch reconstruction was an effective surgical technique and colonic nerve preservation was effective in the longer term.

Reversal of freshening trend of Antarctic Bottom Water in the Australian-Antarctic Basin during 2010s.

The Antarctic continental margin supplies the densest bottom water to the global abyss. From the late twentieth century, an acceleration in the long-term freshening of Antarctic Bottom Waters (AABW) has been detected in the Australian-Antarctic Basin. Our latest hydrographic observations reveal that, in the late 2010s, the freshening trend has reversed broadly over the continental slope. Near-bottom salinities in 2018-2019 were higher than during 2011-2015. Along 170° E, the salinity increase between 2011 and 2018 was greater than that observed in the west. The layer thickness of the densest AABW increased during the 2010s, suggesting that the Ross Sea Bottom Water intensification was a major source of the salinity increase. Freshwater content on the continental slope decreased at a rate of 58 ± 37 Gt/a in the near-bottom layer. The decadal change is very likely due to changes in Ross Sea shelf water attributable to a decrease in meltwater from West Antarctic ice shelves for the corresponding period.

Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy through alkali solution treatments.

Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) was performed through three different alkali solution treatments, including the electrochemical (E), hydrothermal (H), and hydrothermal-electrochemical (HE) processes; all of the processes lead to the formation of sodium-contained amorphous titanium oxide layers on TNTZ samples. The TNTZ samples subjected to the E, H, and HE processes exhibit a flat surface, smooth and fine mesh-like structure surface, and rough mesh-like structure surface, respectively. In the bioactive test, namely, simulated body fluid test, apatite inductivity increases as the surface morphology becomes rough. The order of inductivity for the three processes was HE>H>E. The surface chemical composition also affects the apatite induction ability. The surface with fewer niobium species exhibits better apatite inductivity.

Adhesive strength of bioactive oxide layers fabricated on TNTZ alloy by three different alkali-solution treatments.

Bioactive oxide layers were fabricated on Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) by three different alkali solution treatments: hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE). The adhesive strength of the oxide layer to the TNTZ substrate was measured to determine whether this process achieves sufficient adhesive strength for implant materials. Samples subjected to the HE process, in which a current of 15mA/cm(2) was applied at 90°C for 1h (HE90-1h), exhibited a comparatively higher adhesive strength of approximately 18MPa while still maintaining a sufficiently high bioactivity. Based on these results, an oxide layer fabricated on TNTZ by HE90-1h is considered appropriate for practical biomaterial application, though thicker oxide layers with many cracks can lead to a reduced adhesive strength.

Changes in Ocean Heat, Carbon Content, and Ventilation: A Review of the First Decade of GO-SHIP Global Repeat Hydrography.

Global ship-based programs, with highly accurate, full water column physical and biogeochemical observations repeated decadally since the 1970s, provide a crucial resource for documenting ocean change. The ocean, a central component of Earth's climate system, is taking up most of Earth's excess anthropogenic heat, with about 19% of this excess in the abyssal ocean beneath 2,000 m, dominated by Southern Ocean warming. The ocean also has taken up about 27% of anthropogenic carbon, resulting in acidification of the upper ocean. Increased stratification has resulted in a decline in oxygen and increase in nutrients in the Northern Hemisphere thermocline and an expansion of tropical oxygen minimum zones. Southern Hemisphere thermocline oxygen increased in the 2000s owing to stronger wind forcing and ventilation. The most recent decade of global hydrography has mapped dissolved organic carbon, a large, bioactive reservoir, for the first time and quantified its contribution to export production (∼20%) and deep-ocean oxygen utilization. Ship-based measurements also show that vertical diffusivity increases from a minimum in the thermocline to a maximum within the bottom 1,500 m, shifting our physical paradigm of the ocean's overturning circulation.

Effect of GroEL on the re-folding kinetics of alpha-lactalbumin.

