Showing papers by "Peking Union Medical College Hospital published in 2016"

A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223.

Abstract: Aims Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. Methods and results Here we show that a circular RNA (circRNA), which we term heart-related circRNA ( HRCR ), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. Conclusions These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

Abstract: Angiogenesis plays crucial roles in various physiological processes including wound healing and tissue repair. It requires a tight interaction between endothelial cells and their surrounding environment. Mesenchymal stem cells (MSCs), one of the non-endothelial cell types present in the perivascular environment, have been shown to secret exosomes to modulate intercellular communications between MSCs and their target cells. In this study, we initially isolated exosomes secreted by human adipose-derived MSCs (adMSC-Exo) and examined their roles in angiogenesis. We found that adMSC-Exo could be taken up by endothelial cells and significantly promote angiogenesis in vitro and in vivo Further study showed that miR-125a was enriched in adMSC-Exo, and repressed the expression of the angiogenic inhibitor delta-like 4 (DLL4) by targeting its 3' untranslated region. Additionally, adMSC-Exo and its exosomal transferred miR-125a could repress DLL4 expression and modulate endothelial cell angiogenesis through promoting formation of endothelial tip cells. In conclusion, our study indicates that adMSC-Exo can transfer miR-125a to endothelial cells and promote angiogenesis by repressing DLL4. adMSC-Exo, as a pro-angiogenic factor, might be a promising candidate for therapeutical tissue repair.

Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates

Abstract: Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S471–503, S604–625, and S1164–1191 elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S597–603 induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S597–603 and S604–625) and a long-term human B-cell memory response with antisera from convalescent SARS patie...

Novel benzo-bis(1,2,5-thiadiazole) fluorophores for in vivo NIR-II imaging of cancer.

Abstract: Optical imaging of diseases represents a highly dynamic and multidisciplinary research area, and second near-infrared window (NIR-II, 1000-1700 nm) imaging is at the forefront of the research on optical imaging techniques. Small-molecule based NIR-II (1000-1700 nm) dyes are highly promising candidates for in vivo molecular imaging because of their high biocompatibility, fast excretion, and high clinical translation ability. However, research reports on small-molecule based NIR-II dyes and probes are rare. Herein, we designed a series of fluorescent compounds (Q1, Q2, Q3, and Q4) and investigated the relationships between their structures and absorption/fluorescence properties. Q4 (maximum emission at 1100 nm) stood out as the dye with the best physical properties and thus was selected as a scaffold for the facile construction of two types of water-soluble and biocompatible NIR-II probes (Q4NPs and SCH1100). Highly specific gastrin-releasing peptide receptor (GRPR) targeted NIR-II imaging of prostate cancer in living mice was achieved using the small-molecule probe SCH1100, which represents the first small peptide based NIR-II probe for targeted cancer imaging. The attractive imaging properties of Q4-based NIR-II probes open up many opportunities for molecular imaging and clinical translation in the unique NIR-II window.

Iodine Status and Prevalence of Thyroid Disorders After Introduction of Mandatory Universal Salt Iodization for 16 Years in China: A Cross-Sectional Study in 10 Cities.

Abstract: Background: The goal of eliminating iodine deficiency worldwide was successfully achieved in China after the implementation of a mandatory universal salt iodization program for the last 16 years. Thus, China has been assessed as a country with more than adequate iodine levels. This survey aimed to investigate the current iodine status in China and the effects of an increased iodine intake on the spectrum and prevalence of thyroid disorders. Methods: A total of 15,008 adult subjects from 10 cities in eastern and central China were investigated. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and urine iodine concentration (UIC) were measured, and an ultrasonography of the thyroid was performed in all subjects. Free thyroxine (fT4) and free triiodothyronine (fT3) levels were only measured if the serum TSH was outside the normal range. Results: The median UIC values were 197 μg/L in school-age children (SAC) and 205 μg/L in a cohort population. Six cities were...

T2DM Self-Management via Smartphone Applications: A Systematic Review and Meta-Analysis.

