2-O-methylisohemigossylic acid lactone, a sesquiterpene, isolated from roots of mokumen (Gossampinus malabarica) induces cell death and morphological change indicative of apoptotic chromatin condensation in human promyelotic leukemia HL-60 cells

2-O-methylisohemigossylic acid lactone, a sesquiterpene, was purified from roots of mokumen (Gossampinus malabarica) and identified by Mass, and (1)H- and (13)-NMR. This sesquiterpene displayed strong growth inhibitory effect against human promyelotic leukemia HL-60 cells. Apoptotic morphological change of the nucleus, including chromatin condensation was induced in the HL-60 cells treated with the sesquiterpene. The fragmentation of DNA by the sesquiterpene to oligonucleosomal-sized fragments, a characteristic of apoptosis, was observed to be dose- and time-dependent in the HL-60 cells. Inhibitors of caspases suppressed the DNA fragmentation induced by the sesquiterpene. These findings suggest that growth inhibition by the sesquiterpene of HL-60 cells results from the induction of apoptosis by the sesqui-terpene, and that caspase cascade is involved in the induction of apoptosis by the compound in the HL-60 cells.     

Prognostic significance of the Ki67 index and programmed death-ligand 1 expression after radical cystectomy in patients with muscle-invasive bladder cancer

ObjectivesTo investigate the association between Ki67 index and programmed death-ligand 1 (PD-L1) expression in muscle-invasive bladder cancer (MIBC) patients after RC.Materials and MethodsWe retrospectively evaluated 262 MIBC patients treated with RC between April 2004 and April 2020. The impact of Ki67 index and PD-L1 expression on prognosis was evaluated by univariate Cox regression analysis. In addition, a pathomolecular risk score, including Ki67 and PD-L1, was developed to predict prognosis and pathological factors. We also evaluated the link between the Ki67 index and PD-L1 under the IL-6 stimulation in the bladder cancer cell lines of T24 and 5637 cells.ResultsThe median age and follow-up period was 69 years and 52 months, respectively. Ki67 index and PD-L1 expression were significantly associated with tumor recurrence. Univariate Cox regression analysis showed that pT3–4, mixed histology, lymphovascular invasion positive (LVI+), pN+, Ki67-high (>17%), and PD-L1+ were significantly associated with recurrence-free survival (RFS). The pathomolecular risk score was developed using resection margin+ (1 point), mixed histology (1 point), LVI+ (1 point), pN+ (1 point), and Ki67-high (1 point). RFS and overall survival were significantly shorter in patients with higher pathomolecular risk scores (>1) than in those with lower risk scores (≤1). Cell proliferation was significantly increased in the T24 and 5637 cells under the IL-6 stimulation, while PD-L1 expression was not.ConclusionsA significant effect of Ki67-high and PD-L1 expression on poor prognosis was observed in patients with MIBC. Further studies are necessary to elucidate the precise mechanisms of cell proliferation and PD-L1 expression in patients with MIBC.     

A double-blind trial on the effect of bunazosin hydrochloride for the symptoms of benign prostatic hypertrophy]

A multicenter clinical trial was carried out on 372 patients in double-blind conditions in order to determine the clinical effects of Ea-0643 (bunazosin hydrochloride) on voiding disorders in benign prostatic hypertrophy, compared with paraprost and placebo. Of the 372 patients, 129 were assigned to bunazosin hydrochloride, 118 to paraprost and 125 to placebo. The improvement rating for all five subjective symptoms improved with passage of time in all the bunazosin hydrochloride, paraprost and placebo groups. A higher improvement rating was obtained in the bunazosin hydrochloride group for retarded urination, urinary stream condition and abdominal pressure at voiding, while the improvement rating was higher for prolonged urination in the placebo group and for residual urine in the paraprost group, but there was no significant difference in improvement ratings between the groups. The daily frequency of voiding decreased to a significant extent in the bunazosin hydrochloride and placebo group at week 1, and there was a significant difference between the bunazosin hydrochloride and the paraprost groups and between the placebo and the paraprost groups. The improvement rating for conditions of voiding was higher with the bunazosin hydrochloride group, when "slightly or better improved" cases were taken into account, but there was no difference between the groups. As for objective symptoms, maximum and average flow rate, useful measures for clinical evaluation of drug effects on voiding disorders, were significantly increased, with a decrease to match in residual urine ratio in the bunazosin hydrochloride group. In terms of maximum and average flow rate bunazosin hydrochloride was significantly superior to paraprost at weeks 1 and 2 and superior to placebo at weeks 2 and 4 and at the final evaluation as well. In terms of residual urine ratio bunazosin hydrochloride was superior to both paraprost and placebo. The global improvement rating, as assessed by the U- and chi 2-tests, was significantly higher in the bunazosin hydrochloride group than in the paraprost group, and there was a significant difference in global improvement ratings, as assessed by the chi 2-test, between the placebo and the paraprost groups, when "moderately or better improved" cases were taken into account. The stratified analysis of the prostate glands, subjective symptoms, maximum flow rate and residual urine ratio revealed that in patients with more advanced conditions the bunazosin hydrochloride group showed significantly superior improvement rates than the paraprost and placebo groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Recurrent breast cancer at 21 years after resection detected by serum tumor markers and manifested as dermatomyositis