The effect of GroEL on the re-folding kinetics of apo- and holo-alpha-lactalbumin from the acidic molten globule state has been investigated by stopped-flow fluorescence measurements. GroEL retards the re-folding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. The binding constant was estimated to be in the order of 10(5) M-1 by analyzing the kinetic data quantitatively and was found to be much weaker than the binding between GroEL and disulfide-bond reduced alpha-lactalbumin, whose binding constant is in the order of 10(7) M-1. Our present results, together with the previous results, suggest that the state recognized by GroEL is not unique and that the binding strength varies with the state of a target protein. The binding between GroEL and the molten globule state of apo-alpha-lactalbumin becomes stronger with an increasing salt concentration; the binding constant is increased tenfold (from 10(5) to 10(6) M-1) by an increase in salt concentration from 0.05 to 0.25 M. The study of the effect of GroEL on the re-folding kinetics of holo-alpha-lactalbumin, which is represented by a bi-phasic process, shows that the slow phase is affected by GroEL in the same manner as observed in the apo-alpha-lactalbumin re-folding but that the fast phase is not affected by GroEL at all. This indicates that the binding rate of GroEL is faster than the slow phase but slower than the fast phase of the re-folding, and the bi-molecular rate constant of GroEL binding to the molten globule state of alpha-lactalbumin was estimated to be in the order of 10(6) M-1S-1.

Dominant forces in the recognition of a transient folding intermediate of alpha-lactalbumin by GroEL.

GroEL is known to retard the refolding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. In order to investigate the dominant forces in this interaction, the GroEL-affected kinetic refolding of apo-alpha-lactalbumin from its acidic molten globule state was studied at different temperatures and in the presence of different kinds of monovalent cations at a fixed temperature (25 degrees C), by stopped-flow fluorescence measurements. The binding constant between GroEL and alpha-lactalbumin in the molten globule state was evaluated quantitatively from the kinetic refolding curves in the absence and presence of GroEL. The binding was found to be entropy-driven at room temperature and the heat capacity change for the binding was found to be largely negative (-3.6 kJ mol-1.K-1), indicating that GroEL binds to alpha-lactalbumin through hydrophobic interactions. The study of the effect of different monovalent cations at various ionic strengths shows that the binding is strengthened by electrostatic screening by ions, demonstrating the importance of electrostatic interactions. The relationship of these results with a putative target recognition site of GroEL will be discussed.

1,25-dihydroxyvitamin D3 as well as its analogue OCT lower blood calcium through inhibition of bone resorption in hypercalcemic rats with continuous parathyroid hormone-related peptide infusion.

The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue 22-oxa-1,25(OH)2D3 (22-oxacalcitriol) (OCT) on calcium and bone metabolism were examined in an animal model of hypercalcemia with continuous infusion of parathyroid hormone-related peptide (PTHrP), to determine whether active vitamin D could counteract the skeletal action of PTHrP in addition to its reported effect in suppressing the production of PTHrP in cancer cells. Parathyroid glands were removed from 8-week-old Sprague-Dawley rats to eliminate the confounding effects of endogenous PTH. Animals were then continuously infused with human PTHrP(1-34) at a constant rate via osmotic minipumps for 2 weeks, and at the same time treated orally or intravenously with OCT or 1,25(OH)2D3 four to nine times during the 2-week period. Under these conditions, OCT and, surprisingly, 1,25(OH)2D3 alleviated hypercalcemia in a dose-dependent manner. 1,25(OH)2D3 and OCT suppressed the urinary excretion of deoxypyridinoline, although they did not affect renal calcium handling, suggesting that the antihypercalcemic effect is attributable to the inhibition of bone resorption. These active vitamin D compounds also counteracted the effects of PTHrP at the proximal renal tubules, as reflected by a decrease in phosphate excretion. Histomorphometric analysis of bone revealed a dose-related decrease in parameters of bone resorption. These results suggest that 1,25(OH)2D3 as well as OCT has the potential to alleviate hypercalcemia, at least in part, through the inhibition of bone resorption in hypercalcemic rats with constant PTHrP levels. We propose that the main function of active vitamin D in high bone-turnover states is to inhibit bone resorption, and this may have important implications for the understanding of the role of active vitamin D in the treatment of metabolic bone diseases, such as osteoporosis.

Effect of combination treatment with a vitamin D analog (OCT) and a bisphosphonate (AHPrBP) in a nude mouse model of cancer-associated hypercalcemia.

Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 microg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.

Nucleotide sequence of the ribostamycin phosphotransferase gene and of its control region in Streptomyces ribosidificus.

