First-trimester pre-eclampsia biomarker profiles in Asian population: multicenter cohort study.

OBJECTIVES: To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. METHODS: This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. RESULTS: In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. CONCLUSIONS: Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1.

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukaemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA) is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1(L) to MCL-1(s) in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested that Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumour cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-x(L) antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-x(L) antagonists may have therapeutic utility for CLL.

Effect of the tongue rotation exercise training on the oral functions in normal adults - Part 1 investigation of tongue pressure and labial closure strength.

The aim of this study was to investigate the effect of the tongue rotation exercise training on the oral functions using the measurement of maximum tongue pressure (MTP) and labial closure strength (LCS) in normal adults. In experiment 1, the differences in MTP and LCS at the measurement point for both groups with and without tongue rotation exercise training were examined. We instructed subjects to perform the tongue rotation exercise for 2 months. We measured MTP and LCS at the point before training and at the points of 1 and 2 months after the beginning of training. In experiment 2, the changes of MTP and LCS based on the sex differences and the measurement points in training were examined. We instructed subjects to perform the tongue rotation exercise for 3 months, and measured MTP and LCS at the point before training and at the points of 2 weeks and 1, 2 and 3 months after the beginning of training. The results of experiment 1 showed MTP and LCS increased with the progress of continuous training. The results of experiment 2 showed MTP and LCS were always higher in men than in women and increased significantly at 2 weeks of training in both sexes (P < 0.01). These results might be suggested that the tongue rotation exercise training was effective for the recovery of the activity of the stomatognathic system.

Association between perioral muscle pressure and masticatory performance.

The aim of this study was to determine the association between strength of the perioral muscles and masticatory performance. Subjects were 56 healthy adults (30 men and 26 women; mean age of 24·9 years) with normal occlusion. Perioral muscle pressure was measured using JMS tongue pressure measurement device, and maximum tongue pressure and cheek pressure on the habitual chewing side (H) and non-habitual side (non-H) were measured. The masticatory performance was evaluated using gummy jelly, and the amount of glucose extracted was measured after chewing under condition H or non-H. The association between sex and maximum tongue pressure was analysed using Student's t-test. Cheek pressure and the amount of the glucose extracted between condition H and non-H or between men and women were analysed by two-way repeated-measures anova. In addition, the correlations between maximum tongue pressure and cheek pressure on condition H, maximum tongue pressure and the amount of glucose extracted under condition H, and cheek pressure and the amount of glucose extracted under condition H were analysed using Pearson's correlation coefficients for men and women. The maximum tongue pressure, cheek pressure and the amount of glucose extracted were higher in men than in women. The amount of glucose extracted was higher under condition H than under condition non-H, but no significant difference in chewing side was observed in cheek pressure between men and women. Additionally, positive correlations were shown between maximum tongue pressure, habitual-side cheek pressure and the amount of glucose extracted on men and women. In conclusion, the association between higher perioral muscle pressure and better masticatory performance was shown.

PP077. Effect of maternal antioxidant concentrations on expressions of angiogenesis-related genes in the villous trophoblasts from early pregnancy.

INTRODUCTION: The pathogenesis of preeclampsia is associated with oxidative stress of villous trophoblasts in early pregnancy. We have reported that antioxidant supplementations from 12weeks of gestation could prevent mild preeclampsia in pregnant women with oxidative stress. OBJECTIVES: To prove the effect of maternal antioxidant concentrations on expressions of angiogenesis-related genes in the villous trophoblasts from early pregnancy. METHODS: Villous tissue and blood samples were obtained from pregnant women who had artificial abortions between 6 and 11weeks of gestation. RNA was extracted from villous tissue, and gene expression levels of fms-like tyrosine kinase-1 (FLT-1), endoglin (ENG), and placental growth factor (PGF) in villous tissue were measured by reverse transcription polymerase chain reaction. Serum vitamin C and E concentrations were measured by enzyme-linked immunosorbent assay. This study was approved by the Ethics Committee of Showa University Hospital. RESULTS: Negative correlations between maternal serum vitamin C levels and gene expressions of ENG (r=-0.856, p=0.007) and FLT-1 (r=-0.898, p=0.002) in the villous trophoblasts were observed. There was no correlation of maternal serum vitamin E concentration with any other gene expression in the villous trophoblasts. CONCLUSION: It is suggested that maternal oxidative stress may increase the gene expressions of anti-angiogenic factors in villous trophoblasts of early gestation, which may lead to the pathogenesis of preeclampsia.

