External validation of a genitourinary cancer-specific prognostic scoring system to predict survival for patients with bone metastasis (modified B-FOM scoring model): Comparison with other scoring models in terms of accuracy.

OBJECTIVE: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score. METHODS: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves. RESULTS: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models. CONCLUSIONS: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected.

Comparison of cancer detection rates by transrectal prostate biopsy for prostate cancer using two different nomograms based on patient's age and prostate volume.

BACKGROUND: The aim of this study is to evaluate the efficacy of two different Nara Urological Research and Treatment Group (NURTG) nomograms allocating 6-12 biopsy cores based on age and prostate volume. MATERIALS AND METHODS: From April 2006 to July 2014, a total of 1,605 patients who underwent initial prostate biopsy were enrolled. Based on a nomogram taking the patient's age and prostate volume into consideration, 6-12 biopsy cores were allocated. Two types of nomogram were used, for the former group (before March 2009) and latter group (March 2009 onward). Cancer detection rates in all patients and those with prostate-specific antigen values in the gray zone (4.0-10 ng/mL) were compared. Predictive parameters for detection of prostate cancer in gray-zone patients were also investigated. RESULTS: The cancer detection rates in all patients and those in the gray zone were 48% and 38% in the former group and 54% and 41% in the latter group, respectively. The cancer detection rate in all patients was significantly higher in the latter group compared with the former group, but detection in gray-zone patients did not show a significant difference between the two groups (P=0.011 and P=0.37, respectively). Multivariate analysis indicated that age, digital rectal examination, prostate volume, transrectal ultrasonography findings, and volume/biopsy ratio were significant predictive parameters in gray-zone patients. The clinically insignificant cancer detection rate was significantly lower in the latter group compared with the former group (P=0.0008). CONCLUSION: The latter nomogram provided more acceptable detection rates of clinically significant and insignificant cancer than the former one, and we consider that an initial maximum 12-core transrectal ultrasound-guided needle biopsy may be sufficient for prostate cancer diagnosis.

Clinical benefit of early treatment with bone-modifying agents for preventing skeletal-related events in patients with genitourinary cancer with bone metastasis: A multi-institutional retrospective study.

OBJECTIVES: To evaluate the clinical benefit of bone-modifying agents and identify the risk factors of skeletal-related events in patients with genitourinary cancer with newly diagnosed bone metastasis. METHODS: This was a multicenter retrospective study including a total of 650 patients with bone metastasis of the following cancer types: hormone-sensitive prostate cancer (n = 443), castration-resistant prostate cancer (n = 50), renal cell carcinoma (n = 80) and urothelial carcinoma (n = 77). Clinical factors at the time of diagnosis of bone metastasis were analyzed. Early treatment with bone-modifying agents was defined as follows: administration of bone-modifying agents before the development of skeletal-related events and within 6 months from the diagnosis of bone metastasis. RESULTS: During the follow-up period (median 19.0 months, interquartile range 6.0-43.8 months), skeletal-related events were reported in 88 (20%) patients with hormone-sensitive prostate cancer, 17 (34%) patients with castration-resistant prostate cancer, 58 (73%) patients with renal cell carcinoma and 34 (44%) patients with urothelial carcinoma. Early treatment with bone-modifying agents significantly prolonged the time to the first skeletal-related event in castration-resistant prostate cancer, renal cell carcinoma and urothelial carcinoma, but not in hormone-sensitive prostate cancer. Bone pain and elevated alkaline phosphatase levels were independent predictive risk factors of the first skeletal-related event. The subgroup analysis showed that early treatment with bone-modifying agents was associated with prolonged time to the first skeletal-related events in patients with bone pain or elevated alkaline phosphatase levels. CONCLUSIONS: Early treatment with bone-modifying agents should be considered, especially for patients with bone pain and elevated alkaline phosphatase levels, to prevent skeletal-related events in patients with genitourinary cancer with bone metastasis.

[THE RISK FACTORS AND CHEMOPREVENTION OF FEBRILE URINARY TRACT INFECTION AFTER TRANSURETHRAL URETEROLITHOTRIPSY].

