SUV39H1 is a New Client Protein of Hsp90 Degradated by Chaetocin as a Novel C-Terminal Inhibitor of Hsp90

Hsp90 is often overexpressed with activated form in cancer cells, and many key cellular proteins are dependent upon the Hsp90 machinery (these proteins are called “client protein”). Nowadays, more client proteins and more inhibitors of Hsp90 are being discovered. Chaetocin has been identified as an inhibitor of histone methyl transferase SUV39H1. Herein, we find that Chaetocin is an inhibitor of Hsp90 which binds to the C-terminal of Hsp90α. Chaetocin inhibited a variety of Hsp90 client proteins including AMl1-ETO and BCL-ABL, the mutant fusion-protein in the K562 and HL-60 cells. SUV39H1 mediates epigenetic events in the pathophysiology of hematopoietic disorders. We found that inhibition of Hsp90 by Chaetocin and 17-AAG had ability to induce degradation of SUV39H1 through proteasome pathway. In addition, SUV39H1 interacted with Hsp90 through co-chaperone HOP.These results suggest that SUV39H1 belongs to a client protein of Hsp90. Moreover, Chaetocin was able to induce cell differentiation in the two cells in the concentration range of Hsp90 inhibition. Altogether, our results demonstrate that SUV39H1 is a new client protein of Hsp90 degradated by Chaetocin as a novel C-terminal inhibitor of Hsp90. The study establishes a new relationship of Chaetocin and SUV39H1, and paves an avenue for exploring a new strategy to target SUV39H1 by inhibition of Hsp90 in leukemia.

Prognostic value of PD-L1 expression level in metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective:To explore the prognostic value of PD-L1 expression level in patients with metastatic renal cell carcinoma (mRCC).Methods:The clinicopathological and survival data of patients with mRCC in our hospital from Jan 2014 to Apr 2016 were retrospectively analyzed including 46 males and 15 females. The median age of these patients was 56 years(range: 29-75 years), with 41 patients ≤60 years and 20 patients >60 years. The baseline data before the systemic therapy showed 36 patients(59.0%)had 1 metastatic organ and 25 patients (41.0%) had equal or more than 2 organs to be metastasized. Among them, 17 patients(27.9%)had lung metastasis and 54 patients(88.5%)had liver metastasis. Abnormal baseline LDH occurred in 4 patients and 52 patients had normal LDH. Favorite and intermediate risk patients categorized by MSKCC risk stratification accounted for 59.6%(34 patients)and 40.4%(23 patients), respectively. Six patients(9.8%)experienced distant metastasis at initial diagnosis, with 4 of them undergoing primary site resection, and the other 55 patients undergoing radical nephrectomy. PD-L1 expression was detected by the immunohistochemical staining method. PD-L1 staining rate ≥1% detected on the tumor cell membrane was defined as positive expression. The correlation between PD-L1 expression and clinicopathological characteristics were compared. Kaplan-Meier method and log-rank test were used to compare the differences about DFS and OS under different factors. Cox proportional hazards regression model is used for multivariable analysis of survival data.Results:The detailed pathological types of the 61 patients with renal cell carcinoma were classified as 53 clear cell carcinomas, 3 papillary carcinomas, 1 collecting duct carcinoma, 2 translocation renal cell carcinomas and 2 being unclassified. There were 4, 20, 19 and 9 patients categorized as WHO/ISUP nuclear grade 1, 2, 3 and 4, and 26, 12, 20 and 2 patients were categorized as T 1, T 2, T 3 and T 4 stage, respectively. Five patients had regional lymph node metastasis(N+), and the other 56 patients had no regional lymph node metastasis(N-). The numbers of patients categorized as stage Ⅰ, Ⅱ, Ⅲ and Ⅳ diseases according to TNM staging system were 20, 11, 21 and 8, respectively. The total PD-L1 positive rate was 24.6%(15/61). The corresponding PD-L1 expression rate of patients with WHO/ISUP nuclear grade 1-4 were 0(0 patient), 5.0%(1 patient), 31.6%(6 patients)and 44.4%(4 patients), respectively; With the increasing WHO/ISUP nuclear grade, the positive rate of PD-L1 gradually escalated with a linear correlation ( P=0.006). The PD-L1 expression of the normal and abnormal LDH group were 19.2%(10 patients)and 75.0%(3 patients), respectively, with significant difference( P=0.035). Univariate analysis of disease-free survival time(DFS)showed that the prognostic factors include PD-L1( P=0.045), age group( P=0.014), WHO/ISUP nuclear grade( P<0.001), T stage( P=0.015), N stage( P=0.026)and TNM stage( P=0.005). However multivariate analysis only suggested WHO/ISUP nuclear grade as the independent prognostic factors for DFS( HR=1.8, 95% CI 1.1-2.9, P=0.018). Either in univariate or multivariate analysis, PD-L1 was not a prognostic factor for overall survival (OS)of mRCC patients(univariate analysis: P=0.154; multivariate analysis: P=0.902). The independent prognostic factors of OS include WHO/ISUP nuclear grade( HR=3.0, 95% CI 1.1-8.0, P=0.033)and MSKCC risk stratification( HR=5.9, 95% CI 1.2-29.7, P=0.03). Conclusions:This study showed that the higher the WHO/ISUP nuclear grade of patients with mRCC, the higher the positive rate of PD-L1. PD-L1 expression was not the independent prognostic factor for DFS or OS of mRCC.