Drug delivery observation of hydrophobe ferrofluid and magnetite nanoparticals by SPring-8 synchrotron radiation.

In this study, the composite magnetic nanoparticles of coated SiO nano film with about 8 nm size and high saturation magnetization value, were synthesized by liquid phase precipitation method. The magnetic nanoparticles can be dispersed in various liquid media, widely known as magnetic fluids or ferrofluids with both magnetic and liquid properties. The materials been collected great interests and more and more attentions to focus into Drug Delivery System (DDS) as a new technology in this paper. We use the composite nanoparticles to disperse H2O and inject the solutions into rat's in-vivo organs. And, in the experiments by using a strong photon beam of SPring-8 Synchrotron Radiation facility, the distribution stat and the effects of magnetic field as well as drug delivery behaviour of nanoparticles in the rat' kidney are verified by the in-vivo observations.

Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography.

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P<0.05). Within the tumour, downregulation of RUNX3 expression ranged from 74.7 to 85.7% in the three groups. The rate of downregulation of RUNX3 of adjacent mucosa was 39.2% (11 in 28 cases) in RB and 47.6% (10 in 21 cases) in RM, which are significantly higher than that of the GCI group (19.5%, 17 in 87 cases). In noncancerous mucosa of the remnant stomach in the RB group, RUNX3 expression decreased more near the anastomosis area. In the RM group, however, there were no significant differences in RUNX3 expression by sampling location. Based on RUNX3 downregulation and clinical features, residual stomach mucosa of the RM group would have a higher potential of gastric carcinogenesis compared to the RB or GCI group. Gastric stump mucosa of the RB group has higher potential especially than other areas of residual stomach mucosa. Measurement of RUNX3 expression and detection of RUNX3 methylation in remnant gastric mucosa may estimate the forward risk of carcinogenesis in the remnant stomach.

[Evaluation of spinal cord ischemia in endovascular stent graft repair and surgical operation of descending thoracic or thoracoabdominal aortic aneurysms].

Between October 1996 and June 2003, endovascular stent graft repair was performed in 87 patients with descending thoracic aortic aneurysms, graft replacement was performed in 24 patients with thoracoabdominal aortic aneurysms, and endovascular stent graft repair with concomitant surgical bypass of abdominal visceral arteries was performed in 3 patients with thoracoabdominal aortic aneurysms. The retrievable stent graft was inserted and evoked spinal cord potential were monitored in order to predict spinal cord ischemia for stent graft repair. There was no paraplegia or hospital death, although 3 patients had paraparesis in stent graft repair. Two of the 3 patients with paraparesis made a full neurologic recovery. There were no cases of paraplegia or paraparesis in surgical operations with thoracoabdominal aortic aneurysm. The concomitant surgical procedure was a good technique for patients in whom cardiopulmonary bypass could not be used. Our results of stent graft repair and surgical operation for descending thoracic or thoracoabdominal aortic aneurysms were acceptable. The retrievable stent graft was useful for prediction of spinal cord ischemia before endovascular stent graft repair of descending thoracic or thoracoabdominal aortic aneurysm.

A synthetic library of cell-permeable molecules.

Small molecules that induce or stabilize the association of macromolecules have proven to be useful effectors of a wide variety of biological processes. To date, all examples of such chemical inducers of dimerization have involved known ligands to well-characterized proteins. The generality of this approach could be broadened by enabling the discovery of heterodimerizers that target known macromolecules having no established ligand, or heterodimerizers that produce a novel biologic response in screens having no predetermined macromolecular target. Toward this end, we report the construction of a diversified library of synthetic heterodimerizers consisting of an invariant ligand that targets the FK506-binding protein (AP1867) attached to 320 substituted tetrahydrooxazepines (THOXs). The THOX components were generated by a combination of liquid- and solid-phase procedures employing sequential Mitsonobu displacements to join two structurally diversified olefin-containing monomers, followed by ruthenium-mediated olefin metathesis to effect closure of the seven-membered ring. The 320 resin-bound THOX ligands were coupled in parallel to AP1867, and the products were released from the resin to yield candidate heterodimerizers in sufficient yield and purity to be used directly in biologic testing. A representative panel of 25 candidate heterodimerizers were tested for their ability to pass through the membrane of human fibrosarcoma cells, and all were found to possess activity in this tissue culture system. These studies pave the way for further studies aimed at using small-molecule inducers of heterodimerization to effect novel biological responses in intact cells.