The nucleotide sequence of an aminoglycoside phosphotransferase gene (rph) from Streptomyces ribosidificus (a ribostamycin producer) was determined. Molecular size, amino acid composition and N-terminal amino acid sequence of the purified rph product confirmed the position of the coding region deduced from the nucleotide sequence. The 5' region of rph has been tested for its transcriptional controls; high-resolution mung-bean nuclease mapping of in vivo transcripts revealed one major start point, rphS1, controlled by the rphP1 promoter. This transcript was also observed in vitro in run-off experiments using purified Streptomyces RNA polymerase. This transcriptional start point coincided with the translational start site, with the mRNA 5' terminus being pppATG. The results of promoter-probing tests and insertion of a transcriptional termination fragment into the rph promoter region have shown that the rphP1 transcript was sufficient and essential for rph expression.

The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord.

A capsaicin test involving peripheral nociception, which produces behaviour similar to that elicited by formalin, is described in mice. Capsaicin was injected subcutaneously (s.c.) into the dorsal surface of a hindpaw and the time the animals spent licking the paw was recorded. Doses of capsaicin of 6.25-1600 ng induced nociception, during a period of 5 min, starting immediately after injection and disappearing completely at 10 min. Intrathecally (i.t.) administered [D-Arg1,D-Trp7,9,Leu11]substance P (spantide), a tachykinin antagonist and [D-Phe7,D-His9]substance P (6-11), a selective antagonist of substance P (SP), inhibited the capsaicin-induced behaviour, in a dose-dependent manner. This licking behaviour was also inhibited by intrathecal administration of SP antiserum but not by somatostatin (SOM) antiserum. Intrathecal pretreatment with capsaicin resulted in a marked reduction of the licking response, following subcutaneous injection of capsaicin into the paw. Capsaicin-induced licking was not affected by intrathecal administration of cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-(OBz)-Thr], a SOM antagonist and by intrathecal pretreatment with cysteamine, a SOM depletor. This nociceptive test may allow discrimination between SP- and SOM-mediated responses in the spinal cord of the mouse.

Plasma tumor necrosis factor alpha levels and the -238*A promoter polymorphism in patients with antiphospholipid syndrome.

OBJECTIVES: To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFalpha in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNFalpha and disease. PATIENTS AND METHOD: We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFalpha levels were determined in plasma from 35 patients' and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. RESULTS: TNFalpha levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p <0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306.5], p <0.0001). CONCLUSIONS: Raised plasma TNFalpha levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFalpha may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNF genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.

The role of orally administered dimethylarsinic acid, a main metabolite of inorganic arsenics, in the promotion and progression of UVB-induced skin tumorigenesis in hairless mice.

The effect of dimethylarsinic acid (DMA) on skin tumorigenesis by UVB irradiation was examined. Hairless mice (Hos: HR-1) irradiated with UVB at a dose of 2 kJ/m(2) twice weekly, were fed with drinking water containing 1000 ppm DMA, a main metabolite of inorganic arsenics, produced more skin tumors than DMA-untreated mice. Histopathological examination revealed that the mouse malignant tumors with severe atypism appeared only in the treatment group of UVB plus 1000 ppm DMA. These positive results point out the importance of dimethylated metabolites of inorganic arsenic in the process of skin carcinogenesis.

Hydrogen-exchange kinetics of reduced alpha-lactalbumin bound to the chaperonin GroEL.

alpha-Lactalbumin in which all the disulfide bonds are fully reduced (RLA) is known to bind strongly to the chaperonin GroEL. Although RLA is more unfolded than the native state and the molten globule state of alpha-lactalbumin, the CD spectrum of RLA in the far-UV region shows that RLA is not fully unfolded but has an appreciable amount of secondary structure. To investigate whether the secondary structure elements present in RLA are responsible for the recognition of RLA by GroEL or not, we have examined the hydrogen-exchange kinetics of RLA in the presence and absence of GroEL. Our results show that the hydrogen-exchange kinetics of RLA bound to GroEL is identical to that of free RLA. This implies that the secondary structure elements in RLA are not important for the recognition by GroEL, but the unstructured parts of RLA that are not relevant to the stability of the secondary structure provide strong recognition sites of RLA.