(Objectives) Transurethral Ureterolithotripsy (TUL) has become an increasingly more common treatment for ureteric stones since the reduction in ureteroscope diameter and other device improvements. At the same time, TUL sometimes shows postoperative febrile urinary tract infection (fUTI) with severe complications. Therefore we investigated the occurrence and risk factors of fUTI in our hospital, and assessed the effect of antibiotic prophylaxis prior to TUL. (Materials and methods) The subjects were 260 patients who underwent TUL in our department during the period from January 2011 to October 2014. We retrospectively reviewed the data of those who developed postoperative fUTI and identified the risk factors of postoperative fUTI. From November 2014 to August 2016, we enrolled 110 patients undergoing TUL with one or more risk factors in a prospective clinical trial of prophylactic oral levofloxacin (500 mg) for 1 week before TUL. The chi-squared test, Mann-Whitney U-test, and logistic regression analysis were used for data analysis (significance level of 0.05). (Results) Postoperative fUTI occurred in 43 (16.5%) of 260 patients. The risk factors of postoperative fUTI included preoperative pyelonephritis (P=0.02), preoperative ureteral stent placement (P=0.017), and operative time >90 min (P=0.005). Operative time was correlated with and could be substituted for pre-TUL stone size (P<0.0001). Chemopreventive therapy before TUL in patients with preoperative pyelonephritis, preoperative ureteral stent placement, or stones of >20 mm significantly reduced their risk of fUTI (P=0.012). (Conclusions) The use of antibiotic prophylaxis significantly reduces the risk of postoperative fUTI in patients with preoperative pyelonephritis, preoperative ureteral stent placement, or stones of >20 mm.

SEVEN FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA CASES IN THREE UNRELATED JAPANESE FAMILIES AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ANALYSIS OF THE THYROXINE BINDING PROFILE.

OBJECTIVE: Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. One- and 2-step immunoassays of serum samples from FDH patients (e.g., Japanese patients) with the HSA R218P mutation can yield false-positive free thyroxine (FT4) results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of thyroid-stimulating hormone (TSH) (e.g., syndrome of resistance to thyroid hormone, TSH-producing pituitary adenoma), even when multiple assays are used. To investigate T4 to HSA binding, we examined serum samples from 7 patients from 3 Japanese families with FDH. Clinically, abnormal thyroid function tests were noted in pregnant Patient 1. Patients 2 and 3 had histories of inappropriate treatment with antithyroid drugs and surgery. METHODS: All patients and affected family members were diagnosed with FDH using direct sequencing analysis. Gel filtration high-performance liquid chromatography was used for the biochemical analyses. RESULTS: The genomic analysis revealed a heterozygous missense mutation in HSA (R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. The results for the albumin effluent from healthy volunteer and TSHoma patient sera showed no corresponding TT4 peak. CONCLUSION: In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. ABBREVIATIONS: F = free; FDH = familial dysalbuminemic hyperthyroxinemia; HPLC = high-performance liquid chromatography; HSA = human serum albumin; PCR = polymerase chain reaction; SITSH = syndrome of inappropriate secretion of TSH; T = total; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WT = wild-type.

Insignificant role of bacillus Calmette-Guérin maintenance therapy after complete transurethral resection of bladder tumor for intermediate- and high-risk non-muscle-invasive bladder cancer: Results from a randomized trial.

OBJECTIVES: To investigate the effect of bacillus Calmette-Guérin maintenance therapy on patients with intermediate- and high-risk non-muscle-invasive bladder cancer receiving aggressive complete transurethral resection of bladder tumors standardized by well-trained surgeons. METHODS: A total of 95 patients were prospectively enrolled. Patients were diagnosed with multiple or recurrent non-muscle-invasive bladder cancer (Ta and T1), or with carcinoma in situ after complete transurethral resection of bladder tumors. Patients with Ta or T1 tumors without carcinoma in situ received six bacillus Calmette-Guérin instillations as induction therapy. Those with carcinoma in situ underwent eight bacillus Calmette-Guérin instillations as induction therapy. The patients were randomized into maintenance and non-maintenance groups. The maintenance group received intravesical bacillus Calmette-Guérin instillations once a week for 3 weeks at 3, 6, 12 and 18 months after bacillus Calmette-Guérin instillation. The primary end-point was recurrence-free survival. RESULTS: A total of 88 patients were evaluated. The average follow-up period was 48.3 ± 19.0 months. Five-year recurrence-free survival rates for the maintenance and non-maintenance groups were 80.1% and 79.3%, respectively. Five-year progression-free survival rates of the maintenance and non-maintenance groups were 92.4% and 85.3%, respectively. Recurrence- and progression-free survival rates did not significantly increase in the maintenance group compared with that in the non-maintenance group. CONCLUSIONS: Bacillus Calmette-Guérin maintenance therapy did not improve recurrence- and progression-free survival rates after the initial complete transurethral resection of bladder tumors compared with that after bacillus Calmette-Guérin induction therapy alone.