Abstract: Background Mobile health interventions (mHealth) based on smartphone applications (apps) are promising tools to help improve diabetes care and self-management; however, more evidence on the efficacy of mHealth in diabetes care is needed. The objective of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effect of mHealth apps on changes in hemoglobin A1c (HbA1c), blood glucose, blood pressure, serum lipids, and body weight in type 2 diabetes mellitus (T2DM) patients.

CCAT1: a pivotal oncogenic long non-coding RNA in human cancers.

Abstract: Long non-coding RNAs (lncRNAs) are a group greater than 200 nucleotides in length. An increasing number of studies has shown that lncRNAs play important roles in diverse cellular processes, including proliferation, differentiation, apoptosis, invasion and chromatin remodelling. In this regard, deregulation of lncRNAs has been documented in human cancers. TUG1 is a recently identified oncogenic lncRNA whose aberrant upregulation has been detected in different types of cancer, including B-cell malignancies, oesophageal squamous cell carcinoma, bladder cancer, hepatocellular carcinoma and osteosarcoma. In these malignancies, knock-down of TUG1 has been shown to suppress cell proliferation, invasion and/or colony formation. Interestingly, TUG1 has been found to be downregulated in non-small cell lung carcinoma, indicative of its tissue-specific function in tumourigenesis. Pertinent to clinical practice, TUG1 may act as a prognostic biomarker for tumours. In this review, we summarize current knowledge concerning the role of TUG1 in tumour progression and discuss mechanisms associated with it.

Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway

Abstract: In tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Accumulating evidence suggests that exosomes, a novel way of cell communication, play an important role in such cross-talk. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Since mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, there is an urgent need to reveal the effect of tumor exosomes on MSCs and to further explore the underlying molecular mechanisms. Exosomes were harvested from lung cancer cell line A549 and added to MSCs. Secretion of inflammation-associated cytokines in exosome-treated MSCs were analyzed by RT-PCR and ELISA. The growth-promoting effect of exosome-treated MSCs on lung tumor cells was evaluated by in vivo mouse xenograft model. Signaling pathway involved in exosomes-treated MSCs was detected by PCR array of human toll-like receptor signaling pathway, RT-PCR, and Western blot. Data showed that lung tumor cell A549-derived exosomes could induce a pro-inflammatory phenotype in MSCs named P-MSCs, which have significantly elevated secretion of IL-6, IL-8, and MCP-1. P-MSCs possess a greatly enhanced ability in promoting lung tumor growth in mouse xenograft model. Analysis of the signaling pathways in P-MSCs revealed a fast triggering of NF-κB. Genetic ablation of Toll-like receptor 2 (TLR2) by siRNA and TLR2-neutralizing antibody could block NF-κB activation by exosomes. We further found that Hsp70 present on the surface of lung tumor exosomes contributed to the induction of P-MSCs by A549 exosomes. Our studies suggest a novel mechanism by which lung tumor cell-derived exosomes induce pro-inflammatory activity of MSCs which in turn get tumor supportive characteristics.

A morphological study of the foveal avascular zone in patients with diabetes mellitus using optical coherence tomography angiography.

Abstract: To investigate the area and radius of the foveal avascular zone (FAZ) in patients with diabetes mellitus (DM) using optical coherence tomography (OCT) angiography. Sixty-five patients with DM (113 eyes) and 62 healthy controls (85 eyes) were included in the study. All of the participants underwent examination with OCT angiography. The vertical radius (VR), horizontal radius (HR) and area of the FAZ were measured. The differences in HR, VR and area between the control and DM groups were statistically significant (p = 0.01, 0.00 and 0.00, respectively). There were no statistically significant differences between the control group and the no-diabetic retinopathy (DR) group in HR or VR (p = 0.07 and 0.08, respectively), but there was a statistically significant difference in area (p = 0.04). The size of the FAZ was greater in patients with DR compared to the control group. The differences in HR, VR and area were statistically significant (p = 0.01, 0.00 and 0.00, respectively). In addition, the clinically significant macular oedema (CSME) group also had a larger FAZ area than the non-CSME group (p = 0.02). Patients with DM had a larger FAZ, and patients with more severely damaged retinas had a much larger FAZ. OCT angiography is a new convenient and noninvasive method for studying the FAZ. This novel examination will yield considerable amounts of data that cannot be obtained using previous research methods.

Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study

Abstract: Objective Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc. Methods In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. Results Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide 40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis. Conclusion In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to 'widen' the still very narrow 'window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.

Glucagon-like Peptide-1 Receptor PET/CT with 68Ga-NOTA-exendin-4 for Detecting Localized Insulinoma: a Prospective Cohort Study

Abstract: Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with 68Ga-NOTA-MAL-cys40-exendin-4 (68Ga-NOTA-exendin-4) is efficient in detecting insulinoma. Methods: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and 99mTc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30–60 min after the injection of 68Ga-NOTA-exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. Results: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. 68Ga-NOTA-exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, 99mTc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. Conclusion:68Ga-NOTA-exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.

Long noncoding RNA MIR31HG exhibits oncogenic property in pancreatic ductal adenocarcinoma and is negatively regulated by miR-193b

Abstract: Long noncoding RNAs (lncRNAs) play important regulatory roles in a variety of diseases, including many tumors. However, the functional roles of these transcripts and mechanisms responsible for their deregulation in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly understood. In this study, we discovered that lncRNA MIR31HG is markedly upregulated in PDAC. Knockdown of MIR31HG significantly suppressed PDAC cell growth, induced apoptosis and G1/S arrest, and inhibited invasion, whereas enhanced expression of MIR31HG had the opposite effects. Online database analysis tools showed that miR-193b could target MIR31HG and we found an inverse correlation between MIR31HG and miR-193b in PDAC specimens. Inhibition of miR-193b expression significantly upregulated the MIR31HG level, while overexpression of miR-193b suppressed MIR31HG's expression and function, suggesting that MIR31HG is negatively regulated by miR-193b. Moreover, using luciferase reporter and RIP assays, we provide evidence that miR-193b directly targeted MIR31HG by binding to two microRNA binding sites in the MIR31HG sequence. On the other hand, MIR31HG may act as an endogenous 'sponge' by competing for miR-193b binding to regulate the miRNA targets. Collectively, these results demonstrate that MIR31HG functions as an oncogenic lncRNA that promotes tumor progression, and miR-193b targets not only protein-coding genes but also the lncRNA, MIR31HG.

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial

Abstract: Summary Background Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. Methods We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m 2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. Findings Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit–risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7–16·0). Median progression-free survival was 5·5 months (95% CI 5·4–5·6) in the afatinib group and 5·6 months (5·3–7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86–1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Interpretation Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Funding Boehringer Ingelheim.

Multicentric epidemiologic study on six thousand three hundred and ninety five cases of femoral head osteonecrosis in China

Abstract: Osteonecrosis of femoral head (ONFH) is a common joint disease with high morbidity in mainland China. We performed a retrospective case investigation based on the widest range of patients ever to reveal the demographic and clinical characteristics of ONFH in mainland China. We collected data from hospitalized patients of nine large tertiary hospitals in China, focusing on the aetiology of ONFH. Medical records and self-design questionnaires were used to collect data. We determined the patients’ aetiology according to established guidelines and categorized patients into different subgroups. We further analysed the underlying illness of the steroid-induced osteonecrosis of femoral head. A total of 6,395 patients with complete medical records were included in the study. The age (mean ± SD) of the patients was 46.45 ± 13.80 years. Males dominate with 70.1 % of all ONFH patients. In all the ONFH patients, 24.1 % are steroid induced, 30.7 % are alcoholic, 16.4 % are traumatic and 28.8 % are idiopathic. Among steroid-induced osteonecrosis of femoral head patients, 546 patients have autoimmune disorder (46.63 %), which is the most common underling illness, among these, the most common disease is systemic lupus erythematosus (SLE). The most common age when ONFH occurs is between 40 and 50 years old. Male patients developed ONFH 3.4 years earlier than female patients. The number of the male patients is greater than the female, reaching the overall gender proportion of 7:3. Autoimmune disease is the primary cause of steroid-induced ONFH, among which SLE is the most common disease.

Post-mortem assessment in vascular dementia: advances and aspirations

Abstract: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer’s disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer’s disease, vascular dementia and mixed Alzheimer’s disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.

