Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multicenter international trial.

BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. PATIENTS AND METHODS: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). RESULTS: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. CONCLUSIONS: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.

An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.

Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.

Alternative splicing of the fibronectin EIIIB exon depends on specific TGCATG repeats.

The fibronectin EIIIB exon is alternatively spliced in a cell-type-specific manner, and TGCATG repeats in the intron downstream of EIIIB have been implicated in this regulation. Analysis of the intron sequence from several vertebrates shows that the pattern of repeats in the 3' half of the intron is evolutionarily conserved. Point mutations in certain highly conserved repeats greatly reduce EIIIB inclusion, suggesting that a multicomponent complex may recognize the repeats. Expression of the SR protein SRp40, SRp20, or ASF/SF2 stimulates EIIIB inclusion. Studies of the interplay between mutations in the repeats and SRp40-stimulated inclusion suggest that the repeats are recognized in many, if not all, cell types, and that EIIIB inclusion may be regulated by quantitative changes in multiple factors.

Periodontal disease -- the emergence of a risk for systemic conditions: pre-term low birth weight.

This paper addresses the problem of adverse pregnancy outcome in relation to periodontal disease. There is compelling evidence that a link exists between pre-term low birth weight (PLBW) and periodontitis. Although 25% to 50% of PLBW deliveries occur without any known aetiology, there is increasing evidence that infection may play a significant role in pre-term delivery. A model explaining the plausible relationship is proposed based upon the concept of infection leading to a cascade of inflammatory reactions associated with pre-term labour and periodontal disease. Current evidence has pointed to an interest in dental intervention studies to control periodontal disease as one of the potential strategies to reduce pre-term labour. This paper reviews the potential association between periodontal infection and adverse pregnancy outcomes.

Stressful life events of dental students and salivary immunoglobulin A.

To study the perceived sources of stressful events in dental students and the relationship between their self-perceived stress levels and salivary IgA. Undergraduates as well as postgraduates at the Faculty of Dentistry, National University of Singapore were surveyed one month after the new term. A 38-item dental environmental stress (DES) questionnaire, with subscales of academic work (AW), clinical factors (CF), faculty and administration factors (FA) and personal factors (PF), was used to identify the potential stressors in the dental environment. A 4-point perceived stress scale was used to rank their self-perceived stress levels. Enzyme linked immunosorbent assay method was used to determine the salivary IgA level. One hundred and thirty students (81.3%--valid response rate) participated in the study. Overall, students ranked AW with the highest score (mean 2.76), followed by CF (2.67), FA (2.24) and PF (2.16). Among the 38 items of DES questionnaire, 1st year students perceived "fear of being unable to catch up if behind" as the most stressful event (mean 3.30). For 2nd and 3rd year students, examination and grades had the highest scores (mean 3.28, 3.19, respectively). Completing graduation requirements was the most important stressor for 4th year students (mean 3.89). Post graduates perceived atmosphere created by clinical faculty was most stressful to them (mean 3.05). The mean total perceived stress scores were highest (22.1) in 1st year students and lowest (21.0) in postgraduates, however, no significant different among various classes. First year students had had the lowest IgA secretion rates (geometric mean [GM] 46.8 microg/min), significantly lower (p<0.05) than postgraduates (GM 79.4 microg/min). An inverse correlation was noted between perceived stress scale and log IgA secretion rates (r= -0.20, p= 0.002). AW was also significantly inversely correlated with salivary IgA (r= -0.18, p= 0.04). Dental students in different academic years perceived different important stressors. Salivary IgA secretion rate correlated inversely with self perceived stress.

Chinese health beliefs and oral health practices among the middle-aged and the elderly in Hong Kong.

The purpose of this paper was to study possible relationships between traditional Chinese health beliefs and health practices in adult Chinese in a modernized society. The study populations comprised 398 35-44-yr-old and 559 65-74-yr-old Hong Kong Chinese. The respondents were categorized into three groups with weak, moderate, or strong Chinese beliefs on the basis of interview questions on the causes of gum disease. Chinese preventive practices and Chinese pain practices were defined according to respondents' reported use of recommended traditional cures. Questions on generally accepted oral practices were phrased in terms of frequency of daily brushing of teeth, use of toothpicks the previous day, and whether or not teeth were flossed the previous day. Around one-third of the respondents had weak, almost one-half had moderate, and around one-quarter expressed strong Chinese health beliefs. No significant differences in Chinese health beliefs were found between men and women in either age group, or between the age groups. In the 35-44 age group, more of those with a higher education were in the "weak" Chinese health belief category, whereas, conversely, more of those with a lower education expressed stronger Chinese health beliefs (P < 0.05). Women in both age groups reported significantly more frequent brushing. Toothpicks were used by around three-quarters of both age groups, but flossing was extremely rare.(ABSTRACT TRUNCATED AT 250 WORDS)

Periodontal conditions among the middle-aged and the elderly in Hong Kong.