Clinical characteristics and prognosis of metastatic papillary renal cell carcinoma / 中国肿瘤临床

Objective: To investigate the clinical characteristics, treatment methods, and prognosis of metastatic papillary renal cell car-cinoma (pRCC). Methods: The clinical data of metastatic pRCC patients treated at the Department of Kidney Cancer and Melanoma, Pe-king University Cancer Hospital, were retrospectively analyzed. The prognosis of these patients was stratified through international metastatic renal cell carcinoma database consortium (IMDC) model. Survival and influencing factors were further analyzed using the Kaplan-Meier method and Cox proportional risk regression model. Results: From January 2003 to March 2018, 93 patients (median age, 50.0 years) were diagnosed with metastatic pRCC: 89 (95.7%) typeⅡcases and 4 (4.3%) typeⅠcases. The median follow-up dura-tion was 23.1 months, with 90, 44, and 14 patients having received first-line, second-line, and third-line treatments, respectively. The median overall survival (OS) of the 93 patients was (31.5±5.9) months [95% confidence interval (CI): 19.9-43.1], while the median OS of patients with low-, intermediate-, and high-risk (classified as per the International Metastatic Renal Cell Carcinoma Database Con-sortium [IMDC]) were (100.0±32.8), (38.3±8.2), and (16.4±1.2) months, respectively (high-risk vs. low/intermediate-risk, P<0.001; low-risk vs. intermediate-risk, P=0.015). The median progression free survival (PFS) with first-line treatment was (6.6±0.5) months. And the median PFS of the corresponding three groups stratified by IMDC score were (17.5±5.7), (7.1±2.3), and (5.2±1.5) months, respectively (high-risk vs . low-risk, P=0.002; high-risk vs . intermediate-risk, P=0.01). Conclusions: Metastatic pRCC is noted to have unique biologi-cal characteristics. The IMDC model can be used to predict the efficacy of first-line treatment using tyrosine kinase inhibitors as well as the prognosis of metastatic papillary renal cell carcinoma in such patients.