Familial Dysalbuminemic Hyperthyroxinemia in a Japanese Man Caused by a Point Albumin Gene Mutation (R218P).

Familial dysalbuminemic hyperthyroxinemia (FDH) is a familial autosomal dominant disease caused by mutation in the albumin gene that produces a condition of euthyroid hyperthyroxinemia. In patients with FDH, serum-free thyroxine (FT4) and free triiodothyronine (FT3) concentrations as measured by several commercial methods are often falsely increased with normal thyrotropin (TSH). Therefore, several diagnostic steps are needed to differentiate TSH-secreting tumor or generalized resistance to thyroid hormone from FDH. We herein report a case of a Japanese man born in Aomori prefecture, with FDH caused by a mutant albumin gene (R218P). We found that a large number of FDH patients reported in Japan to date might have been born in Aomori prefecture and have shown the R218P mutation. In conclusion, FDH needs to be considered among the differential diagnoses in Japanese patients born in Aomori prefecture and showing normal TSH levels and elevated FT4 levels.

The best objective response of target lesions and the incidence of treatment-related hypertension are associated with the survival of patients with metastatic renal cell carcinoma treated with sunitinib: a Japanese retrospective study.

BACKGROUND: The aim of this study is to investigate the prognostic relevance of the best objective response of metastatic target lesions during sunitinib treatment in patients with metastatic renal cell carcinoma. METHODS: Radiographic analysis of the best objective response according to the Response Evaluation Criteria in Solid Tumors was assessed in 50 patients. Clinicopathological characteristics including the Heng risk classification and sunitinib-related adverse reactions were compared among four patient subgroups [complete response or partial response (CR/PR), stable disease (SD), progressive disease (PD), and those without treatment evaluation (NE)]. Kaplan-Meier and Cox proportional regression analyses of progression-free survival and overall survival were performed to identify prognostic variables. RESULTS: The best objective response was CR/PR in 12 (24 %) patients, SD in 22 (44 %), PD in 6 (12 %), and NE in 10 (20 %). The incidence of hypertension and hypothyroidism was associated with a better objective response. Progression-free survival was 15.0, 9.2, 6.8, and 2.2 months in the CR/PR, SD, PD, and NE groups, respectively (P = 0.0004, log-rank test), while the corresponding median overall survival was 59.7, 24.2, 17.1, and 18.1 months, respectively (P = 0.007). Multivariate analysis revealed that hazard ratios for risk of death of the SD, PD, and NE groups were 4.51 (P = 0.06), 7.93 (P = 0.02), and 4.88 (P = 0.04), respectively, as compared to the CR/PR group. CONCLUSIONS: Our findings suggested that the best objective response of target lesions was a prognostic marker for both progression-free survival and overall survival in sunitinib treatment. Furthermore, the incidence of sunitinib-induced hypertension was associated with a longer progression-free survival.

The optimal number of initial prostate biopsy cores in daily practice: a prospective study using the Nara Urological Research and Treatment Group nomogram.

BACKGROUND: To elucidate the optimal number of prostate biopsy cores using a nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and prostate volume (PV). METHODS: We enrolled 936 patients who received an initial prostate biopsy from April 2006 to January 2009. A number of 6-12 biopsy cores was allocated based on age and PV Nara Urological Research and Treatment Group (NURTG) nomogram. To elucidate the predictive parameters of cancer detection in patients with a prostate specific antigen (PSA) value in the gray zone, univariate and multivariate logistic regression analysis were carried out. RESULTS: The total cancer detection rate and the cancer detection rate in the PSA gray zone (4.1-10.0 ng/mL) were 48.0 and 37.6 %, respectively. The cancer detection rates in the gray zone stratified by patient age of ≤59, 60-64, 65-69, 70-74, 75-79, and ≥80 years were 28.4, 35.0, 26.9, 37.9, 45.7, and 54.8 %, respectively. The significant predictive parameters of cancer detection in the gray zone were age, volume biopsy ratio (VBR: PV divided by number of biopsy cores), PSA density (PSAD), digital rectal examination findings, and transrectal ultrasound findings in univariate analyses. Finally, age, VBR, and PSAD were independent parameters to predict cancer detection in the gray zone. The adverse event profile was acceptable. CONCLUSIONS: Our present study revealed that the cancer detection rate using the NURTG nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and PV, could provide similar efficacy as previous studies involving more biopsy cores. In older patients the number of biopsy cores could be reduced.

Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice.

BACKGROUND: Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. MATERIALS AND METHODS: We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. RESULTS: Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. CONCLUSION: DG3 proved to be promising as an antitumor agent, similarly to GcMAF.

Effects of green tea polyphenols on iodide-induced autoimmune thyroiditis in nonobese diabetic mice.

Because green tea polyphenols (GTPs) possess anti-inflammatory properties and are effective in inhibiting autoimmune diseases in experimental settings, we examined whether GTPs prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis (HT). Mice were given 0.05% iodide water or iodide water supplemented with 0.2% GTPs for 8 weeks. GTPs administration led to an enhanced production of interleukin-10 by concanavalin A-stimulated splenocytes but did not interfere with thyroiditis development. Serum thyroxine levels were not influenced by GTPs. Our data suggest that administration of GTPs may not be an effective strategy for the prevention of HT.

ß-Galactosidase treatment is a common first-stage modification of the three major subtypes of Gc protein to GcMAF.

BACKGROUND: The 1f1f subtype of the group-specific component (Gc) protein is converted into Gc protein-derived macrophage-activating factor (GcMAF) by enzymatic processing with ß-galactosidase and sialidase. We previously demonstrated that preGc(1f1f)MAF, a full Gc(1f1f) protein otherwise lacking a galactosyl moiety, can be converted to GcMAF by treatment with mouse peritoneal fluid. Here, we investigated the effects of the ß-galactosidase-treated 1s1s and 22 subtypes of Gc protein (preGc(1s1s)MAF and preGc22MAF) on the phagocytic activation of mouse peritoneal macrophages. RESULTS: We demonstrated the presence of Gal-GalNAc disaccharide sugar structures in the Gc(1s1s) protein by western blotting using peanut agglutinin and Helix pomatia agglutinin lectin. We also found that preGc(1s1s)MAF and preGc22MAF significantly enhanced the phagocytic activity of mouse peritoneal macrophages in the presence and absence of mouse peritoneal fluid. CONCLUSION: We demonstrate that preGc(1s1s)MAF and preGc22MAF proteins can be used as effective macrophage activators.

Assisting the diagnosis of overt hypothyroidism with pattern recognition methods, making use of a set of routine tests, and their multiple correlation with total T4.

In our previous papers we proposed a novel screening method that assists the diagnosis of patients with overt Graves' hyperthyroidism by making use of routine test data and pattern recognition methods. This method can be applied by non-specialists during physical check-ups at low cost and is expected to lead to rapid referrals for examination and treatment by thyroid specialists, that is, to improve patients' QOL. In this report, we investigate whether a similar screening method is also applicable for overt hypothyroidism. Fifty-six subjects with 12 routine test data with a known diagnosis (30 patients with overt hypothyroidism and 52 healthy female volunteers, and 26 patients with overt hypothyroidism and 48 healthy male volunteers) were used as training data. Then, test samples of patients who had also undergone the same routine tests at the Tohoku university hospital were screened by our method for overt hypothyroidism. The present examination of the screening method showed its high screening ability with the set of four parameters used (lactate dehydrogenase [LDH], total cholesterol [TC], red blood cell [RBC] and serum creatinine [S-Cr]). It was found that there was a strong multiple correlation between the set of routine test parameters and serum total thyroxine (TT4) in the patients with overt hypothyroidism, which supports the usefulness of our screening method.

Effect of the Gc-derived macrophage-activating factor precursor (preGcMAF) on phagocytic activation of mouse peritoneal macrophages.

BACKGROUND: The 1f1f subtype of the Gc protein (Gc(1f1f) protein) was converted into Gc-derived macrophage-activating factor (GcMAF) by enzymatic processing in the presence of ß-galactosidase of an activated B-cell and sialidase of a T-cell. We hypothesized that preGc(1f1f)MAF, the only Gc(1f1f) protein lacking galactose, can be converted to GcMAF in vivo because sialic acid is cleaved by residual sialidase. Hence, we investigated the effect of preGc(1f1f)MAF on the phagocytic activation of mouse peritoneal macrophages. RESULTS: We examined the sugar moiety of preGc(1f1f)MAF with a Western blot using peanut agglutinin (PNA) and Helix pomatia agglutinin (HPA) lectin. We also found that preGc(1f1f)MAF significantly enhanced phagocytic activity in mouse peritoneal macrophages but only in the presence of the mouse peritoneal fluid; the level of phagocytic activity was the same as that observed for GcMAF. CONCLUSION: PreGc(1f1f)MAF can be used as an effective macrophage activator in vivo.