Ruptured intracranial aneurysm associated with unruptured abdominal aortic aneurysm--case report.

A 61-year-old male with hypertension presented with sudden onset of headache and nausea due to subarachnoid hemorrhage (SAH). He had two siblings with history of SAH due to ruptured intracranial aneurysms. Right carotid angiography on admission showed an anterior communicating artery aneurysm. At that time, the extracranial arteries were not examined. The aneurysm was clipped with no complications. A pulsating mass was palpable in the abdomen 37 days after the onset. Ultrasonography and computed tomography showed an abdominal aortic aneurysm with intraluminal thrombus, measuring 8 x 9 x 8 cm. Normal pressure hydrocephalus had already developed. The patient underwent elective abdominal aortic aneurysm resection before ventriculoperitoneal shunting. After shunting, he recovered fully. The present case indicates that unpredictable sudden enlargement of associated abdominal aortic aneurysm is possible in patients with ruptured intracranial aneurysms.

An improved rapid procedure for fluorescence in situ hybridization that is applicable to intraoperative cancer cytodiagnosis.

Fluorescence in situ hybridization (FISH) is among the most simple and useful methods for detecting numerical and structural aberration of chromosomes but it requires 12-24 h to complete. We devised a rapid FISH method that can be performed within 2 h. Here we describe the technique, which we have found to be extreme simple and as sensitive and specific as standard FISH, making it highly suitable for clinical use.

Genomic alterations in primary gastric cancers analyzed by comparative genomic hybridization and clinicopathological factors.

BACKGROUND/AIMS: Genetic changes during the oncogenesis and progression of gastric cancer remain unclear. The aim of our study was to analyze chromosomal aberrations in primary gastric cancers. METHODOLOGY: Using comparative genomic hybridization, we screened 47 primary gastric cancers for changes in the number of copies of DNA sequences. RESULTS: Gains of chromosome arms 20q (55%), 20p (36%), 17q (32%), 19q (30%) and 16p (30%), and losses of chromosome arms 4q (40%), 17p (40%), 5q (38%), 18q (30%) and 4p (28%) were detected most frequently. In addition, a high level of amplification was observed at 3q21 (2%), 6p21 (4%), 7q31 (6%), 8q23-24 (2%), 19q12-13 (2%), and 20q13 (2%). Among these alterations, the gain of 20q was the most frequent change. We then compared these changes with clinicopathological factors and identified signet ring cell carcinomas in 6 cases. Our study demonstrated no amplification of chromosome 20q in signet ring cell carcinoma in contrast to that in the other histologic types of gastric cancer. CONCLUSIONS: Our findings may be related to the morphologic and clinical features of signet ring cell carcinoma, and several oncogenes mapped on 20q may play an important role as determinants of the clinical and histologic features of gastric cancer.

[The mental health of school children after the Great Hanshin-Awaji Earthquake: I. Epidemiological study and risk factors for mental distress].