Effects of FBI-1 silencing on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231 / 生理学报

This work aimed to observe the effects of short hairpin RNA (shRNA)-silenced FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231. qRT-PCR and Western blot analysis were applied to detect the mRNA and/or protein expression of FBI-1, Bcl-2, Bax, cleaved-Caspase 3 and Survivin. RNA interference method was used to silence FBI-1 expression in MDA-MB-231 cells. CCK-8 and colony formation assay were employed to detect the cell proliferation. Flow cytometry was employed for examining cell apoptosis. In vivo tumorigenicity of MDA-MB-231 cells was detected by tumor transplantation in nude mice. The results showed that the mRNA and protein expressions of FBI-1 were higher in MDA-MB-231 cells compared with those in normal human mammary epithelial cells MCF-10A. FBI-1 gene silencing inhibited proliferation and induced apoptosis of MDA-MB-231 cells in vitro, together with decreased Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Moreover, FBI-1 gene silencing inhibited the tumorigenesis of MDA-MB-231 cells in vivo. These results suggest that silencing of FBI-1 gene inhibits proliferation, induces apoptosis and suppresses the tumorigenesis of MDA-MB-231 cells.

Effect of downregulation of FBI-1 on proliferation of human breast carcinoma cell line and its mechanism / 中国癌症杂志

Background and purpose: Factor that binds to the inducer of short transcripts of human immuno-deficiency virus-1 (FBI-1) in a variety of malignant tumors showed high expression levels, which may be closely related to tumor proliferation and differentiation, angiogenesis, metastasis, but its relationship with breast cancer has not been fully elucidated. The purpose of this study was to investigate the expression of FBI-1 in breast cancer cells, and to study the effect of FBI-1 gene expression on the proliferation of breast cancer cells and its possible mechanism. Methods:Real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) and Western blot analysis were applied to detect FBI-1 expression in normal human mammary epithelial cell line MCF-10A and breast cancer cell MCF-7. RNA interference method was used to down-regulate FBI-1 expression in MCF-7 cells. The cell proliferation was measured by CCK-8 kit and colony formation assay. RTFQ-PCR and Western blot were used to detect the expression of FBI-1 and NF-κBp65 in MCF-7 cells before and after the interference of FBI-1 expression. Results: The expression of FBI-1 was higher in breast cancer cells than that in normal human mammary epithelial cells (P<0.05). The effects of FBI-1 down-regulation inhibited proliferation in MCF-7 cells (P<0.05). At the same time, after inhibition of FBI-1, the NF-κBp65 mRNA and protein expression levels were significantly decreased (P<0.05). Conclusion: FBI-1 is highly expressed in breast cancer cells. Down-regulated FBI-1 expression can inhibit the proliferation of breast cancer cells,and its mechanism may be related to the inhibition of NF-κB signaling pathway.

Ultrasonic Elastography Strain Rate Ratio Combined with MRI in Diagnosis of Breast Tumor / 中国医学影像学杂志

PurposeTo evaluate the significance of ultrasonic elastography strain ratio, MRI and the combination of both in diagnosis of breast tumor.Materials and MethodsFifty-four cases with single breast tumor underwent preoperative ultrasound elasticity imaging and MRI. Accuracy of ultrasound elastography strain rate ratio (SRR) of the tumor and surrounding normal breast tissue was measured by quantitative ultrasound elastography, and its combination with MRI were analyzed. ResultsThere was signiifcant differences on SRR between the benign group and the malignant group (2.24±1.28vs 4.96±1.73, t=2.648,P0.05). Combined both had higher diagnosis accuracy when compared with SR and MRI separately (χ2=6.000 and 3.967,P<0.05).Conclusion Ultrasonic elastography strain ratio is accurate and objective in differentiating benign from malignant breast tumors. It is a valuable quantitative index in clinical practice. Moreover, SRR combined with MRI can reduce the misdiagnosis rate.