Effects of synthetic retinoid Am80 on iodide-induced autoimmune thyroiditis in nonobese diabetic mice.

We examined whether a synthetic retinoid Am80 prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic mice, an animal model of Hashimoto's thyroiditis (HT). Am80 (0, 0.1 or 1 mg/kg/day) was orally administered in feed during the 8-week iodide treatment. While iodide ingestion effectively induced thyroiditis, Am80 administration failed to interfere with thyroiditis development and serum anti-thyroglobulin antibody levels regardless of the dose of the retinoid. Splenic T cell numbers, splenocyte proliferation and interferon-γ production were decreased in the Am80-treated mice. Our data suggest that Am80 is not a candidate for use in the prevention of HT.

The primary therapy chosen for patients with localized prostate cancer between the university hospital and its affiliated hospitals in Nara Uro-Oncological Research Group registration.

BACKGROUND: We investigated the differences between the preferential primary therapy conceived by the primary doctors and the primary therapy actually conducted for prostate cancer patients in Nara, Japan. METHODS: The distribution of primary therapy and clinical characteristics of 2303 prostate cancer patients - diagnosed between 2004 and 2006 at Nara Medical University and its 23 affiliated hospitals - were assessed. Moreover, the preferential primary therapy for the patients at each clinical stage (cT1-T3bN0M0) conceived by the primary doctors was investigated and compared to the actual therapy. RESULTS: Of all patients, 51% received primary androgen deprivation therapy (PADT), 30% underwent radical prostatectomy (RP), and 14% received radiation therapy (RT). The preferential primary therapy for cT1-2N0M0 was RP (92%) while 38% of the patients actually received PADT (RP: 40%). For cT3aN0M0, the preferential primary therapy was both RP and external beam radiation therapy (EBRT) while 58% of the patients actually received PADT (RP: 16%, EBRT: 24%). For cT3bN0M0, the most preferential primary therapy was EBRT (46%) while 67% of the patients actually received PADT (EBRT: 21%). This trend was more notable in the affiliated hospitals than in the University hospital. The hospitals with lower volume of RP per year significantly conducted PADT compared with those with higher volume of RP. CONCLUSIONS: PADT was commonly used to treat localized prostate cancer as well as locally advanced prostate cancer in Japan. There was a definite discrepancy between the preferential primary therapy conceived by the primary doctors and the actual therapy provided to the patients.

The sphingosine 1-phosphate receptor modulator FTY720 prevents iodide-induced autoimmune thyroiditis in non-obese diabetic mice.

FTY720 is an immunomodulator that alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. This compound has been shown to be effective in suppressing autoimmune diseases in experimental and clinical settings. In the present study, we tested whether FTY720 prevented autoimmune thyroiditis in iodide-treated non-obese diabetic (NOD) mice, a model of Hashimoto's thyroiditis (HT) in humans. Mice were given 0.05% iodide water for 8 weeks, and this treatment effectively induced thyroiditis. Iodide-treated mice were injected intraperitoneally with either saline or FTY720 during the iodide treatment. FTY720 clearly suppressed the development of thyroiditis and reduced serum anti-thyroglobulin antibody levels. The number of circulating lymphocytes and spleen cells including CD4(+) T cells, CD8(+) T cells, and CD4(+)Foxp3(+) T cells was decreased in FTY720-treated mice. Our results indicate that FTY720 has immunomodulatory effects on iodide-induced autoimmune thyroiditis in NOD mice and may be a potential candidate for use in the prevention of HT.

A retrospective study of a calcium agent (E-Ca) using data on bone mineral density obtained by DXA method.

AIM: We performed a retrospective analysis of a calcium hydroxide-containing calcium agent (TACHIKAWA DENKAI CALCIUM™: E-Ca) based on data of bone mineral density obtained by dual-energy X-ray absorptiometry (DXA) to clarify the relationship between bone mineral density and E-Ca intake on an empty stomach in those who regularly use E-Ca. RESULTS: We found the percentage of volunteers with their age-matched (AM) values of above 100% to be 89%, and also a moderate positive correlation between AM values and the intake period of E-Ca. CONCLUSION: Our findings demonstrate that AM values can be used as an effective indicator assessing osteogenesis by regularly administrated calcium agents which exert their effects after long-term use.

Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety.

We presented here design, syntheses and inhibitory activities of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2.