The aim of this study was to describe the periodontal conditions in 372 35-44-yr-old and 537 noninstitutionalized 65-74-yr-old Hong Kong Chinese who were examined clinically for loss of attachment, recession, probing depth, calculus, and bleeding after probing. Community Periodontal Index (CPI) data and treatment need indications were compiled from index teeth or their substitutes. The prevalence of loss of attachment varied considerably in both cohorts according to the definition of the threshold (> or = 6, > or = 9, and > or = 12 mm, respectively). The mean numbers of teeth with loss of attachment at the > or = 6-mm threshold and at higher thresholds were small. In both age cohorts, about one-fifth of subjects had probing depths > or = 6-mm, while at the > or = 9-mm threshold only 2-3% were so affected. Although recession was an important component of loss of attachment in the younger cohort, in the older cohort the prevalence and extent of recession were greater than for probing depths at thresholds > or = 4 mm. All subjects had one or more teeth with calculus, bleeding, or both, most teeth being so affected. Eighty-four of the 537 65-74-yr-old subjects were excluded either because of edentulousness or because extractions indicated for the remaining teeth would have rendered the subjects edentulous. The distribution of subjects according to their highest CPI score was remarkably similar for the two cohorts. No subjects in either age group were assessed as "healthy" (CPI code 0) or had "bleeding only" (code 1) as their highest score. While most subjects scored CPI code 2 or 3 as their highest score, only 17% of the younger and 15% of the older cohort scored Community Periodontal Index of Treatment Needs (CPITN) code 4.(ABSTRACT TRUNCATED AT 250 WORDS)

The Hong Kong adult oral health survey--1991: background, study population, and methods.

This second adult oral health survey was conducted with the following main aims: 1) to describe the oral health conditions and to analyse the oral health care needs and demands of 65-74-yr-olds in Hong Kong, and to propose appropriate strategies for meeting their needs in the light of societal obligations; 2) to describe the oral health conditions and to analyse the oral health care needs and demands of 35-44-yr-olds in Hong Kong with special emphasis on assessment of changes in this age group since 1984 (when the first adult oral health survey was conducted); 3) to assess the impact of sociodemographic and dental care system factors on the oral health status of selected adult age groups: and 4) to utilize survey data to refine curriculum development and research strategies in the Faculty of Dentistry, as well as in the proposal of appropriate action to governmental committees on dental health policy. For enhanced comparability with the previous study, the 35-44-yr-olds were selected from the same geographic areas of Hong Kong Island. Multistage cluster sampling was used to recruit the study population, defined geographic units and addresses being used as the starting-point. A sample of 398 subjects was selected, of whom 93% were both interviewed and clinically examined. The 65-74-yr-olds were recruited from housing estates in all principal areas of Hong Kong, yielding a sample of 559 subjects, of whom 96% were both interviewed and clinically examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex differences in the periodontal status of Hong Kong adults aged 35-44 years.

Epidemiological studies on periodontal diseases conducted in many countries employing different indices have generally shown advanced periodontal destruction to be more prevalent in adult males than in adult females. The 1984 Hong Kong survey of adult oral health, using the Community Periodontal Index of Treatment Needs (CPITN) to determine periodontal status, revealed that in males aged 35 to 44 years the prevalence of deep pockets was 23 per cent, compared with 9 per cent in females (P less than 0.01). Males had a mean of 0.4 sextants with deep pockets whereas females had a mean of only 0.1 sextants so affected (P less than 0.01). Females were found to have a significantly larger proportion of healthy sextants (P less than 0.01). The observed sex difference in disease prevalence may have been influenced by the fact that fewer teeth were present in the females, but it could not be explained by differences in reported oral hygiene measures and practices.

Paediatric extracranial germ cell tumours: a retrospective review.