A pilot study of sunitinib as first-line therapy for metastatic renal cell carcinoma on a 2 weeks on/1 week off intermittent dosing schedule / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule.</p><p><b>METHODS</b>A total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response.</p><p><b>RESULTS</b>The objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation.</p><p><b>CONCLUSIONS</b>Sunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.</p>

A Comparison of the Short-term Morbidity and Mortality Between Late Preterm and Term Newborns

<p><b>INTRODUCTION</b>Late preterm babies are defined as those born between 34 to 36 completed weeks. There has been a recent increased awareness that this group of babies has a higher incidence of morbidity as compared to term babies. The aim of this study was to evaluate the short-term morbidities occurring in this group of babies managed in the neonatal unit at Singapore General Hospital (SGH).</p><p><b>MATERIALS AND METHODS</b>A retrospective study was done of babies managed in the neonatal unit at SGH from January 2005 to December 2008. Maternal, perinatal and neonatal data were obtained from the departmental database. The outcomes of late preterm infants were compared with term infants.</p><p><b>RESULTS</b>A total of 6826 babies were admitted. Ten percent (681 out of 6826) of babies were late preterm babies, making up 63% (681 out of 1081) of all preterm babies. Late preterm babies had significantly greater need for resuscitation at birth. They also had statistically significant increased risks of developing hyaline membrane disease (2.5% vs 0.1%), transient tachypnoea of the newborn (TTN) (8.1% vs 1.7%), pneumonia (7.0% vs 2.8%), patent ductus arteriosus (PDA) (4.3% vs 1.1%), hypotension (0.7% vs 0%), apnoea (3.7% vs 0%), gastrointestinal (GI) bleeding (1.5% vs 0.3%), polycythaemia (2.2% vs 1.0%), anaemia (3.4% vs 1.2%), thrombocytopenia (3.2% vs 0.6%), hypoglycaemia (6.6% vs 1.7%), neonatal jaundice requiring phototherapy (41.1% vs 12.2%) and sepsis (1.7% vs 0.6%).</p><p><b>CONCLUSION</b>Late preterm infants are indeed a vulnerable group of infants with significant morbidities that need to be addressed and treated. Despite their relatively large size and being almost term, the understanding that late preterm infants are not similar to term infants is important to both obstetricians and neonatologists.</p>

Parental knowledge, attitudes and perceptions regarding infant basic life support

<p><b>INTRODUCTION</b>Out-of-hospital cardiopulmonary arrest (CPA) in children is rare but significant, with poor survival rates and high morbidity. Asystole is the most common dysrhythmia, and cardiopulmonary resuscitation (CPR) is of great importance in such cases. We aimed to survey the knowledge, attitudes and perceptions of parents in Singapore regarding infant basic life support (IBLS).</p><p><b>METHODS</b>A questionnaire survey was administered to parents of children managed at the Neonatal Department of Singapore General Hospital, Singapore, between 1 September and 31 December 2008. The questionnaire consisted of three sections--section A collected demographic data, section B included questions on knowledge, and section C explored attitudes and perceptions. Knowledge T-scores were analysed for the entire cohort and subanalysed with respect to prior IBLS training.</p><p><b>RESULTS</b>In our study cohort (n = 375), the median Basic Knowledge (BK) T-score was 7 (range 1-9) and the pass rate was 55%. Median BK T-scores were significantly different between untrained (6; range 3-9) and previously trained (8; range 3-9) participants. A majority of the trained participants obtained pass marks. Median Total Knowledge T-score, involving advanced questions, for previously trained participants was 11 (range 3-14), but pass rate was low (35.7%). Higher educational qualification was a significant factor impacting all scores. Untrained participants indicated interest in attending IBLS courses, while trained participants were interested in refresher courses.</p><p><b>CONCLUSION</b>IBLS training, as part of basic cardiac life support training, is important given that CPR can significantly alter the outcome in children with CPA. Our survey revealed knowledge gaps that could be bridged through formal training. Refresher courses to regularly update parents' knowledge are recommended.</p>

Strategic thinking and practice on building research-oriented hospital / 中华医院管理杂志

Based on hospital development cycle and the core rigidities theory,the authors made a strategic analysis on the building of research-oriented hospital of the Eastern Hepatobiliary Surgery Hospital.They put forward that building a research-oriented hospital is key to exceeding the core rigidities of the hospital and promoting core competence.In their practice,they developed the model featuring innovation culture as the leader,hospital-institute in one as the pattern,composite talents as the core,integrated innovation as the mechanism,and high-level medical cooperation as promoter.