Comparison of subcutaneous versus submuscular expander placement in the first stage of immediate breast reconstruction

Abstract: Summary Background and Aim Tissue expander-based two-stage reconstruction remains the most commonly used technique in immediate breast reconstruction. This study compares the subcutaneous expander placement to the traditional submuscular placement and describes our early experience with the expander insertion plane-choosing algorithm. Methods A retrospective study of patients who underwent two-stage immediate breast reconstruction from May 2012 to October 2014 was conducted. All expander insertion planes were chosen using the same algorithm. Expansion, pain, and complications were compared between two groups. Results The study included 88 patients (158 expanders; 50 subcutaneous and 108 submuscular). The subcutaneous group had a higher intraoperative expansion ratio ( p p p = 0.02), less number of expansion visits ( p = 0.002), and less average pain during admission ( p = 0.004). Significant differences in the intraoperative and first postoperative expansion ratios in patients with postmastectomy radiation therapy were also found between the two groups ( p = 0.005 and 0.01, respectively). Complications during expansion and after second-stage autologous flap reconstruction were comparable between two groups. Conclusion The subcutaneous expander placement was associated with greater intraoperative and first postoperative expansion, shorter expansion duration, less expansion visits, and less pain. With the expander insertion plane-choosing algorithm, subcutaneous expander placement could be performed with comparable complications rates with the submuscular placement during expansion and after second-stage autologous flap reconstruction. Further studies can be performed due to the lack of long-term complications following second-stage implant reconstruction in the subcutaneous approach.

Detection of virus in CSF from the cases with meningoencephalitis by next-generation sequencing.

Abstract: We screened for viral DNA in cerebrospinal fluid samples using next-generation sequencing (NGS) technology to diagnose CNS viral infections. We collected CSF samples from four cases with clinically suspected viral meningoencephalitis. DNA extracted from the samples was analyzed with NGS, and the results were further validated using PCR. Herpes simplex virus 1 (HSV-1) was detected in the CSF of two patients, HSV-2 and human herpes virus type 3 (HHV-3, VZV) in the CSF of two other patients separately. The number of unique reads of the identified viral genes ranged from 144 to 44205 (93.51 to 99.57 %). The coverage of identified viral genes ranged from 12 to 98 % with a depth value of 1.1 to 35, respectively. The results were further confirmed using PCR in three cases. The clinical presentation and outcomes of these four cases were consistent with the diagnostic results of NGS. NGS of CSF samples can be used as a diagnostic assay for CNS viral infection. Its further application for “pan-viral” or even “pan-microbial” screening of CSF might influence the diagnosis of CNS infectious diseases.

MicroRNA-421 regulated by HIF-1α promotes metastasis, inhibits apoptosis, and induces cisplatin resistance by targeting E-cadherin and caspase-3 in gastric cancer.

Abstract: Hypoxia and dysregulation of microRNAs (miRNAs) have been identified as crucial factors in carcinogenesis. However, the potential mechanisms of HIF-1α and miR-421 in gastric cancer have not been well elucidated. In this study, we found that miR-421 was up-regulated by HIF-1α. Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer in vivo and in vitro. E-cadherin and caspase-3 were identified as targets of miR-421. Besides, relative mRNA expression of miR-421 was significantly increased in gastric cancer tumor tissues compared with non-tumor tissues in a cohort of gastric cancer specimens (n=107). The expression of miR-421 was higher in advanced gastric cancers compared with localized ones. Moreover, Kaplan-Meier analysis illustrated that those patients with low levels of miR-421 had a significant longer overall survival (p = 0.006) and time to relapse (p = 0.007). Therefore, miR-421 could serve as an important prognostic marker and a potential molecular target for therapy in gastric cancer.

Therapeutic drug monitoring of vancomycin: a guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society

Abstract: Background Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin. Objectives To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China. Methods We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations. Results The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose. Conclusions We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China.