INTRODUCTION: Germ cell tumours (GCTs) are rare, constituting 3% of all childhood malignancies. The aim of this study was to analyse the epidemiology and outcome of these patients. MATERIALS AND METHODS: A retrospective, cohort study was conducted on 38 paediatric patients presenting with extracranial GCTs, treated at the Singapore General Hospital, Tan Tock Seng Hospital and Kandang Kerbau Women's and Children's Hospital from 1 January 1989 to 30 June 1999. The median age at diagnosis was 1.7 years (0 to 13 years). RESULTS: There was no sex or racial preponderance. Eighteen patients (47.3%) had teratomas, 16 (42.1%) had yolk sac tumours, 1 (2.6%) had dysgerminoma and 3 (7.9%) had mixed GCTs. Thirty-four patients (89.5%) had Stage I disease, 1 (2.6%) had Stage II disease, 1 (2.6%) had Stage III disease and 2 (5.3%) had metastatic disease. Complete tumour resection was achieved in 36 of the 38 patients (95%). Cisplatin-based combination chemotherapy was given to 11 patients (28.9%). None of the patients received radiotherapy. Complications from chemotherapy included anaemia requiring packed red cell transfusion (n = 3), Port-a-cath sepsis requiring removal (n = 1), febrile neutropenia (n = 1) and nephropathy (n = 1). CONCLUSION: Using the Kaplan-Meier life tables, the overall and event-free survivals at 10 years for the patients with malignant GCTs were 96% and 88%, respectively, with a mean follow-up period of 5.1 years (0.7 to 10 years). The majority of the patients presented with early Stage I disease and this contributed to our high survival rate.

Survey of dental fees charged by dentists in Singapore.

A survey on dental fees was conducted among all private dental clinics registered with the Medical Audit and Accreditation Unit of the Ministry of Health in Singapore. Replies were received from 74 dental clinics. Analysis of results showed that there was a general increase in the median of fees charged in 1998 compared to the fees listed in the Minimum Fee Schedule issued by the Singapore Dental Association in 1994. 93% of the respondents indicated that there is a need to revise the Minimum Fee Schedule.

PDGF-simvastatin delivery stimulates osteogenesis in heat-induced osteonecrosis.

Heat generated during implant osteotomy might lead to osteonecrosis and delayed bone repair, thus resulting in impaired early osseointegration and fixation of bone-anchoring devices. In this study, we proposed to overcome heat-induced injury to bone by fabricating core-shell polymeric biodegradable microspheres encapsulating a mitogenic factor, platelet-derived growth factor (PDGF), and a differentiation factor, simvastatin, in a simultaneous or sequential release profile. Microspheres encapsulating bovine serum albumin (BSA), PDGF, simvastatin, PDGF-in-core with simvastatin-in-shell, and simvastatin-in-core with PDGF-in-shell were delivered to fill standardized osteotomy sites on edentulous ridges of rat maxillae under irrigated or non-irrigated conditions. In the absence of irrigation, significant reduction of cell viability and increase in inflammation and sequestrum formation without evidence of osteogenesis were observed. Both PDGF and simvastatin deliveries facilitated cell viability and reduced osteonecrosis. Localized osteogenesis was seen under simvastatin treatment, while generalized but primitive osteogenesis was noted in PDGF-treated osteotomy sites. In addition, sequential PDGF-simvastatin delivery further augmented osteogenesis and promoted bone maturation. The results suggested that sequential PDGF-simvastatin delivery was an effective modality to prevent heat-induced complications and facilitate bone apposition after implant osteotomy, potentially favoring the early fixation of bone-anchoring devices and oral implant osseointegration.

Relationship between markers of metabolic control and inflammation on severity of periodontal disease in patients with diabetes mellitus.

AIM: The aim of this study was to investigate the relationship between markers of metabolic control and inflammation and periodontal disease parameters in patients with diabetes. MATERIAL & METHODS: One hundred and eighty one adult patients with diabetes attending treatment at two diabetes centres were invited to participate in the study. Periodontal examination included full-mouth assessment for probing depths and bleeding on probing (BOP). Blood analyses were carried out for glycated haemoglobin, (HbA1c), high-sensitivity C reactive protein, (hsCRP) and lipid profile comprising total cholesterol, low-density lipoprotein cholesterol (LDL chol), high-density lipoprotein cholesterol (HDL chol) and triglycerides. RESULTS: Upon multivariate analysis, periodontal disease severity in terms of increased percentage of BOP and mean percentage of sites with probing depths > or = 5 mm were found to be associated with inadequate glycaemic control as measured by HbA1c (p<0.01). HsCRP was also found to be a significant predictor for mean percentage of sites with probing depths > or = 5 mm (p<0.05). After controlling for age, gender, smoking habits and number of teeth, positive correlations were found between HbA1c and percentage sites with probing depths > or = 5 mm, percentage sites BOP, total cholesterol, LDL chol and triglycerides (p<0.05). Using the adjusted differences, subjects with acceptable glycaemic control (HbA1c < 8%) showed a lower percentage of sites with BOP and probing depths > or = 5 mm (p<0.05) when compared with those having inadequate glycaemic control. There was also a trend towards lower blood cholesterol in the well-controlled group. CONCLUSION: The level of glycaemic control as measured by HbA1c emerged as the most consistent risk factor associated with the extent and severity of periodontal disease in this study cohort.