UNLABELLED: We conducted surveys to study the magnitude and nature of psychological consequences of school children affected by the Great Hanshin Awaji Earthquake, which occurred in Kobe on January 17th, 1995. It measured 7.2 in magnitude, killed more than 6000 people and destroyed at least 170,000 buildings and houses. The investigations were carried out 4 months following of the disaster. SUBJECTS: About 9000 school children in the 3rd grade, the 5th grade, the 8th grade living in the disaster areas. About 2000 children living in distant areas were also surveyed as control subjects. METHOD: The questionnaire was in a self-descriptive format and consisted of 10 items regarding situation and behavior when the earthquake occurred and 22 items about mental health condition. The responses were rated from 1 to 4 depending on the frequency of the symptoms, and statistically analyzed. RESULT: By factor analysis, three factors were elicited. Factor 1 was interpreted as being related to fear and anxiety, factor 2 as related to depression and physical symptoms, and factor 3 as related to pro-social tendencies. The highest mean score of factor 1 was associated with the most heavily damaged areas. Less severe damage was associated with a lower mean score, and the control areas showed the lowest score. These results show that the children in the damaged areas were strongly affected. Factor 2 shows a different pattern from factor 1. The score of heavily damaged areas is conspicuously high. However, the differences between the other areas were not significant, the control areas had scores almost the same as these of the slightly damaged areas. These results may mean that in less damaged areas than in more heavily damaged areas, there was a more remarkable "heroic phase" after the disaster, which hid depressive moods and lasted longer than in the more severely damaged areas, where people had to face stern reality in the early stages. Factor 3 shows the reverse pattern of factor 2. The slightly damaged areas had the highest score. This result also shows the influence of the "heroic stage". As for the mean scores of factors 1 and 2, younger children showed higher scores. There were no differences in the scores of factor 3 between students in the 3rd grade and 5th grade. The score of the students in the 8th grade was the lowest among all. It can be seen that adolescents generally lessen their consideration for society as a developmental stage in their growth. All of the mean scores of factors 1, 2 and 3 of females are higher than those of males. In the heavily damaged areas, factor 1 is associated with an experience of being rescued and injuries of the children themselves. Factor 2 is associated with injuries of the children themselves. In the moderately damaged areas, factors 1 and 2 are associated with injuries of the children themselves and taking in victims in the children's homes. In the slightly damaged areas, factor 1 is associated with injuries within families. Factor 2 is associated with injuries within families and taking in victims in the childrens' homes. CONCLUSIONS: School-aged children exposed to a high-magnitude natural disaster had 3 categories of emotions: "fear and anxiety," "depressive mood and physical symptoms" and "pro-social tendency." The severity of disaster, younger age, and female gender were high risk factors for distress. In the heavily damaged areas, an experience of being rescued and injuries of the children themselves had a great influence on the mental health of children. In lesser damaged areas, taking in victims in the childrens' homes and injuries within families had an influence.

[Hypertensive putaminal hemorrhage with extensive subarachnoid hemorrhage presenting extravasation of contrast material during angiography: case report].

The authors describe a case of hypertensive putaminal hemorrhage with extensive subarachnoid hemorrhage. On admission, the patient aged 71 presented right-sided motor weakness. CT scan on admission revealed left putaminal hemorrhage with extension into the ipsilateral thalamus and lateral ventricle as well as into the subarachnoid space of the suprasellar, ambient, interhemispheric and contralateral sylvian cisterns. To exclude vascular lesions, left carotid angiography was performed just after admission. The lateral view was unremarkable, but the anterior-posterior view demonstrated extravasation of contrast material from the left lateral lenticulostriate artery. The angiographic sylvian point was shifted to the lateral side. No abnormal vessels were revealed. CT scan after angiography showed exacerbation of both intracerebral and subarachnoid hemorrhages, but the consciousness level was unchanged. CT-guided stereotactic aspiration of the hematoma was performed 4 days after the onset, but failed to remove much hemtoma. The patient died of aspiration pneumonia 9 days after onset. The authors emphasize that extensive subarachnoid hemorrhage in cases with hypertensive putaminal hemorrhage may be an important finding which indicates high risk of rebleeding.

Laparoscopic cholecystectomy in a patient on continuous ambulatory peritoneal dialysis.

The patient was a 72-year-old man who was receiving continuous ambulatory peritoneal dialysis (CAPD) with a diagnosis of chronic renal failure. Although his response to dialysis therapy was favorable, right hypochondralgia and fever occurred, and gallstones were detected by abdominal ultrasonography and computed tomography. Drip-infusion cholangiography (DIC) revealed neither dilation nor calculus in the common bile duct. The patient was diagnosed as having acute cholecystitis and cholecystolithiasis and, in consideration of his general condition, laparoscopic cholecystectomy was carried out. Pneumoperitoneum was performed through a CAPD tube, and a 10 mm-trocar was carefully introduced through a supraumbilical incision so as not to injure the CAPD tube. Since intraoperative cholangiography showed a condition similar to preoperative DIC, only cholecystectomy was undertaken. The postoperative course was uneventful, with neither postoperative hemorrhage nor leakage of dialysate from the wound.