A 52-year-old Japanese woman developed dermatomyositis. She had undergone a standard radical mastectomy for left breast cancer 21 years earlier. Though no physical sign of recurrent breast cancer appeared clinically, levels of tumor markers were abnormally elevated. Therefore, tamoxifen and CAF therapy were given. Further, the clinical course of dermatomyositis almost paralleled the level of serum tumor markers and the clinical course of her recurrent breast cancer. These markers were useful for detecting the recurrence, following the metastatic disease, and monitoring her response to therapy.     

Seroreactivity clarification and viral load quantitation in HIV-1 and HIV-2 infections in Ghana

In Ghana, West Africa, the prevalence of dual HIV-1 and HIV-2 infections remains to be clarified, and HIV viral load measurement is yet to be established. Conventional assays for HIV-1 RNA measurements have been limited specifically to HIV-1 subtype B, preventing their utilization for Ghana where HIV-1 subtypes A, D and G are prevalent. Therefore, we set out to distinguish the types of HIV infection existing in Ghana so as to determine the extent of actual dual infections, and to measure plasma HIV-1 RNA. Blood samples were collected from 563 sick and healthy Ghanaians who visited hospitals in 1996 and 1997. After T cells were counted, HIV antibody was screened and confirmed by six different commercial assays and one in-house test. Nested PCR was then used to verify HIV-1 and HIV-2 presence by type-specific primers. Plasma HIV-1 RNA was measured by an improved commercial RT-PCR assay, sensitive to all HIV-1 group M subtypes. HIV-1 alone (89%) clearly dominated over HIV-2 alone (2%), and HIV-1 and HIV-2 dual infections were found in 9%. Valid viral load measurements were obtained on test plasma representing the main HIV-1 subtype (A) prevailing in Ghana. A high amount of HIV-1 RNA (5.9 mean log10 RNA copies/ml) was observed in the typical stages of HIV infection represented by groups of CD44 cell counts. We have clarified the seroprevalence of HIV-1 and HIV-2 amongst HIV seropositives, and the high viral load of HIV-1 reflects its influence on AIDS in Ghana.     

Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation

BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.     

Anticoagulation after valve replacement: a multicenter retrospective study

Anticoagulant therapy after cardiac valve replacement was evaluated retrospectively in 1,200 patients attending 8 cardiac surgery clinics in the Tokyo area as part of the Tokyo Area Study on Anticoagulation After Cardiac Valve Replacement Using PT-INR (TAS). A prospective trial is also in progress and will be reported later. The prothrombin time international normalized ratio (PT-INR) was determined at the time of thromboembolic and bleeding complications in 1,200 patients. During the 5 year study period, thromboembolisms occurred in 21 patients, and bleeding complications occurred in 15 patients. In 71% of patients with thromboembolism and 47% of those with bleeding complications, the PT-INR was within the range of 1.6 to 2.8, which is the accepted therapeutic range in Japan. Therefore, the correct PT-INR therapeutic range for Japanese patients with mechanical heart valves needs to be reexamined, and data from the prospective TAS trial that is currently underway will be used for this purpose.     

A case of ductal carcinoma in situ (DCIS; non-comedo type) detected by ultrasonography: Demonstration of occult multiple foci

We report a case of ductal carcinoma in situ (DCIS) of the breast detected by ultrasonographic mass screening in a 51-year-old woman. In a mass screening program for breast cancer, physical examination with inspection and palpation, and ultrasonography (US) were performed. A hypoechoic mass with a slightly irregular margin was detected by US in the lateral upper quadrant of the right breast, at a distance 2 cm from the edge of the nipple. The mass was not detected by physical examinations or by mammography (MMG). The mass, which measured 0.8 x 0.5 cm and was examined by fine needle aspiration biopsy (FNAB) under US guidance, was cytologically diagnosed as class X. Modified radical mastectomy (Auchincloss method) was performed with the patient's consent. Pathological examination of the resected specimen revealed DCIS (noncomedo type) and occult multiple foci of malignancy which was considered tracking centripetally underneath the nipple. This case suggests that US and FNAB performed under US guidance are useful in the detection and diagnosis, respectively, of a breast mass. We should take multifocality into consideration, particularly with tendency tracking to the nipple, in the treatment of small breast cancers such as DCIS.