Dental trauma management awareness of Singapore pre-school teachers.

The purpose of this study was to assess the awareness of pre-school teachers concerning the management of traumatized teeth. A questionnaire survey of teachers' backgrounds, attitudes/practices and knowledge was distributed to all teachers who attended a dental education program organized by the Singapore Dental Health Foundation. Of a total of 291 teachers surveyed, 29% had received tertiary education, while the rest (71%) had received secondary education. The mean teaching experience was 6.8 +/- 6.9 years. About a quarter had previous experience in handling dental trauma. Sixty-three percent admitted having no knowledge of dental trauma; 79% were unsatisfied with their level of knowledge in this area; 95% were keen to have further education in dental trauma; 65% thought dental trauma emergency should be dealt with as soon as possible. Concerning knowledge, during-office hour emergency services were more familiar (84%) than after-office hour emergency services (15%), as was the concept of management of avulsed teeth (71%) compared to that of fractured teeth (51%). Knowledge about optimal storage media for avulsed permanent teeth was especially poor--being as low as 15%. Using multiple logistic regression analysis, it was found that teaching experience significantly influenced the respondents' self-assessed knowledge and their level of satisfaction with their knowledge (P = 0.012). Teachers with more teaching experience had better knowledge about the replantation of permanent teeth (P = 0.003). It is recommended that public education targeted at teachers should be carried out to increase dental trauma management awareness.

Comparison of various modalities of "simple" periodontal therapy on oral cleanliness and bleeding.

550 Chinese employees of both sexes aged 25-44 from an industrial organisation participated in a 16-month longitudinal study. Subjects were divided into 4 groups: an oral hygiene group (group A), a scaling group (group B), an oral hygiene + scaling group (group C) and a control (group D). The experimental subjects were examined at baseline, 2 weeks, 4 months, 10 months and 16 months. After 10 months, group A received scaling while group B was given oral hygiene instruction for the 1st time. The control group did not receive any treatment until completion of the programme. At 16 months, all 3 experimental groups had significantly lower plaque and bleeding scores than the control. The plaque and bleeding levels of the experimental groups were lower at all review appointments when compared with baseline. Some variations in the clinical parameters were found between groups at 2 weeks, 4 months and 10 months. The scaling + oral hygiene group showed the best response. Although a proportion of subjects showed a substantial improvement in bleeding scores following scaling, the significant resource implications in providing such treatment has to be considered in planning community health programmes to promote periodontal health, wherein oral hygiene education must still have the highest priority.

A computational analysis of sequence features involved in recognition of short introns.

Splicing of short introns by the nuclear pre-mRNA splicing machinery is thought to proceed via an "intron definition" mechanism, in which the 5' and 3' splice sites (5'ss, 3'ss, respectively) are initially recognized and paired across the intron. Here, we describe a computational analysis of sequence features involved in recognition of short introns by using available transcript data from five eukaryotes with complete or nearly complete genomic sequences. The information content of five different transcript features was measured by using methods from information theory, and Monte Carlo simulations were used to determine the amount of information required for accurate recognition of short introns in each organism. We conclude: (i) that short introns in Drosophila melanogaster and Caenorhabditis elegans contain essentially all of the information for their recognition by the splicing machinery, and computer programs that simulate splicing specificity can predict the exact boundaries of approximately 95% of short introns in both organisms; (ii) that in yeast, the 5'ss, branch signal, and 3'ss can accurately identify intron locations but do not precisely determine the location of 3' cleavage in every intron; and (iii) that the 5'ss, branch signal, and 3'ss are not sufficient to accurately identify short introns in plant and human transcripts, but that specific subsets of candidate intronic enhancer motifs can be identified in both human and Arabidopsis that contribute dramatically to the accuracy of splicing simulators.