Diagnostic accuracy of cardiovascular magnetic resonance for patients with suspected cardiac amyloidosis: a systematic review and meta-analysis

Abstract: This study is a systematic review and meta-analysis of the diagnostic value of cardiovascular magnetic resonance (CMR) in cardiac amyloidosis (CA). A wide variety of electronic databases were searched for studies of CMR that reported the diagnostic accuracy in patients with suspected CA. Research manuscripts were subjected to further systematic review and meta-analysis. Methodological evaluation was performed under the guidance of the Quality Assessment of Diagnostic Accuracy Studies −2 (QUADAS–2). Heterogeneity was assessed, and a random-effects model was used to assess the diagnostic effects of CMR on pooled sensitivity, pooled specificity, and summary receiver operating characteristics (SROC). Seven studies that reported the performance of CMR for CA were included in the present systematic review, among which five studies (257 patients) that evaluated the diagnostic accuracy of late gadolinium enhancement (LGE) CMR were analyzed in the present meta-analysis. Heterogeneity was observed only in specificity. A summary sensitivity and specificity of 85 % (95 % CI: 77–91 %) and 92 % (95 % CI: 83–97 %) indicated a high diagnostic accuracy of LGE for CA. The AUC of SROC curve was 0.9530, suggesting that LGE is an effective way of diagnosing patients with possible cardiac involvement in amyloidosis. LGE–CMR seems to have a relatively high diagnostic accuracy for amyloidosis patients with possible cardiac involvement. Combined CMR techniques may provide important information for the selection of suitable therapy.

Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis

Abstract: // Changjun Wang 1, * , Bo Pan 1, * , Hanjiang Zhu 2 , Yidong Zhou 1 , Feng Mao 1 , Yan Lin 1 , Qianqian Xu 1 , Qiang Sun 1 1 Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China 2 Department of Dermatology, University of California, San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Qiang Sun, email: sunqiangpumch@sina.com Keywords: androgen receptor, breast cancer, triple negative breast cancer, prognostic value, meta-analysis Received: April 12, 2016 Accepted: June 03, 2016 Published: June 21, 2016 ABSTRACT Background: Androgen receptor (AR) is a promising therapeutic target for breast cancer. However, its prognostic value remains controversial in triple negative breast cancer (TNBC). Here we present a meta-analysis to investigate the correlation between AR expression and TNBC prognosis. Results: Thirteen relevant studies with 2826 TNBC patients were included. AR positive rate was 24.4%. AR+ patients tended to have lower tumor grade ( p < 0.001), but more lymph node metastases ( p < 0.01). AR positivity was associated with prolonged disease free survival (HR 0.809, 95% CI = 0.659-0.995, p < 0.05), but had no significant impact on overall survival (HR 1.270, 95% CI=0.904-1.782, p = 0.168). No difference in survival existed between subgroups using different AR or estrogen receptor cutoff values. Materials and methods: Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases to identify relevant articles on AR and TNBC prognosis. Fixed- and random-effect meta-analyses were conducted based on the heterogeneity of included studies. Heterogeneity and impacts of covariates were further evaluated by subgroup analyses and meta-regression. Conclusion: AR positivity is associated with lower risk of disease recurrence in TNBC. Further clinical studies are warranted to clarify its prognostic role on TNBC recurrence and survival.

MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.

Abstract: Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21.

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Abstract: Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1(flox/flox)) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers β-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-α (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism.

Non-invasive Imaging of Idiopathic Pulmonary Fibrosis Using Cathepsin Protease Probes.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal, chronic, progressive disease characterized by formation of scar tissue within the lungs. Because it is a disease of unknown etiology, it is difficult to diagnose, to predict disease course and to devise treatment strategies. Recent evidence suggests that activated macrophages play key roles in the pathology of IPF. Therefore, imaging probes that specifically recognize these pools of activated immune cells could provide valuable information about how these cells contribute to the pathobiology of the disease. Here we demonstrate that cysteine cathepsin-targeted imaging probes can be used to monitor the contribution of macrophages to fibrotic disease progression in the bleomycin-induced murine model of pulmonary fibrosis. Furthermore, we show that the probes highlight regions of macrophage involvement in fibrosis in human biopsy tissues from IPF patients. Finally, we present first-in-human results demonstrating non-invasive imaging of active cathepsins in fibrotic lesions of patients with IPF. Together, our findings validate small molecule cysteine cathepsin probes for clinical PET imaging and suggest that they have the potential to be used to generate mechanistically-informative molecular information regarding cellular drivers of IPF disease severity and progression.