Profile of children diagnosed with autistic spectrum disorder managed at a tertiary child development unit

<p><b>INTRODUCTION</b>There has been a rising trend in childhood developmental and behavioural disorders (CDABD). This study reports the profile of children with autistic spectrum disorders (ASD) initially referred for evaluation of CDABD.</p><p><b>METHODS</b>The CDABD database prospectively collected data of all consenting children referred in 2003 to the then Child Development Unit at KK Women's and Children's Hospital. All received medical consultation, followed by further assessments and intervention. Patients were tracked for one year.</p><p><b>RESULTS</b>Among 542 referred children, 32% (n = 170) received a diagnosis of ASD one year after the first consultation. Most were male, with a male to female ratio of 4.5:1. The median age at the first consultation was 41 (19,109) months. The main presenting concern was a delay in the development of speech and language skills in 78% of the children. A significant number had behavioural (63%) and social interaction (34%) issues. Criteria for the diagnosis of ASD according to the Diagnostic Statistical Manual IV-Revised were fulfilled in almost 90%. With the remaining refusing or deferring evaluation, only 74% received a psychological assessment. ASD was assessed to be severe or moderate in 86% of the children. Three-quarters remained on follow-up one year after the first consultation. The majority were referred for either centre- or school-based intervention programmes, with 70% assessed to have improved at the one-year mark.</p><p><b>CONCLUSION</b>This is the first presentation of local data that aids programme planning and resource allocation. Children with ASD have varied outcomes. It is important to identify and intervene early in order to optimise development and functionality.</p>

Children with developmental and behavioural concerns in Singapore

<p><b>INTRODUCTION</b>Childhood developmental and behavioural disorders (CDABD) have been increasingly recognised in recent years. This study evaluated the profiles and outcomes of children referred for developmental and behavioural concerns to a tertiary child developmental centre in Singapore. This is the first such regional database.</p><p><b>METHODS</b>Baseline information, obtained through a questionnaire, together with history at first consultation, provided information for referral, demographic and presentation profiles. Clinical formulations were then made. Definitive developmental and medical diagnoses, as well as outcomes based on clinical assessment and standardised testing, were recorded at one year post first consultation.</p><p><b>RESULTS</b>Out of 1,304 referrals between January 1, 2003 and December 1, 2004, 45% were 2-4 years old and 74% were boys. The waiting time from referral to first consultation exceeded four months in 52% of children. Following clinical evaluation, 7% were found to be developmentally appropriate. The single most common presenting concern was speech and language (S&L) delay (29%). The most common clinical developmental diagnosis was autism spectrum disorder (ASD) (30%), followed by isolated S&L disorder, global developmental delay (GDD) and cognitive impairment (CI). Recommendations included S&L therapy (57%), occupational therapy (50%) and psychological/behavioural services (40%). At one year, ASD remained the most common definitive developmental diagnosis (31%), followed by S&L disorder, CI and GDD. Most were children with high-prevalence, low-moderate severity disorders who could potentially achieve fair-good prognosis with early intervention.</p><p><b>CONCLUSION</b>Better appreciation of the profile and outcome of children with CDABD in Singapore could enable better resource planning for diagnosis and intervention.</p>