Effect of amino acid injection in broiler breeder eggs on embryonic growth and hatchability of chicks.

Two experiments were conducted to evaluate the effect of amino acid (AA) injections in ovo in Cobb broiler breeder eggs on hatchability and subsequent chick BW. In Experiment 1, moisture, crude fat (CF), and CP were analyzed over time during incubation (Day 0, 7, 14, and 19 of incubation). Moisture, CP, and CF of the embryo increased, and moisture, CP, and CF of eggs decreased, as incubation time increased (P < 0.05). Combined egg and embryo AA contents, except Gly and Pro, decreased (P < 0.05) as incubation time increased. However, the pattern of AA in the egg did not change as the embryo developed. In Experiment 2, AA were injected into the yolk or air cell at Day 0 and 7 of incubation. Hatchability was reduced (P < 0.05) when AA were injected at Day 0 of incubation. However, when the AA solution was injected into the yolk sac at Day 7 of incubation, hatchability was not affected, and BW of chicks increased relative to egg weight prior to incubation. These results suggest that in ovo administration of AA may be an effective method of increasing chick BW at hatch.

The expression of the pathogenic yeast Candida albicans catalase gene in response to hydrogen peroxide.

The catalase gene of the pathogenic yeast Candida albicans was cloned and its expression was examined. Activity of the catalase was detected when cells which were in the early logarithmic stage were treated with hydrogen peroxide. Additionally, activity was detected without any treatment to cells in the late logarithmic and stationary phases. When cells were cultured in galactose, glycerol, or ethanol, catalase activity was always observed without the hydrogen peroxide treatment, suggesting that glucose represses the induction of catalase expression. To elucidate the molecular mechanism of catalase expression, the putative gene for catalase and its 5' untranscribed region were cloned. Sequences of the gene and its potential regulatory region revealed several motifs, including a GC box-like element and stress-responsive element (STRE), which could be involved in the transcriptional regulation. Northern analysis showed that hydrogen peroxide and sorbitol activated transcription of the catalase. On the other hand, treatment of glucose strictly repressed the expression of the catalase even when co-treated with hydrogen peroxide. The expression of catalase against treatment with hydrogen peroxide took place very quickly and decreased slowly in the experimental condition adopted here. From these results, we assumed that the expression of the catalase in Candida albicans is regulated by various environmental conditions via motifs for transcriptional activation as in other yeast catalases.

Interleukin-18 induces interferon-gamma production through NF-kappaB and NFAT activation in murine T helper type 1 cells.

Interleukin-18 (IL-18) combined with anti-CD3 monoclonal antibody (mAb) induced interferon-gamma (IFN-gamma) production by T helper type 1 (Th1) cells. Neither IL-18 nor anti-CD3 mAb alone induced production of IFN-gamma. Although treatment with IL-18 alone induced full activation of NF-kappaB in Th1 cells, it was not sufficient for the production of IFN-gamma. To examine the importance of NF-kappaB activation in IFN-gamma production, we established Th1 cells which expressed a transdominant IkappaBalpha mutant. In these cells, activation of NF-kappaB and production of IFN-gamma by IL-18 were suppressed. On the other hand, we examined the T cell receptor (TCR)/CD3-mediated signaling pathway. FK506, an inhibitor of NFAT activation, inhibited IFN-gamma production by IL-18 without any effect on the NF-kappaB activation. We conclude that dual signaling consisting of IL-18-induced NF-kappaB activation and TCR/CD3-mediated NFAT activation is crucial for IFN-gamma production by IL-18 in murine Th1 cells.

Inhibition of protein kinases by balanol: specificity within the serine/threonine protein kinase subfamily.

Balanol is a potent inhibitor of cyclic AMP-dependent protein kinase and protein kinase C, acting competitively with ATP with an affinity 3000 times that of ATP. We tested the capacity of balanol to inhibit representative serine- and threonine-specific protein kinases from the protein kinase subfamily that shares a common conserved catalytic core with cyclic AMP-dependent protein kinase. Balanol's pattern of interactions indicates considerable diversity of the ATP/balanol-binding sites of protein kinases within familial groups and even among isoforms of the same kinase. We propose that balanol is a protean structure that may be modified to produce selective, high-affinity inhibitors and probes of the ATP-binding sites of serine/threonine protein kinases.