Auricular anthropometry of newborns at the Singapore General Hospital

<p><b>INTRODUCTION</b>External ear abnormalities accompany many syndromes and genetic conditions. Yet, there are currently limited Asian references and no local norms for ear measurements and definitions for "low-set ears". The authors therefore describe ear measurements in a Singapore newborn population and seek to establish the applicability of the general accepted definition of "low-set ears" being that of "less than a third of the entire ear height being above the inter-medial canthal line".</p><p><b>MATERIALS AND METHODS</b>Babies managed by the Department of Neonatal and Developmental Medicine during a 3-week period were measured by 2 investigators using the Feingold and Bossert technique. Intra- and inter-rater reliabilities were calculated. The influence of various anthropometric factors on and their relationships with ear length (EL) and width (EW) was analysed.</p><p><b>RESULTS</b>A total of 104 neonates (20% preterm at birth) were included in this study. Median gestation was 38 weeks (range, 32 to 42). Mean birth weight was 2910 +/- 657 g. Mean EW and EL for term infants were 2.1 +/- 0.1 cm and 3.6 +/- 0.3 cm respectively, without significant differences for different-sided ears, investigators, race or gender. Mean percentage of right and left ear above the denoted line was 52 +/- 9% and 47 +/- 10% respectively (P = 0.000), with 3rd percentile being 33%.</p><p><b>CONCLUSIONS</b>Singaporean neonatal ears are comparable with other Asian neonates - larger than Hong Kong Chinese babies, though similar to Japanese newborns - but smaller than Caucasian neonates. The definition of "low-set ears" is consistent with the general accepted definition.</p>

Does visual turbidity correlate with serum triglyceride levels in babies on total parenteral nutrition?

<p><b>INTRODUCTION</b>Intravenous lipid is commonly used as part of total parenteral nutrition (TPN) in premature babies. The gold standard of measuring lipid tolerance involves measuring serum triglyceride levels. Many hospitals in Asia do not have this facility and rely on visual turbidity to titrate the rate of lipid infusion. The aim of this study was to determine if visual turbidity correlates with serum triglyceride levels.</p><p><b>MATERIALS AND METHODS</b>Twenty-seven samples were taken from 8 babies on intravenous (IV) lipid infusion for the analysis of serum triglyceride levels and visual turbidity (assessed by 2 senior neonatologists independently). Serum turbidity was classified either as clear or turbid. Lipid intolerance was defined as triglyceride levels greater than 200 mg/dL (2.25 mmol/L).</p><p><b>RESULTS</b>Both neonatologists similarly classified 20 out of 27 specimens. Serum triglyceride levels for clear samples (n = 10) were significantly lower than those for turbid samples (n = 10) (P <0.01). The clear specimens all had normal serum triglyceride levels (mean, 1.16 mmol/L; range, 0.43 to 1.96). Not all turbid specimens had unacceptable serum triglyceride levels (mean, 2.37 mmol/L; range, 1.37 to 5.75). In the remaining 7 specimens, there was a difference in opinion regarding serum turbidity. The triglyceride levels for these 7 samples were all normal (mean, 1.17 mmol/L; range, 0.66 to 1.72).</p><p><b>CONCLUSION</b>Serum turbidity may be used as a screening tool in assessing lipid tolerance in babies on TPN as all clear samples had acceptable serum triglyceride level if we set the maximum cutoff at 2.25 mmol/L. Patients with turbid samples should ideally have their serum triglyceride taken to confirm lipid intolerance before altering their lipid infusion rate as they may have acceptable triglyceride levels.</p>

Intensional definition of research-oriented hospitals and research on their features / 中华医院管理杂志

Proceeding from such perspectives as the development of medical science and technology,the prevention and treatment of diseases,and the needs of hospitals for self-development,the paper discusses the significance of building research-oriented hospitals.It also expounds the concept and intensional features of research-oriented hospitals in light of the successful experience of specialty hospitals that have developed through science and education,the development strategies and measures of research-oriented enterprises and universities,and the unique features of hospitals.At the same time the paper puts forward suggestions for appropriately handling certain relationships in the building of research-oriented hospitals.

Adopting the system of overall responsibility by the attending physician in large general hospitals / 中华医院管理杂志

By analyzing the situation that large general hospitals face at present in their development and the background of reform in the system of overall responsibility by the attending physician in the hospital, the authors offer an account of the guiding ideology for large general hospitals to adopt the system of overall responsibility by the attending physician, the specific steps taken and the initial results attained. They also discuss the impact of the system of overall responsibility by the attending physician on the hospital from the perspectives of human resources, technological innovation, managerial system, and information system. The positive significance of the system of overall responsibility by the attending physician in the management of the hospital reform is also identified.